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Li X, Li L, Tian J, Su R, Sun J, Li Y, Wang L, Zhou H, Sha S, Xiao J, Dong H, Huo C, Hu Y, Yang H. SREBP2-dependent lipid droplet formation enhances viral replication and deteriorates lung injury in mice following IAV infection. Emerg Microbes Infect 2025; 14:2470371. [PMID: 39968754 DOI: 10.1080/22221751.2025.2470371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 01/27/2025] [Accepted: 02/16/2025] [Indexed: 02/20/2025]
Abstract
Influenza A virus (IAV) is a significant zoonotic pathogen that poses a considerable challenge to public health due to its continuous mutations. Lipid droplets (LDs) have been shown to play an important role in the process of several viral infections. However, their role in IAV infection remains unclear. Here, we found that IAV infection altered the lipid metabolism and increased the content of LDs in the lungs of mice. In vitro, IAV infection also mediated the formation of LDs in A549 cells. Besides, inhibition of the formation of lipid droplets can significantly suppress IAV replication and the release of inflammatory factors, indicating that LDs could facilitate the virus replication and inflammatory response. Furthermore, we discovered that IAV infection could activate the SREBP2, a crucial lipid-regulating transcription factor that regulates the expressions of downstream proteins named HMGCR and HMGCS. HMGCR and HMGCS involved in the process of cholesterol synthesis, which further promoted the formation of LDs. Additionally, the use of fatostatin that specifically inhibits the maturation of SREBP2 was able to significantly suppress the viral replication of H5N1 in cells and effectively ameliorated IAV-induced lung injury in mice, which eventually promoted the survival rate of infected mice. Taken together, we demonstrate the essential roles of lipid metabolism and LD formation in IAV replication and pathogenesis, which may better facilitate the advancement of new strategies against IAV infection, especially the highly pathogenic H5N1 virus.
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Affiliation(s)
- Xinsen Li
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China
| | - Lu Li
- Infectious Disease Department, Peking University Third Hospital, Beijing, People's Republic of China
| | - Jijing Tian
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China
| | - Ruijing Su
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China
| | - Jiali Sun
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China
| | - Yuli Li
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China
| | - Lige Wang
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China
| | - Hongye Zhou
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China
| | - Shuhan Sha
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China
| | - Jin Xiao
- Key Laboratory of Veterinary Bioproduction and Chemical Medicine of the Ministry of Agriculture, Zhongmu Institutes of China Animal Husbandry Industry Co., Ltd, Beijing, People's Republic of China
| | - Hong Dong
- Beijing Key Laboratory of Traditional Chinese Veterinary Medicine, Beijing University of Agriculture, Beijing, People's Republic of China
| | - Caiyun Huo
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China
| | - Yanxin Hu
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China
| | - Hanchun Yang
- National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China
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Fujita Y, Kozawa J, Horii T, Kawata S, Ishibashi C, Y Baden M, Eguchi H, Shimomura I. Hyperplasia of Fat-Containing Cells With Mature Adipocyte Marker Is Associated With Pancreatic Fat Enlargement. Pancreas 2025; 54:e221-e226. [PMID: 39999314 DOI: 10.1097/mpa.0000000000002422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/27/2025]
Abstract
OBJECTIVES To elucidate the specific characteristics of fat-containing cells in the pancreas and the mechanism of intrapancreatic fat deposition in humans. MATERIALS AND METHODS Fifteen Japanese patients who had undergone pancreatic resection were enrolled, and the normal region from each samples was examined. Immunostaining for adiponectin and perilipin 1 was performed, and the relationships between the pancreatic fat-cell area or clinical parameters and the density or the diameter of the fat cells were analyzed. RESULTS The expression of adiponectin in the cytoplasm and perilipin 1 along the plasma membrane was observed in fat-containing cells in the pancreas. The fat-containing cell area had a significant positive correlation with cell density. In addition, fat-containing cell density was significantly positively correlated with homeostasis model assessment insulin resistance. The diameter of fat-containing cells had significant positive correlations with BMI, fasting immunoreactive insulin, and homeostasis model assessment insulin resistance. Of all fat-containing cells, 10.4% were intralobular cells, and the diameter of intralobular cells showed a tendency for positive correlation with age. CONCLUSIONS The characteristics of fat-containing cells in the pancreas indicate that some of them may be mature adipocytes, and fat volume may be increased by hyperplasia of fat-containing cells associated with insulin resistance.
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Affiliation(s)
| | | | | | | | | | | | - Hidetoshi Eguchi
- Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
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Dao W, Chen H, Ouyang Y, Huang L, Fan X, Miao Y. Molecular Characteristics and Role of Buffalo SREBF2 in Triglyceride and Cholesterol Biosynthesis in Mammary Epithelial Cells. Genes (Basel) 2025; 16:237. [PMID: 40004566 PMCID: PMC11855135 DOI: 10.3390/genes16020237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 02/15/2025] [Accepted: 02/16/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: Sterol regulatory element-binding transcription factor 2 (SREBF2) is a key transcription factor involved in regulating cholesterol homeostasis. However, its role in buffalo mammary gland lipid metabolism remains unclear. Methods: To address this, we isolated and characterized the SREBF2 gene from buffalo mammary glands and performed an in-depth analysis of its molecular characteristics, tissue-specific expression, and functional roles in buffalo mammary epithelial cells (BuMECs). Additionally, we investigated the single nucleotide polymorphisms (SNPs) of SREBF2 in both river and swamp buffalo. Results: The coding sequence (CDS) of buffalo SREBF2 is 3327 bp long and encodes a protein of 1108 amino acid residues. Bioinformatics analysis revealed that the molecular characteristics of buffalo SREBF2 were highly similar across Bovidae species, with collinearity being observed among them. An expression profile analysis revealed that SREBF2 is expressed in all 11 tested tissues of buffalo, with its expression level in the mammary gland being higher during lactation than in the dry period. The knockdown of SREBF2 in BuMECs during lactation led to a significant reduction in the expression of genes involved in triglyceride (TAG) and cholesterol synthesis, including PI3K, AKT, mTOR, SREBF1, PPARG, INSIG1, ACACA, SCD, DGAT1, LPL, CD36, HMGCR, and SQLE. This knockdown led to a 23.53% and 94.56% reduction in TAG and cholesterol levels in BuMECs, respectively. In addition, a total of 22 SNPs were identified in both buffalo types, of which four non-synonymous substitutions (c.301G>C, c.304A>T, c.1240G>A, and c.2944G>A) were found exclusively in the SREBF2 CDS of swamp buffalo, and the assessment revealed that these substitutions had no impact on SREBF2 function. Conclusions: These findings emphasize the critical role of SREBF2 in regulating both triglyceride and cholesterol biosynthesis, providing valuable insights into its functions in buffalo mammary glands.
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Affiliation(s)
- Wenbin Dao
- Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (W.D.); (L.H.); (X.F.)
| | - Hongyan Chen
- Faculty of Animal Husbandry and Veterinary Medicine, Yunnan Vocational College of Agriculture, Kunming 650212, China;
| | - Yina Ouyang
- Yunnan Institute of Animal Science and Veterinary, Kunming 650224, China;
| | - Lige Huang
- Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (W.D.); (L.H.); (X.F.)
| | - Xinyang Fan
- Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (W.D.); (L.H.); (X.F.)
| | - Yongwang Miao
- Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; (W.D.); (L.H.); (X.F.)
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Yamauchi Y, Abe-Dohmae S, Iwamoto N, Sato R, Yokoyama S. ABCA1 deficiency causes tissue-specific dysregulation of the SREBP2 pathway in mice. Biochim Biophys Acta Mol Cell Biol Lipids 2024; 1869:159546. [PMID: 39089642 DOI: 10.1016/j.bbalip.2024.159546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 07/29/2024] [Accepted: 07/29/2024] [Indexed: 08/04/2024]
Abstract
ABCA1 plays an essential role in the formation of high-density lipoprotein (HDL), and its mutations cause Tangier disease (TD), a familial HDL deficiency. In addition to the disappearance of HDL, TD patients exhibit cholesterol deposition in peripheral tissues through a mechanism poorly understood, which may contribute to the development of premature atherosclerosis. We and others previously showed that ABCA1 deficiency causes hyperactivation of the SREBP2 pathway in vitro. Here, we show using Abca1 knockout mice that ABCA1 deficiency leads to tissue-specific dysregulation of SREBP2 activity in a nutritional status-dependent manner, which may underlie the pathophysiology of TD.
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Affiliation(s)
- Yoshio Yamauchi
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan; Department of Biochemistry II, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
| | - Sumiko Abe-Dohmae
- Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan; Department of Food and Nutritional Sciences, Chubu University, Kasugai 487-8501, Japan
| | - Noriyuki Iwamoto
- Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Ryuichiro Sato
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Shinji Yokoyama
- Department of Food and Nutritional Sciences, Chubu University, Kasugai 487-8501, Japan
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Aksoy MO, Bilinska A, Stachowiak M, Flisikowska T, Szczerbal I. Deciphering the Role of the SREBF1 Gene in the Transcriptional Regulation of Porcine Adipogenesis Using CRISPR/Cas9 Editing. Int J Mol Sci 2024; 25:12677. [PMID: 39684387 DOI: 10.3390/ijms252312677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 11/23/2024] [Accepted: 11/24/2024] [Indexed: 12/18/2024] Open
Abstract
Sterol regulatory element-binding protein 1 (SREBP1) is an important transcription factor that controls lipid metabolism and adipogenesis. Two isoforms, SREBP1a and SREBP1c, are generated by alternative splicing of the first exon of the SREBF1 gene. The porcine SREBF1 gene has mainly been studied for its role in lipid metabolism in adipose tissues, but little is known about its involvement, and the role of its two isoforms, in adipogenesis. The aim of the present study was to introduce a deletion in the 5'-regulatory region of the SREBF1c gene, considered crucial for adipogenesis, using the Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 (CRISPR/Cas9) method. This approach allows for the evaluation of how inhibiting SREBF1c transcription affects the expression of other genes essential for adipocyte differentiation, particularly PPARG, CEBPA, CEBPB, CEBPD, GATA2, and FABP4. It was observed that disrupting the SREBF1c isoform had no effect on the GATA2 gene but did result in a decrease in the expression of the CEBPA and CEBPD genes, an increase in the expression of CEBPB, and an inhibition in the expression of the PPARG and FABP4 genes. These changes in gene expression blocked adipogenesis, as could be seen by the failure of lipid droplets to accumulate. Our results provide evidence highlighting the pivotal role of the SREBP1c isoform in the regulation of porcine adipogenesis.
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Affiliation(s)
- Mehmet Onur Aksoy
- Department of Genetics and Animal Breeding, Poznan University of Life Sciences, Wolynska 33, 60-637 Poznan, Poland
| | - Adrianna Bilinska
- Department of Genetics and Animal Breeding, Poznan University of Life Sciences, Wolynska 33, 60-637 Poznan, Poland
| | - Monika Stachowiak
- Department of Genetics and Animal Breeding, Poznan University of Life Sciences, Wolynska 33, 60-637 Poznan, Poland
| | - Tatiana Flisikowska
- Chair of Livestock Biotechnology, School of Life Sciences, Technical University of Munich (TUM), D-85354 Freising, Germany
| | - Izabela Szczerbal
- Department of Genetics and Animal Breeding, Poznan University of Life Sciences, Wolynska 33, 60-637 Poznan, Poland
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Guo G, Wang W, Tu M, Zhao B, Han J, Li J, Pan Y, Zhou J, Ma W, Liu Y, Sun T, Han X, An Y. Deciphering adipose development: Function, differentiation and regulation. Dev Dyn 2024; 253:956-997. [PMID: 38516819 DOI: 10.1002/dvdy.708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 03/02/2024] [Accepted: 03/10/2024] [Indexed: 03/23/2024] Open
Abstract
The overdevelopment of adipose tissues, accompanied by excess lipid accumulation and energy storage, leads to adipose deposition and obesity. With the increasing incidence of obesity in recent years, obesity is becoming a major risk factor for human health, causing various relevant diseases (including hypertension, diabetes, osteoarthritis and cancers). Therefore, it is of significance to antagonize obesity to reduce the risk of obesity-related diseases. Excess lipid accumulation in adipose tissues is mediated by adipocyte hypertrophy (expansion of pre-existing adipocytes) or hyperplasia (increase of newly-formed adipocytes). It is necessary to prevent excessive accumulation of adipose tissues by controlling adipose development. Adipogenesis is exquisitely regulated by many factors in vivo and in vitro, including hormones, cytokines, gender and dietary components. The present review has concluded a comprehensive understanding of adipose development including its origin, classification, distribution, function, differentiation and molecular mechanisms underlying adipogenesis, which may provide potential therapeutic strategies for harnessing obesity without impairing adipose tissue function.
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Affiliation(s)
- Ge Guo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Wanli Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Mengjie Tu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Binbin Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Jiayang Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Jiali Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Yanbing Pan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Jie Zhou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Wen Ma
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Yi Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Tiantian Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Xu Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
| | - Yang An
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, China
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7
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Casey AK, Stewart NM, Zaidi N, Gray HF, Cox A, Fields HA, Orth K. FicD regulates adaptation to the unfolded protein response in the murine liver. Biochimie 2024; 225:114-124. [PMID: 38740171 DOI: 10.1016/j.biochi.2024.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 05/07/2024] [Accepted: 05/10/2024] [Indexed: 05/16/2024]
Abstract
The unfolded protein response (UPR) is a cellular stress response that is activated when misfolded proteins accumulate in the endoplasmic reticulum (ER). Regulation of the UPR response must be adapted to the needs of the cell as prolonged UPR responses can result in disrupted cellular function and tissue damage. Previously, we discovered that the enzyme FicD (also known as Fic or HYPE) through its AMPylation and deAMPylation activity can modulate the UPR response via post-translational modification of BiP. FicD AMPylates BiP during homeostasis and deAMPylates BiP during stress. We hypothesized that FicD regulation of the UPR will play a role in mitigating the deleterious effects of UPR activation in tissues with frequent physiological stress. Here, we explore the role of FicD in the murine liver. As seen in our pancreatic studies, livers lacking FicD exhibit enhanced UPR signaling in response to short term physiologic fasting and feeding stress. However, in contrast to studies on the pancreas, livers, as a more regenerative tissue, remained remarkably resilient in the absence of FicD. The livers of FicD-/- did not show marked changes in UPR signaling or damage after either chronic high fat diet (HFD) feeding or acute pathological UPR induction. Intriguingly, FicD-/- mice showed changes in UPR induction and weight loss patterns following repeated pathological UPR induction. These findings indicate that FicD regulates UPR responses during mild physiological stress and in adaptation to repeated stresses, but there are tissue specific differences in the requirement for FicD regulation.
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Affiliation(s)
- Amanda K Casey
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Howard Hughes Medical Institute, Dallas, TX, 75390, USA
| | - Nathan M Stewart
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Howard Hughes Medical Institute, Dallas, TX, 75390, USA
| | - Naqi Zaidi
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Hillery F Gray
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Howard Hughes Medical Institute, Dallas, TX, 75390, USA
| | - Amelia Cox
- Washington and Lee University, Lexington, VA, 24450, USA
| | - Hazel A Fields
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Kim Orth
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Howard Hughes Medical Institute, Dallas, TX, 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
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8
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Huang P, Zhu Y, Qin J. Research advances in understanding crosstalk between organs and pancreatic β-cell dysfunction. Diabetes Obes Metab 2024; 26:4147-4164. [PMID: 39044309 DOI: 10.1111/dom.15787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/25/2024]
Abstract
Obesity has increased dramatically worldwide. Being overweight or obese can lead to various conditions, including dyslipidaemia, hypertension, glucose intolerance and metabolic syndrome (MetS), which may further lead to type 2 diabetes mellitus (T2DM). Previous studies have identified a link between β-cell dysfunction and the severity of MetS, with multiple organs and tissues affected. Identifying the associations between pancreatic β-cell dysfunction and organs is critical. Research has focused on the interaction between the liver, gut and pancreatic β-cells. However, the mechanisms and related core targets are still not perfectly elucidated. The aims of this review were to summarize the mechanisms of β-cell dysfunction and to explore the potential pathogenic pathways and targets that connect the liver, gut, adipose tissue, muscle, and brain to pancreatic β-cell dysfunction.
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Affiliation(s)
- Peng Huang
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Yunling Zhu
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Jian Qin
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
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9
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Velez‐delValle C, Hernandez‐Mosqueira CP, Castro‐Rodriguez LI, Vazquez‐Sandoval A, Marsch‐Moreno M, Kuri‐Harcuch W. Gene expression and characterization of clonally derived murine embryonic brown and brite adipocytes. FEBS Open Bio 2024; 14:1503-1525. [PMID: 38972757 PMCID: PMC11492321 DOI: 10.1002/2211-5463.13861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 05/29/2024] [Accepted: 06/25/2024] [Indexed: 07/09/2024] Open
Abstract
White adipocytes store energy, while brown and brite adipocytes release heat via nonshivering thermogenesis. In this study, we characterized two murine embryonic clonal preadipocyte lines, EB5 and EB7, each displaying unique gene marker expression profiles. EB5 cells differentiate into brown adipocytes, whereas EB7 cells into brite (also known as beige) adipocytes. To draw a comprehensive comparison, we contrasted the gene expression patterns, adipogenic capacity, as well as carbohydrate and lipid metabolism of these cells to that of F442A, a well-known white preadipocyte and adipocyte model. We found that commitment to differentiation in both EB5 and EB7 cells can be induced by 3-Isobutyl-1-methylxanthine/dexamethasone (Mix/Dex) and staurosporine/dexamethasone (St/Dex) treatments. Additionally, the administration of rosiglitazone significantly enhances the brown and brite adipocyte phenotypes. Our data also reveal the involvement of a series of genes in the transcriptional cascade guiding adipogenesis, pinpointing GSK3β as a critical regulator for both EB5 and EB7 adipogenesis. In a developmental context, we observe that, akin to brown fat progenitors, brite fat progenitors make their appearance in murine development by 11-12 days of gestation or potentially earlier. This result contributes to our understanding of adipocyte lineage specification during embryonic development. In conclusion, EB5 and EB7 cell lines are valuable for research into adipocyte biology, providing insights into the differentiation and development of brown and beige adipocytes. Furthermore, they could be useful for the characterization of drugs targeting energy balance for the treatment of obesity and metabolic diseases.
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Affiliation(s)
- Cristina Velez‐delValle
- Department of Cell BiologyCenter for Research and Advanced Studies (Cinvestav)Mexico CityMexico
| | | | | | | | - Meytha Marsch‐Moreno
- Department of Cell BiologyCenter for Research and Advanced Studies (Cinvestav)Mexico CityMexico
| | - Walid Kuri‐Harcuch
- Department of Cell BiologyCenter for Research and Advanced Studies (Cinvestav)Mexico CityMexico
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10
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He Y, Qi S, Chen L, Zhu J, Liang L, Chen X, Zhang H, Zhuo L, Zhao S, Liu S, Xie T. The roles and mechanisms of SREBP1 in cancer development and drug response. Genes Dis 2024; 11:100987. [PMID: 38560498 PMCID: PMC10978545 DOI: 10.1016/j.gendis.2023.04.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/24/2023] [Accepted: 04/24/2023] [Indexed: 04/04/2024] Open
Abstract
Cancer occurrence and development are closely related to increased lipid production and glucose consumption. Lipids are the basic component of the cell membrane and play a significant role in cancer cell processes such as cell-to-cell recognition, signal transduction, and energy supply, which are vital for cancer cell rapid proliferation, invasion, and metastasis. Sterol regulatory element-binding transcription factor 1 (SREBP1) is a key transcription factor regulating the expression of genes related to cholesterol biosynthesis, lipid homeostasis, and fatty acid synthesis. In addition, SREBP1 and its upstream or downstream target genes are implicated in various metabolic diseases, particularly cancer. However, no review of SREBP1 in cancer biology has yet been published. Herein, we summarized the roles and mechanisms of SREBP1 biological processes in cancer cells, including SREBP1 modification, lipid metabolism and reprogramming, glucose and mitochondrial metabolism, immunity, and tumor microenvironment, epithelial-mesenchymal transition, cell cycle, apoptosis, and ferroptosis. Additionally, we discussed the potential role of SREBP1 in cancer prognosis, drug response such as drug sensitivity to chemotherapy and radiotherapy, and the potential drugs targeting SREBP1 and its corresponding pathway, elucidating the potential clinical application based on SREBP1 and its corresponding signal pathway.
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Affiliation(s)
- Ying He
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Shasha Qi
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Lu Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Jinyu Zhu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Linda Liang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Xudong Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Hao Zhang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Lvjia Zhuo
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Shujuan Zhao
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Shuiping Liu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore 169610, Singapore
| | - Tian Xie
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
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11
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Casey AK, Stewart NM, Zaidi N, Gray HF, Cox A, Fields HA, Orth K. FicD regulates adaptation to the unfolded protein response in the murine liver. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.15.589620. [PMID: 38659954 PMCID: PMC11042336 DOI: 10.1101/2024.04.15.589620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
The unfolded protein response (UPR) is a cellular stress response that is activated when misfolded proteins accumulate in the endoplasmic reticulum (ER). The UPR elicits a signaling cascade that results in an upregulation of protein folding machinery and cell survival signals. However, prolonged UPR responses can result in elevated cellular inflammation, damage, and even cell death. Thus, regulation of the UPR response must be tuned to the needs of the cell, sensitive enough to respond to the stress but pliable enough to be stopped after the crisis has passed. Previously, we discovered that the bi-functional enzyme FicD can modulate the UPR response via post-translational modification of BiP. FicD AMPylates BiP during homeostasis and deAMPylates BiP during stress. We found this activity is important for the physiological regulation of the exocrine pancreas. Here, we explore the role of FicD in the murine liver. Like our previous studies, livers lacking FicD exhibit enhanced UPR signaling in response to short term physiologic fasting and feeding stress. However, the livers of FicD -/- did not show marked changes in UPR signaling or damage after either chronic high fat diet (HFD) feeding or acute pathological UPR induction. Intriguingly, FicD -/- mice showed changes in UPR induction and weight loss patterns following repeated pathological UPR induction. These findings show that FicD regulates UPR responses during mild physiological stress and may play a role in maintaining resiliency of tissue through adaptation to repeated ER stress.
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12
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Chen J, Zhou Y, Liu Z, Lu Y, Jiang Y, Cao K, Zhou N, Wang D, Zhang C, Zhou N, Shi K, Zhang L, Zhou L, Wang Z, Zhang H, Tang K, Ma J, Lv J, Huang B. Hepatic glycogenesis antagonizes lipogenesis by blocking S1P via UDPG. Science 2024; 383:eadi3332. [PMID: 38359126 DOI: 10.1126/science.adi3332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 12/20/2023] [Indexed: 02/17/2024]
Abstract
The identification of mechanisms to store glucose carbon in the form of glycogen rather than fat in hepatocytes has important implications for the prevention of nonalcoholic fatty liver disease (NAFLD) and other chronic metabolic diseases. In this work, we show that glycogenesis uses its intermediate metabolite uridine diphosphate glucose (UDPG) to antagonize lipogenesis, thus steering both mouse and human hepatocytes toward storing glucose carbon as glycogen. The underlying mechanism involves transport of UDPG to the Golgi apparatus, where it binds to site-1 protease (S1P) and inhibits S1P-mediated cleavage of sterol regulatory element-binding proteins (SREBPs), thereby inhibiting lipogenesis in hepatocytes. Consistent with this mechanism, UDPG administration is effective at treating NAFLD in a mouse model and human organoids. These findings indicate a potential opportunity to ameliorate disordered fat metabolism in the liver.
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Affiliation(s)
- Jie Chen
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Yabo Zhou
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Zhuohang Liu
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Yan Lu
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Yishen Jiang
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Kexin Cao
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Nannan Zhou
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Dianheng Wang
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Chaoqi Zhang
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
- Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ning Zhou
- Department of Pathology, Sichuan Mianyang 404 Hospital, Sichuan 621000, China
| | - Keqing Shi
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
| | - Lu Zhang
- Tianjin Centers for Disease Control and Prevention, Tianjin 300011, China
| | - Li Zhou
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Zhenfeng Wang
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Huafeng Zhang
- Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ke Tang
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jingwei Ma
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jiadi Lv
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Bo Huang
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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13
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Danielewski M, Rapak A, Kruszyńska A, Małodobra-Mazur M, Oleszkiewicz P, Dzimira S, Kucharska AZ, Słupski W, Matuszewska A, Nowak B, Szeląg A, Piórecki N, Zaleska-Dorobisz U, Sozański T. Cornelian Cherry ( Cornus mas L.) Fruit Extract Lowers SREBP-1c and C/EBPα in Liver and Alters Various PPAR-α, PPAR-γ, LXR-α Target Genes in Cholesterol-Rich Diet Rabbit Model. Int J Mol Sci 2024; 25:1199. [PMID: 38256272 PMCID: PMC10816641 DOI: 10.3390/ijms25021199] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 01/13/2024] [Accepted: 01/16/2024] [Indexed: 01/24/2024] Open
Abstract
Cornelian cherry (Cornus mas L.) fruits, abundant in iridoids and anthocyanins, are natural products with proven beneficial impacts on the functions of the cardiovascular system and the liver. This study aims to assess and compare whether and to what extent two different doses of resin-purified cornelian cherry extract (10 mg/kg b.w. or 50 mg/kg b.w.) applied in a cholesterol-rich diet rabbit model affect the levels of sterol regulatory element-binding protein 1c (SREBP-1c) and CCAAT/enhancer binding protein α (C/EBPα), and various liver X receptor-α (LXR-α), peroxisome proliferator-activated receptor-α (PPAR-α), and peroxisome proliferator-activated receptor-γ (PPAR-γ) target genes. Moreover, the aim is to evaluate the resistive index (RI) of common carotid arteries (CCAs) and aortas, and histopathological changes in CCAs. For this purpose, the levels of SREBP-1c, C/EBPα, ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), fatty acid synthase (FAS), endothelial lipase (LIPG), carnitine palmitoyltransferase 1A (CPT1A), and adiponectin receptor 2 (AdipoR2) in liver tissue were measured. Also, the levels of lipoprotein lipase (LPL), visceral adipose tissue-derived serine protease inhibitor (Vaspin), and retinol-binding protein 4 (RBP4) in visceral adipose tissue were measured. The RI of CCAs and aortas, and histopathological changes in CCAs, were indicated. The oral administration of the cornelian cherry extract decreased the SREBP-1c and C/EBPα in both doses. The dose of 10 mg/kg b.w. increased ABCA1 and decreased FAS, CPT1A, and RBP4, and the dose of 50 mg/kg b.w. enhanced ABCG1 and AdipoR2. Mitigations in atheromatous changes in rabbits' CCAs were also observed. The obtained outcomes were compared to the results of our previous works. The beneficial results confirm that cornelian cherry fruit extract may constitute a potentially effective product in the prevention and treatment of obesity-related disorders.
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Affiliation(s)
- Maciej Danielewski
- Department of Pharmacology, Wroclaw Medical University, J. Mikulicza-Radeckiego 2, 50-345 Wroclaw, Poland; (W.S.); (A.M.); (B.N.); (A.S.)
| | - Andrzej Rapak
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigla 12, 53-114 Wroclaw, Poland; (A.R.); (A.K.)
| | - Angelika Kruszyńska
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigla 12, 53-114 Wroclaw, Poland; (A.R.); (A.K.)
| | - Małgorzata Małodobra-Mazur
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland;
| | - Paweł Oleszkiewicz
- Department of Radiology and Imaging Diagnostics II, Lower Silesian Center of Oncology, Pulmonology and Hematology, Grabiszynska 105, 53-439 Wroclaw, Poland;
| | - Stanisław Dzimira
- Department of Pathology, Wroclaw University of Environmental and Life Sciences, C. K. Norwida 31, 50-375 Wroclaw, Poland;
| | - Alicja Z. Kucharska
- Department of Fruit, Vegetable, and Plant Nutraceutical Technology, Wroclaw University of Environmental and Life Sciences, J. Chelmonskiego 37, 51-630 Wroclaw, Poland;
| | - Wojciech Słupski
- Department of Pharmacology, Wroclaw Medical University, J. Mikulicza-Radeckiego 2, 50-345 Wroclaw, Poland; (W.S.); (A.M.); (B.N.); (A.S.)
| | - Agnieszka Matuszewska
- Department of Pharmacology, Wroclaw Medical University, J. Mikulicza-Radeckiego 2, 50-345 Wroclaw, Poland; (W.S.); (A.M.); (B.N.); (A.S.)
| | - Beata Nowak
- Department of Pharmacology, Wroclaw Medical University, J. Mikulicza-Radeckiego 2, 50-345 Wroclaw, Poland; (W.S.); (A.M.); (B.N.); (A.S.)
| | - Adam Szeląg
- Department of Pharmacology, Wroclaw Medical University, J. Mikulicza-Radeckiego 2, 50-345 Wroclaw, Poland; (W.S.); (A.M.); (B.N.); (A.S.)
| | - Narcyz Piórecki
- Bolestraszyce Arboretum and Institute of Physiography, Bolestraszyce 130, 37-722 Wyszatyce, Poland;
- Institute of Physical Culture Sciences, Medical College, University of Rzeszow, Cicha 2A, 35-326 Rzeszow, Poland
| | - Urszula Zaleska-Dorobisz
- Department of General and Pediatric Radiology, Wroclaw Medical University, M. Sklodowskiej-Curie 50/52, 50-369 Wroclaw, Poland;
| | - Tomasz Sozański
- Department of Preclinical Sciences, Pharmacology and Medical Diagnostics, Faculty of Medicine, Wroclaw University of Science and Technology, Wybrzeze Wyspianskiego 27, 50-370 Wroclaw, Poland;
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14
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Chandrasekaran P, Weiskirchen R. The Role of SCAP/SREBP as Central Regulators of Lipid Metabolism in Hepatic Steatosis. Int J Mol Sci 2024; 25:1109. [PMID: 38256181 PMCID: PMC10815951 DOI: 10.3390/ijms25021109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 01/09/2024] [Accepted: 01/14/2024] [Indexed: 01/24/2024] Open
Abstract
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly increasing worldwide at an alarming pace, due to an increase in obesity, sedentary and unhealthy lifestyles, and unbalanced dietary habits. MASLD is a unique, multi-factorial condition with several phases of progression including steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Sterol element binding protein 1c (SREBP1c) is the main transcription factor involved in regulating hepatic de novo lipogenesis. This transcription factor is synthesized as an inactive precursor, and its proteolytic maturation is initiated in the membrane of the endoplasmic reticulum upon stimulation by insulin. SREBP cleavage activating protein (SCAP) is required as a chaperon protein to escort SREBP from the endoplasmic reticulum and to facilitate the proteolytic release of the N-terminal domain of SREBP into the Golgi. SCAP inhibition prevents activation of SREBP and inhibits the expression of genes involved in triglyceride and fatty acid synthesis, resulting in the inhibition of de novo lipogenesis. In line, previous studies have shown that SCAP inhibition can resolve hepatic steatosis in animal models and intensive research is going on to understand the effects of SCAP in the pathogenesis of human disease. This review focuses on the versatile roles of SCAP/SREBP regulation in de novo lipogenesis and the structure and molecular features of SCAP/SREBP in the progression of hepatic steatosis. In addition, recent studies that attempt to target the SCAP/SREBP axis as a therapeutic option to interfere with MASLD are discussed.
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Affiliation(s)
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), Rheinisch-Westfälische Technische Hochschule (RWTH) University Hospital Aachen, D-52074 Aachen, Germany
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15
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Liimatta J, Curschellas E, Altinkilic EM, Naamneh Elzenaty R, Augsburger P, du Toit T, Voegel CD, Breault DT, Flück CE, Pignatti E. Adrenal Abcg1 Controls Cholesterol Flux and Steroidogenesis. Endocrinology 2024; 165:bqae014. [PMID: 38301271 PMCID: PMC10863561 DOI: 10.1210/endocr/bqae014] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/14/2024] [Accepted: 01/30/2024] [Indexed: 02/03/2024]
Abstract
Cholesterol is the precursor of all steroids, but how cholesterol flux is controlled in steroidogenic tissues is poorly understood. The cholesterol exporter ABCG1 is an essential component of the reverse cholesterol pathway and its global inactivation results in neutral lipid redistribution to tissue macrophages. The function of ABCG1 in steroidogenic tissues, however, has not been explored. To model this, we inactivated Abcg1 in the mouse adrenal cortex, which led to an adrenal-specific increase in transcripts involved in cholesterol uptake and de novo synthesis. Abcg1 inactivation did not affect adrenal cholesterol content, zonation, or serum lipid profile. Instead, we observed a moderate increase in corticosterone production that was not recapitulated by the inactivation of the functionally similar cholesterol exporter Abca1. Altogether, our data imply that Abcg1 controls cholesterol uptake and biosynthesis and regulates glucocorticoid production in the adrenal cortex, introducing the possibility that ABCG1 variants may account for physiological or subclinical variation in stress response.
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Affiliation(s)
- Jani Liimatta
- Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, Bern 3010, Switzerland
- Department for BioMedical Research, University Hospital Inselspital, University of Bern, Bern 3010, Switzerland
- Kuopio Pediatric Research Unit (KuPRU), University of Eastern Finland and Kuopio University Hospital, Kuopio 70200, Finland
| | - Evelyn Curschellas
- Department of Chemistry, Biochemistry and Pharmacy, Medical Faculty, University of Bern, Bern 3010, Switzerland
| | - Emre Murat Altinkilic
- Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, Bern 3010, Switzerland
- Department for BioMedical Research, University Hospital Inselspital, University of Bern, Bern 3010, Switzerland
| | - Rawda Naamneh Elzenaty
- Department for BioMedical Research, University Hospital Inselspital, University of Bern, Bern 3010, Switzerland
| | - Philipp Augsburger
- Department for BioMedical Research, University Hospital Inselspital, University of Bern, Bern 3010, Switzerland
| | - Therina du Toit
- Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, Bern 3010, Switzerland
- Department for BioMedical Research, University Hospital Inselspital, University of Bern, Bern 3010, Switzerland
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland
| | - Clarissa D Voegel
- Department for BioMedical Research, University Hospital Inselspital, University of Bern, Bern 3010, Switzerland
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland
| | - David T Breault
- Department of Pediatrics, Harvard Medical School, Boston Children's Hospital, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Christa E Flück
- Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, Bern 3010, Switzerland
- Department for BioMedical Research, University Hospital Inselspital, University of Bern, Bern 3010, Switzerland
| | - Emanuele Pignatti
- Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, Bern 3010, Switzerland
- Department for BioMedical Research, University Hospital Inselspital, University of Bern, Bern 3010, Switzerland
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16
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Shen S, Shen M, Kuang L, Yang K, Wu S, Liu X, Wang Y, Wang Y. SIRT1/SREBPs-mediated regulation of lipid metabolism. Pharmacol Res 2024; 199:107037. [PMID: 38070792 DOI: 10.1016/j.phrs.2023.107037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 12/05/2023] [Accepted: 12/05/2023] [Indexed: 01/13/2024]
Abstract
Sirtuins, also called silent information regulator 2, are enzymes that rely on nicotinamide adenine dinucleotide (NAD+) to function as histone deacetylases. Further investigation is warranted to explore the advantageous impacts of Sirtuin 1 (SIRT1), a constituent of the sirtuin group, on lipid metabolism, in addition to its well-researched involvement in extending lifespan. The regulation of gene expression has been extensively linked to SIRT1. Sterol regulatory element-binding protein (SREBP) is a substrate of SIRT1 that has attracted significant interest due to its role in multiple cellular processes including cell cycle regulation, DNA damage repair, and metabolic functions. Hence, the objective of this analysis was to investigate and elucidate the correlation between SIRT1 and SREBPs, as well as assess the contribution of SIRT1/SREBPs in mitigating lipid metabolism dysfunction. The objective of this research was to investigate whether SIRT1 and SREBPs could be utilized as viable targets for therapeutic intervention in managing complications associated with diabetes.
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Affiliation(s)
- Shan Shen
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Mingyang Shen
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Lirun Kuang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Keyu Yang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Shiran Wu
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Xinde Liu
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Yuting Wang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Yong Wang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
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17
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Liu K, Zheng J, Wang Y, Li Y, Xiong Y, Wang Y, Cheng J, Huang X, Zhang L, Lin Y. Effect of TEA domain transcription factor 1 ( TEAD1) on the differentiation of intramuscular preadipocytes in goats. Anim Biotechnol 2023; 34:3589-3598. [PMID: 36866843 DOI: 10.1080/10495398.2023.2178932] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2023]
Abstract
TEA domain transcription factor 1 (TEAD1), also called TEF-1, acts as a transcriptional enhancer to regulate muscle-specific gene expression. However, the role of TEAD1 in regulating intramuscular preadipocyte differentiation in goats is unclear. The aim of this study was to obtain the sequence of TEAD1 gene and elucidate the effect of TEAD1 on goat intramuscular preadipocyte differentiation in vitro and its possible mechanism. The results showed that the goat TEAD1 gene CDS region sequence was 1311 bp. TEAD1 gene was widely expressed in goat tissues, with the highest expression in brachial triceps (p < 0.01). The expression of TEAD1 gene in goat intramuscular adipocytes at 72 h was extremely significantly higher than that at 0 h (p < 0.01). Overexpression of goat TEAD1 inhibited the accumulation of lipid droplets in goat intramuscular adipocyte. The relative expression of differentiation marker genes SREBP1, PPARγ, C/EBPβ were significantly down-regulated (all p < 0.01), but PREF-1 was significantly up-regulated (p < 0.01). Binding analysis showed that there were multiple binding sites between the DNA binding domain of goat TEAD1 and the promoter binding region of SREBP1, PPARγ, C/EBPβ and PREF-1. In conclusion, TEAD1 negatively regulates the differentiation of goat intramuscular preadipocytes.
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Affiliation(s)
- Kehan Liu
- Animal Husbandry and Veterinary Medicine, Southwest Minzu University, Chengdu, China
- Ministry of Education/Sichuan Province, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Chengdu, China
| | - Jianying Zheng
- Animal Husbandry and Veterinary Medicine, Southwest Minzu University, Chengdu, China
- Ministry of Education/Sichuan Province, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Chengdu, China
| | - Yong Wang
- Animal Husbandry and Veterinary Medicine, Southwest Minzu University, Chengdu, China
- Ministry of Education/Sichuan Province, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Chengdu, China
| | - Yanyan Li
- Animal Husbandry and Veterinary Medicine, Southwest Minzu University, Chengdu, China
- Ministry of Education/Sichuan Province, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Chengdu, China
| | - Yan Xiong
- Animal Husbandry and Veterinary Medicine, Southwest Minzu University, Chengdu, China
- Ministry of Education/Sichuan Province, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Chengdu, China
| | - Youli Wang
- Animal Husbandry and Veterinary Medicine, Southwest Minzu University, Chengdu, China
- Ministry of Education/Sichuan Province, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Chengdu, China
| | - Jie Cheng
- Animal Husbandry and Veterinary Medicine, Southwest Minzu University, Chengdu, China
| | - Xinzhu Huang
- Animal Husbandry and Veterinary Medicine, Southwest Minzu University, Chengdu, China
| | - Liyi Zhang
- Animal Husbandry and Veterinary Medicine, Southwest Minzu University, Chengdu, China
| | - Yaqiu Lin
- Animal Husbandry and Veterinary Medicine, Southwest Minzu University, Chengdu, China
- Ministry of Education/Sichuan Province, Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Chengdu, China
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18
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Han SI, Nakakuki M, Nakagawa Y, Wang Y, Araki M, Yamamoto Y, Tokiwa H, Takeda H, Mizunoe Y, Motomura K, Ohno H, Kainoh K, Murayama Y, Aita Y, Takeuchi Y, Osaki Y, Miyamoto T, Sekiya M, Matsuzaka T, Yahagi N, Sone H, Daitoku H, Sato R, Kawano H, Shimano H. Rhomboid protease RHBDL4/RHBDD1 cleaves SREBP-1c at endoplasmic reticulum monitoring and regulating fatty acids. PNAS NEXUS 2023; 2:pgad351. [PMID: 37954160 PMCID: PMC10637267 DOI: 10.1093/pnasnexus/pgad351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 10/02/2023] [Indexed: 11/14/2023]
Abstract
The endoplasmic reticulum (ER)-embedded transcription factors, sterol regulatory element-binding proteins (SREBPs), master regulators of lipid biosynthesis, are transported to the Golgi for proteolytic activation to tune cellular cholesterol levels and regulate lipogenesis. However, mechanisms by which the cell responds to the levels of saturated or unsaturated fatty acids remain underexplored. Here, we show that RHBDL4/RHBDD1, a rhomboid family protease, directly cleaves SREBP-1c at the ER. The p97/VCP, AAA-ATPase complex then acts as an auxiliary segregase to extract the remaining ER-embedded fragment of SREBP-1c. Importantly, the enzymatic activity of RHBDL4 is enhanced by saturated fatty acids (SFAs) but inhibited by polyunsaturated fatty acids (PUFAs). Genetic deletion of RHBDL4 in mice fed on a Western diet enriched in SFAs and cholesterol prevented SREBP-1c from inducing genes for lipogenesis, particularly for synthesis and incorporation of PUFAs, and secretion of lipoproteins. The RHBDL4-SREBP-1c pathway reveals a regulatory system for monitoring fatty acid composition and maintaining cellular lipid homeostasis.
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Affiliation(s)
- Song-Iee Han
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Masanori Nakakuki
- Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., Gotemba, Shizuoka 412-8524, Japan
| | - Yoshimi Nakagawa
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
- Division of Complex Biosystem Research, Department of Research and Development, Institute of Natural Medicine, University of Toyama, Toyama, Toyama 930-0194, Japan
| | - Yunong Wang
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Masaya Araki
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yuta Yamamoto
- Department of Chemistry, Rikkyo University, Toshima-ku, Tokyo 171-8501, Japan
| | - Hiroaki Tokiwa
- Laboratory of Organic Chemistry, Gifu Pharmaceutical University, Daigaku-Nishi, Gifu 501-1196, Japan
| | - Hiroyuki Takeda
- Division of Proteo Drug Discovery Sciences, Proteo-Science Center, Ehime University, Matsuyama, Ehime 790-8577, Japan
| | - Yuhei Mizunoe
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Kaori Motomura
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Hiroshi Ohno
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Kenta Kainoh
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yuki Murayama
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yuichi Aita
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yoshinori Takeuchi
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yoshinori Osaki
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Takafumi Miyamoto
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
- Transborder Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
| | - Motohiro Sekiya
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Takashi Matsuzaka
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
- Transborder Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
| | - Naoya Yahagi
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Hirohito Sone
- Department of Internal Medicine, Faculty of Medicine, Niigata University, Niigata, Niigata 951-8510, Japan
| | - Hiroaki Daitoku
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
| | - Ryuichiro Sato
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, Nutri-Life Science Laboratory, The University of Tokyo, Tokyo 113-8657, Japan
| | - Hiroyuki Kawano
- Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., Gotemba, Shizuoka 412-8524, Japan
| | - Hitoshi Shimano
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
- Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Chiyoda-ku, Tokyo 100-0004, Japan
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Itkonen A, Hakkola J, Rysä J. Adverse outcome pathway for pregnane X receptor-induced hypercholesterolemia. Arch Toxicol 2023; 97:2861-2877. [PMID: 37642746 PMCID: PMC10504106 DOI: 10.1007/s00204-023-03575-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 08/02/2023] [Indexed: 08/31/2023]
Abstract
Pharmaceuticals and environmental contaminants contribute to hypercholesterolemia. Several chemicals known to cause hypercholesterolemia, activate pregnane X receptor (PXR). PXR is a nuclear receptor, classically identified as a sensor of chemical environment and regulator of detoxification processes. Later, PXR activation has been shown to disrupt metabolic functions such as lipid metabolism and recent findings have shown PXR activation to promote hypercholesterolemia through multiple mechanisms. Hypercholesterolemia is a major causative risk factor for atherosclerosis and greatly promotes global health burden. Metabolic disruption by PXR activating chemicals leading to hypercholesterolemia represents a novel toxicity pathway of concern and requires further attention. Therefore, we constructed an adverse outcome pathway (AOP) by collecting the available knowledge considering the molecular mechanisms for PXR-mediated hypercholesterolemia. AOPs are tools of modern toxicology for systematizing mechanistic knowledge to assist health risk assessment of chemicals. AOPs are formalized and structured linear concepts describing a link between molecular initiating event (MIE) and adverse outcome (AO). MIE and AO are connected via key events (KE) through key event relationships (KER). We present a plausible route of how PXR activation (MIE) leads to hypercholesterolemia (AO) through direct regulation of cholesterol synthesis and via activation of sterol regulatory element binding protein 2-pathway.
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Affiliation(s)
- Anna Itkonen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
| | - Jukka Hakkola
- Research Unit of Biomedicine and Internal Medicine, Biocenter Oulu, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Jaana Rysä
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.
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20
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Hendrix S, Zelcer N. A new SPRING in lipid metabolism. Curr Opin Lipidol 2023; 34:201-207. [PMID: 37548386 DOI: 10.1097/mol.0000000000000894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/08/2023]
Abstract
PURPOSE OF REVIEW The SREBP transcription factors are master regulators of lipid homeostasis owing to their role in controlling cholesterol and fatty acid metabolism. The core machinery required to promote their trafficking and proteolytic activation has been established close to 20 years ago. In this review, we summarize the current understanding of a newly identified regulator of SREBP signaling, SPRING (formerly C12ORF49), its proposed mechanism of action, and its role in lipid metabolism. RECENT FINDINGS Using whole-genome functional genetic screens we, and others, have recently identified SPRING as a novel regulator of SREBP signaling. SPRING is a Golgi-resident single-pass transmembrane protein that is required for proteolytic activation of SREBPs in this compartment. Mechanistic studies identified regulation of S1P, the protease that cleaves SREBPs, and control of retrograde trafficking of the SREBP chaperone SCAP from the Golgi to the ER as processes requiring SPRING. Emerging studies suggest an important role for SPRING in regulating circulating and hepatic lipid levels in mice and potentially in humans. SUMMARY Current studies support the notion that SPRING is a novel component of the core SREBP-activating machinery. Additional studies are warranted to elucidate its role in cellular and systemic lipid metabolism.
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Affiliation(s)
- Sebastian Hendrix
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 15, Amsterdam, the Netherlands
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Otani Y, Nozaki Y, Mizunoe Y, Kobayashi M, Higami Y. Effect of mitochondrial quantity and quality controls in white adipose tissue on healthy lifespan: Essential roles of GH/IGF-1-independent pathways in caloric restriction-mediated metabolic remodeling. Pathol Int 2023; 73:479-489. [PMID: 37606202 PMCID: PMC11551837 DOI: 10.1111/pin.13371] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 08/03/2023] [Indexed: 08/23/2023]
Abstract
Long-term caloric restriction is a conventional and reproducible dietary intervention to improve whole body metabolism, suppress age-related pathophysiology, and extend lifespan. The beneficial actions of caloric restriction are widely accepted to be regulated in both growth hormone/insulin-like growth factor 1-dependent and -independent manners. Although growth hormone/insulin-like growth factor 1-dependent regulatory mechanisms are well described, those occurring independent of growth hormone/insulin-like growth factor 1 are poorly understood. In this review, we focus on molecular mechanisms of caloric restriction regulated in a growth hormone/insulin-like growth factor 1-independent manner. Caloric restriction increases mitochondrial quantity and improves mitochondrial quality by activating an axis involving sterol regulatory element binding protein-c/peroxisome proliferator-activated receptor γ coactivator-1α/mitochondrial intermediate peptidase in a growth hormone/insulin-like growth factor 1-independent manner, particularly in white adipose tissue. Fibroblast growth factor 21 is also involved in this axis. Moreover, the axis may be regulated by lower leptin signaling. Thus, caloric restriction appears to induce beneficial actions partially by regulating mitochondrial quantity and quality in white adipose tissue in a growth hormone/insulin-like growth factor 1-independent manner.
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Grants
- Fostering Joint International Research (B) / 20KK0 Ministry of Education, Culture, Sports, Science and Technology
- Grant-in-Aid for Scientific Research (B) / 17H0217 Ministry of Education, Culture, Sports, Science and Technology
- Grant-in-Aid for Scientific Research (B) / 20H0413 Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science Ministry of Education, Culture, Sports, Science and Technology
- Ministry of Education, Culture, Sports, Science and Technology
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Affiliation(s)
- Yuina Otani
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical SciencesTokyo University of ScienceChibaJapan
| | - Yuka Nozaki
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical SciencesTokyo University of ScienceChibaJapan
| | - Yuhei Mizunoe
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical SciencesTokyo University of ScienceChibaJapan
| | - Masaki Kobayashi
- Department of Nutrition and Food Science, Graduate School of Humanities and SciencesOchanomizu UniversityTokyoJapan
- Institute for Human Life InnovationOchanomizu UniversityTokyoJapan
| | - Yoshikazu Higami
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical SciencesTokyo University of ScienceChibaJapan
- Research Institute for Biomedical Sciences (RIBS)Tokyo University of ScienceChibaJapan
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22
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Fan Z, Sun X, Chen X, Liu H, Miao X, Guo Y, Xu Y, Li J, Zou X, Li Z. C-C motif chemokine CCL11 is a novel regulator and a potential therapeutic target in non-alcoholic fatty liver disease. JHEP Rep 2023; 5:100805. [PMID: 37555008 PMCID: PMC10404559 DOI: 10.1016/j.jhepr.2023.100805] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/10/2023] Open
Abstract
BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is characterised by accelerated lipid deposition, aberrant inflammation, and excessive extracellular matrix production in the liver. Short of effective intervention, NAFLD can progress to cirrhosis and hepatocellular carcinoma. In the present study we investigated the involvement of the C-C motif ligand 11 (CCL11) in NAFLD pathogenesis. METHODS NAFLD was induced by feeding mice with a high-fat high-carbohydrate diet. CCL11 targeting was achieved by genetic deletion or pharmaceutical inhibition. The transcriptome was analysed using RNA-seq. RESULTS We report that CCL11 expression was activated at the transcription level by free fatty acids (palmitate) in hepatocytes. CCL11 knockdown attenuated whereas CCL11 treatment directly promoted production of pro-inflammatory/pro-lipogenic mediators in hepatocytes. Compared with wild-type littermates, CCL11 knockout mice displayed an ameliorated phenotype of NAFLD when fed a high-fat high-carbohydrate diet as evidenced by decelerated body weight gain, improved insulin sensitivity, dampened lipid accumulation, reduced immune cell infiltration, and weakened liver fibrosis. RNA-seq revealed that interferon regulatory factor 1 as a mediator of CCL11 induced changes in hepatocytes. Importantly, CCL11 neutralisation or antagonism mitigated NAFLD pathogenesis in mice. Finally, a positive correlation between CCL11 expression and NAFLD parameters was identified in human patients. CONCLUSIONS Our data suggest that CCL11 is a novel regulator of NAFLD and can be effectively targeted for NAFLD intervention. IMPACT AND IMPLICATIONS Non-alcoholic fatty liver disease (NAFLD) precedes cirrhosis and hepatocellular carcinoma. In this paper we describe the regulatory role of CCL11, a C-C motif ligand chemokine, in NAFLD pathogenesis. Our data provide novel insights and translational potential for NAFLD intervention.
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Affiliation(s)
- Zhiwen Fan
- Department of Pathology, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, China
| | - Xinyue Sun
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Xuelian Chen
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Huimin Liu
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Xiulian Miao
- College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China
| | - Yan Guo
- College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China
| | - Yong Xu
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
- College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Affiliated with Nanjing University Medical School, Nanjing, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China
| | - Xiaoping Zou
- Department of Gastroenterology, Taikang Xianlin Drum Tower Hospital Affiliated with Nanjing University Medical School, Nanjing, China
- Department of Gastroenterology, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, China
| | - Zilong Li
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
- College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China
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23
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Li T, Jin Y, Wu J, Ren Z. Beyond energy provider: multifunction of lipid droplets in embryonic development. Biol Res 2023; 56:38. [PMID: 37438836 DOI: 10.1186/s40659-023-00449-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 06/23/2023] [Indexed: 07/14/2023] Open
Abstract
Since the discovery, lipid droplets (LDs) have been recognized to be sites of cellular energy reserves, providing energy when necessary to sustain cellular life activities. Many studies have reported large numbers of LDs in eggs and early embryos from insects to mammals. The questions of how LDs are formed, what role they play, and what their significance is for embryonic development have been attracting the attention of researchers. Studies in recent years have revealed that in addition to providing energy for embryonic development, LDs in eggs and embryos also function to resist lipotoxicity, resist oxidative stress, inhibit bacterial infection, and provide lipid and membrane components for embryonic development. Removal of LDs from fertilized eggs or early embryos artificially leads to embryonic developmental arrest and defects. This paper reviews recent studies to explain the role and effect mechanisms of LDs in the embryonic development of several species and the genes involved in the regulation. The review contributes to understanding the embryonic development mechanism and provides new insight for the diagnosis and treatment of diseases related to embryonic developmental abnormalities.
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Affiliation(s)
- Tai Li
- Key Laboratory of Agriculture Animal Genetics, Breeding and Reproduction of the Ministry of Education & Key Laboratory of Swine Genetics and Breeding of the Ministry of Agriculture and Rural Affairs, College of Animal Science, Huazhong Agricultural University, Wuhan, 430070, Hubei, P. R. China
| | - Yi Jin
- Key Laboratory of Agriculture Animal Genetics, Breeding and Reproduction of the Ministry of Education & Key Laboratory of Swine Genetics and Breeding of the Ministry of Agriculture and Rural Affairs, College of Animal Science, Huazhong Agricultural University, Wuhan, 430070, Hubei, P. R. China
| | - Jian Wu
- Key Laboratory of Agriculture Animal Genetics, Breeding and Reproduction of the Ministry of Education & Key Laboratory of Swine Genetics and Breeding of the Ministry of Agriculture and Rural Affairs, College of Animal Science, Huazhong Agricultural University, Wuhan, 430070, Hubei, P. R. China
- Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, 430070, China
- Hubei Hongshan Laboratory, Wuhan, China
| | - Zhuqing Ren
- Key Laboratory of Agriculture Animal Genetics, Breeding and Reproduction of the Ministry of Education & Key Laboratory of Swine Genetics and Breeding of the Ministry of Agriculture and Rural Affairs, College of Animal Science, Huazhong Agricultural University, Wuhan, 430070, Hubei, P. R. China.
- Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, 430070, China.
- Hubei Hongshan Laboratory, Wuhan, China.
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Kim MH, Kim S, Kim S, Park W, Han J. Gryllus bimaculatus-containing diets protect against dexamethasone-induced muscle atrophy, but not high-fat diet-induced obesity. Food Sci Nutr 2023; 11:2787-2797. [PMID: 37324877 PMCID: PMC10261823 DOI: 10.1002/fsn3.3257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 01/20/2023] [Accepted: 01/23/2023] [Indexed: 02/05/2023] Open
Abstract
Sarcopenia and obesity are emerging as major social problems. In this study, we examined whether Gryllus bimaculatus (GB), an edible insect, prevents dexamethasone-induced muscle atrophy (sarcopenia) or high-fat diet (HFD)-induced obesity in mice. We generated a standard chow diet (SCD) + GB (85% SCD and 15% GB powder) and HFD + GB (85% HFD and 15% GB powder). SCD + GB feeding increased gains in body weight and white adipose tissue (WAT). Despite no difference in weight change between HFD + GB- and HFD-fed mice, HFD + GB feeding aggravated insulin resistance compared with HFD feeding. SCD + GB or HFD + GB feeding did not change most gene expressions in the liver and WAT but did increase MyHC1 expression in the muscle, meaning that GB increased muscle generation. Therefore, we fed SCD + GB with dexamethasone, which induces muscle degeneration. As a result, muscle fiber size increased, as did grip strength compared with dexamethasone-injected mice. In addition, SCD + GB reduced the expression of muscle degradation factors, such as atrogin1 and muscle RING-finger protein 1 (MuRF1). Furthermore, SCD + GB feeding increased Akt, mTOR, and p70S6K phosphorylation and MyHC1 expression, meaning that it may have increased protein synthesis. In conclusion, GB has great potential for inhibiting dexamethasone-induced muscle mass loss by increasing muscle protein synthesis and inhibiting muscle protein degradation.
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Affiliation(s)
- Min Hee Kim
- Department of BiochemistryCollege of Medicine, Ewha Womans UniversitySeoulSouth Korea
| | - Su‐Jeong Kim
- Department of BiochemistryChung‐Ang University College of MedicineSeoulSouth Korea
| | - Si‐Hyun Kim
- Department of Human Ecology (Food Science and Nutrition)Korea UniversitySeoulSouth Korea
| | - Woo‐Jae Park
- Department of BiochemistryChung‐Ang University College of MedicineSeoulSouth Korea
| | - Jung‐Soon Han
- Department of Human Ecology (Food Science and Nutrition)Korea UniversitySeoulSouth Korea
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25
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Kozan DW, Derrick JT, Ludington WB, Farber SA. From worms to humans: Understanding intestinal lipid metabolism via model organisms. Biochim Biophys Acta Mol Cell Biol Lipids 2023; 1868:159290. [PMID: 36738984 PMCID: PMC9974936 DOI: 10.1016/j.bbalip.2023.159290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 01/10/2023] [Accepted: 01/19/2023] [Indexed: 02/05/2023]
Abstract
The intestine is responsible for efficient absorption and packaging of dietary lipids before they enter the circulatory system. This review provides a comprehensive overview of how intestinal enterocytes from diverse model organisms absorb dietary lipid and subsequently secrete the largest class of lipoproteins (chylomicrons) to meet the unique needs of each animal. We discuss the putative relationship between diet and metabolic disease progression, specifically Type 2 Diabetes Mellitus. Understanding the molecular response of intestinal cells to dietary lipid has the potential to undercover novel therapies to combat metabolic syndrome.
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Affiliation(s)
- Darby W Kozan
- Department of Biology, Johns Hopkins University, Baltimore, MD, United States; Department of Embryology, Carnegie Institute for Science, Baltimore, MD, United States
| | - Joshua T Derrick
- Department of Biology, Johns Hopkins University, Baltimore, MD, United States; Department of Embryology, Carnegie Institute for Science, Baltimore, MD, United States
| | - William B Ludington
- Department of Biology, Johns Hopkins University, Baltimore, MD, United States; Department of Embryology, Carnegie Institute for Science, Baltimore, MD, United States
| | - Steven A Farber
- Department of Biology, Johns Hopkins University, Baltimore, MD, United States; Department of Embryology, Carnegie Institute for Science, Baltimore, MD, United States.
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26
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Araki M, Nakagawa Y, Saito H, Yamada Y, Han SI, Mizunoe Y, Ohno H, Miyamoto T, Sekiya M, Matsuzaka T, Sone H, Shimano H. Hepatocyte- or macrophage-specific SREBP-1a deficiency in mice exacerbates methionine- and choline-deficient diet-induced nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol 2022; 323:G627-G639. [PMID: 36283088 DOI: 10.1152/ajpgi.00090.2022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Sterol regulatory element-binding proteins (SREBPs) are master transcription factors for lipid synthesis, and SREBP-1 is important for fatty acid and triglyceride synthesis. SREBP-1 has two isoforms, SREBP-1a and SREBP-1c, which are splicing variants transcribed from the Srebf1 gene. Although SREBP-1a exhibits stronger transcriptional activity than SREBP-1c, hepatic SREBP-1c is considered more physiologically important. We generated SREBP-1a flox mice using the CRISPR/Cas9 system and hepatocyte- and macrophage-specific SREBP-1a knockout (KO) mice (LKO, liver-knockout; and mΦKO, macrophage-knockout). There were no significant differences among all the mouse genotypes upon feeding with a normal diet. However, feeding with a methionine- and choline-deficient (MCD) diet resulted in exacerbated liver injury in both KO mice. In LKO mice, fatty liver was unexpectedly exacerbated, leading to macrophage infiltration and inflammation. In contrast, in mΦKO mice, the fatty liver state was similar to that in flox mice, but the polarity of the macrophages in the liver was transformed into a proinflammatory M1 subtype, resulting in the exacerbation of inflammation. Taken together, we found that SREBP-1a does not contribute to hepatic lipogenesis, but in either hepatocytes or macrophages distinctly controls the onset of pathological conditions in MCD diet-induced hepatitis.NEW & NOTEWORTHY Hepatocyte- and macrophage-specific SREBP-1a knockout mice were generated for the first time. This study reveals that SREBP-1a does not contribute to hepatic lipogenesis, but in either hepatocytes or macrophages distinctly controls the onset of pathological conditions in methionine- and choline-deficient diet-induced hepatitis.
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Affiliation(s)
- Masaya Araki
- Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Yoshimi Nakagawa
- Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.,Division of Complex Biosystem Research, Department of Research and Development, Institute of Natural Medicine, University of Toyama, Toyama, Japan.,Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan
| | - Hodaka Saito
- Division of Complex Biosystem Research, Department of Research and Development, Institute of Natural Medicine, University of Toyama, Toyama, Japan
| | - Yasunari Yamada
- Division of Complex Biosystem Research, Department of Research and Development, Institute of Natural Medicine, University of Toyama, Toyama, Japan
| | - Song-Iee Han
- Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.,International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan
| | - Yuhei Mizunoe
- Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Hiroshi Ohno
- Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Takafumi Miyamoto
- Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Motohiro Sekiya
- Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Takashi Matsuzaka
- Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.,Transborder Medical Research Center (TMRC), University of Tsukuba, Tsukuba, Japan
| | - Hirohito Sone
- Department of Hematology, Endocrinology and Metabolism, Faculty of Medicine, Niigata University, Niigata, Japan
| | - Hitoshi Shimano
- Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.,Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan.,International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.,Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
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Hu H, Sun N, Du H, He Y, Pan K, Liu X, Lu X, Wei J, Liao M, Duan C. Mouse promyelocytic leukemia zinc finger protein (PLZF) regulates hepatic lipid and glucose homeostasis dependent on SIRT1. Front Pharmacol 2022; 13:1039726. [PMID: 36438786 PMCID: PMC9684722 DOI: 10.3389/fphar.2022.1039726] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 10/21/2022] [Indexed: 11/11/2022] Open
Abstract
Previous studies have demonstrated that promyelocytic leukemia zinc finger protein (PLZF) promotes the expression of gluconeogenic genes and hepatic glucose output, which leads to hyperglycemia. However, the role played by PLZF in regulating lipid metabolism is not known. In this study, we aimed to examine the function of PLZF in regulating hepatic lipid and glucose homeostasis and the underlying mechanisms. The expression of PLZF was determined in different mouse models with regard to non-alcoholic fatty liver disease (NAFLD). In the next step, adenoviruses that express PLZF (Ad-PLZF) or PLZF-specific shRNA (Ad-shPLZF) were utilized to alter PLZF expression in mouse livers and in primary hepatocytes. For the phenotype of the fatty liver, histologic and biochemical analyses of hepatic triglyceride (TG), serum TG and cholesterol levels were carried out. The underlying molecular mechanism for the regulation of lipid metabolism by PLZF was further explored using luciferase reporter gene assay and ChIP analysis. The results demonstrated that PLZF expression was upregulated in livers derived from ob/ob, db/db and diet-induced obesity (DIO) mice. Liver PLZF-overexpressing C57BL/6J mice showed fatty liver phenotype, liver inflammation, impaired glucose tolerance and insulin sensitivity. On the other hand, hepatic PLZF knockdown in db/db and DIO mice alleviated hepatic steatosis. Of note, we found that PLZF activates SREBP-1c gene transcription through binding directly to the promoter fragment of this gene, which would induce a repressor-to-activator conversion depending on its interaction with SIRT1 in the role played by PLZF in the transcription process through deacetylation. Thus, PLZF is identified as an essential regulator of hepatic lipid and glucose metabolism, where the modulation of its liver expression could open up a therapeutic path for treating NAFLD.
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Affiliation(s)
- Huiling Hu
- Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Nannan Sun
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Haiyan Du
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
| | - Yuqing He
- Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Kunyi Pan
- Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiuli Liu
- Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaoxia Lu
- Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jie Wei
- Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- *Correspondence: Jie Wei, ; Mianmian Liao, ; Chaohui Duan,
| | - Mianmian Liao
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
- *Correspondence: Jie Wei, ; Mianmian Liao, ; Chaohui Duan,
| | - Chaohui Duan
- Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- *Correspondence: Jie Wei, ; Mianmian Liao, ; Chaohui Duan,
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Bengoechea-Alonso MT, Aldaalis A, Ericsson J. Loss of the Fbw7 tumor suppressor rewires cholesterol metabolism in cancer cells leading to activation of the PI3K-AKT signalling axis. Front Oncol 2022; 12:990672. [PMID: 36176395 PMCID: PMC9513553 DOI: 10.3389/fonc.2022.990672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
The sterol regulatory-element binding proteins (SREBPs) are transcription factors controlling cholesterol and fatty acid synthesis and metabolism. There are three SREBP proteins, SREBP1a, SREBP1c and SREBP2, with SREBP1a being the strongest transcription factor. The expression of SREBP1a is restricted to rapidly proliferating cells, including cancer cells. The SREBP proteins are translated as large, inactive precursors bound to the endoplasmic reticulum (ER) membranes. These precursors undergo a two-step cleavage process that releases the amino terminal domains of the proteins, which translocate to the nucleus and function as transcription factors. The nuclear forms of the SREBPs are rapidly degraded by the ubiquitin-proteasome system in a manner dependent on the Fbw7 ubiquitin ligase. Consequently, inactivation of Fbw7 results in the stabilization of active SREBP1 and SREBP2 and enhanced expression of target genes. We report that the inactivation of Fbw7 in cancer cells blocks the proteolytic maturation of SREBP2. The same is true in cells expressing a cancer-specific loss-of-function Fbw7 protein. Interestingly, the activation of SREBP2 is restored in response to cholesterol depletion, suggesting that Fbw7-deficient cells accumulate cholesterol. Importantly, inactivation of SREBP1 in Fbw7-deficient cells also restores the cholesterol-dependent regulation of SREBP2, suggesting that the stabilization of active SREBP1 molecules could be responsible for the blunted activation of SREBP2 in Fbw7-deficient cancer cells. We suggest that this could be an important negative feedback loop in cancer cells with Fbw7 loss-of-function mutations to protect these cells from the accumulation of toxic levels of cholesterol and/or cholesterol metabolites. Surprisingly, we also found that the inactivation of Fbw7 resulted in the activation of AKT. Importantly, the activation of AKT was dependent on SREBP1 and on the accumulation of cholesterol. Thus, we suggest that the loss of Fbw7 rewires lipid metabolism in cancer cells to support cell proliferation and survival.
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Affiliation(s)
- Maria T. Bengoechea-Alonso
- Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Arwa Aldaalis
- Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Johan Ericsson
- Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
- School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
- *Correspondence: Johan Ericsson,
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miR-539-5p regulates Srebf1 transcription in the skeletal muscle of diabetic mice by targeting DNA methyltransferase 3b. MOLECULAR THERAPY - NUCLEIC ACIDS 2022; 29:718-732. [PMID: 36090753 PMCID: PMC9439965 DOI: 10.1016/j.omtn.2022.08.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 08/10/2022] [Indexed: 11/24/2022]
Abstract
Aberrant DNA methylation is associated with diabetes, but the precise regulatory events that control the levels and activity of DNA methyltransferases (DNMTs) is not well understood. Here we show that miR-539-5p targets Dnmt3b and regulates its cellular levels. miR-539-5p and Dnmt3b show inverse patterns of expression in skeletal muscle of diabetic mice. By binding to the 3′ UTR of Dnmt3b, miR-539-5p downregulates its levels in C2C12 cells and in human primary skeletal muscle cells. miR-539-5p-Dnmt3b interaction regulates Srebf1 transcription by altering methylation at CpG islands within Srebf1 in C2C12 cells. Dnmt3b inhibition alone was sufficient to upregulate Srebf1 transcription. In vivo antagonism of miR-539-5p in normal mice induced hyperglycemia and hyperinsulinemia and impaired oral glucose tolerance. These mice had elevated Dnmt3b and decreased Srebf1 levels in skeletal muscle. db/db mice injected with miR-539-5p mimics showed improved circulatory glucose and cholesterol levels. Oral glucose tolerance improved together with normalization of Dnmt3b and Srebf1 levels in skeletal muscle. Our results support a critical role of miR-539-5p and Dnmt3b in aberrant skeletal muscle metabolism during diabetes by regulating Srebf1 transcription; modulating the miR-539-5p-Dnmt3b axis might have therapeutic potential for addressing altered skeletal muscle physiology during insulin resistance and type 2 diabetes.
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Aldaalis A, Bengoechea-Alonso MT, Ericsson J. The SREBP-dependent regulation of cyclin D1 coordinates cell proliferation and lipid synthesis. Front Oncol 2022; 12:942386. [PMID: 36091143 PMCID: PMC9451027 DOI: 10.3389/fonc.2022.942386] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 07/25/2022] [Indexed: 12/15/2022] Open
Abstract
The sterol regulatory-element binding protein (SREBP) family of transcription factors regulates cholesterol, fatty acid, and triglyceride synthesis and metabolism. However, they are also targeted by the ubiquitin ligase Fbw7, a major tumor suppressor, suggesting that they could regulate cell growth. Indeed, enhanced lipid synthesis is a hallmark of many human tumors. Thus, the SREBP pathway has recently emerged as a potential target for cancer therapy. We have previously demonstrated that one of these transcription factors, SREBP1, is stabilized and remains associated with target promoters during mitosis, suggesting that the expression of these target genes could be important as cells enter G1 and transcription is restored. Activation of cyclin D-cdk4/6 complexes is critical for the phosphorylation and inactivation of the retinoblastoma protein (Rb) family of transcriptional repressors and progression through the G1 phase of the cell cycle. Importantly, the cyclin D-cdk4/6-Rb regulatory axis is frequently dysregulated in human cancer. In the current manuscript, we demonstrate that SREBP1 activates the expression of cyclin D1, a coactivator of cdk4 and cdk6, by binding to an E-box in the cyclin D1 promoter. Consequently, inactivation of SREBP1 in human liver and breast cancer cell lines reduces the expression of cyclin D1 and attenuates Rb phosphorylation. Rb phosphorylation in these cells can be rescued by restoring cyclin D1 expression. On the other hand, expression of active SREBP1 induced the expression of cyclin D1 and increased the phosphorylation of Rb in a manner dependent on cyclin D1 and cdk4/6 activity. Inactivation of SREBP1 resulted in reduced expression of cyclin D1, attenuated phosphorylation of Rb, and reduced proliferation. Inactivation of SREBP1 also reduced the insulin-dependent regulation of the cyclin D1 gene. At the same time, SREBP1 is known to play an important role in supporting lipid synthesis in cancer cells. Thus, we propose that the SREBP1-dependent regulation of cyclin D1 coordinates cell proliferation with the enhanced lipid synthesis required to support cell growth.
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Affiliation(s)
- Arwa Aldaalis
- Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University, Education City, Doha, Qatar
| | - Maria T. Bengoechea-Alonso
- Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University, Education City, Doha, Qatar
| | - Johan Ericsson
- Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University, Education City, Doha, Qatar
- School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
- *Correspondence: Johan Ericsson,
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Zhao Q, Lin X, Wang G. Targeting SREBP-1-Mediated Lipogenesis as Potential Strategies for Cancer. Front Oncol 2022; 12:952371. [PMID: 35912181 PMCID: PMC9330218 DOI: 10.3389/fonc.2022.952371] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 06/22/2022] [Indexed: 11/13/2022] Open
Abstract
Sterol regulatory element binding protein-1 (SREBP-1), a transcription factor with a basic helix–loop–helix leucine zipper, has two isoforms, SREBP-1a and SREBP-1c, derived from the same gene for regulating the genes of lipogenesis, including acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase. Importantly, SREBP-1 participates in metabolic reprogramming of various cancers and has been a biomarker for the prognosis or drug efficacy for the patients with cancer. In this review, we first introduced the structure, activation, and key upstream signaling pathway of SREBP-1. Then, the potential targets and molecular mechanisms of SREBP-1-regulated lipogenesis in various types of cancer, such as colorectal, prostate, breast, and hepatocellular cancer, were summarized. We also discussed potential therapies targeting the SREBP-1-regulated pathway by small molecules, natural products, or the extracts of herbs against tumor progression. This review could provide new insights in understanding advanced findings about SREBP-1-mediated lipogenesis in cancer and its potential as a target for cancer therapeutics.
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Affiliation(s)
- Qiushi Zhao
- National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, China
| | - Xingyu Lin
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Xingyu Lin, ; Guan Wang,
| | - Guan Wang
- National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, China
- *Correspondence: Xingyu Lin, ; Guan Wang,
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Baicalin ameliorates alcohol-induced hepatic steatosis by suppressing SREBP1c elicited PNPLA3 competitive binding to ATGL. Arch Biochem Biophys 2022; 722:109236. [DOI: 10.1016/j.abb.2022.109236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/17/2022] [Accepted: 04/11/2022] [Indexed: 11/15/2022]
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Xie Z, Li EW, Gao G, Du Y, Wang M, Wang H, Wang P, Qiao Y, Su Y, Xu J, Zhang X, Zhang Z. Zexie Tang targeting FKBP38/mTOR/SREBPs pathway improves hyperlipidemia. JOURNAL OF ETHNOPHARMACOLOGY 2022; 290:115101. [PMID: 35151834 DOI: 10.1016/j.jep.2022.115101] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 01/25/2022] [Accepted: 02/08/2022] [Indexed: 06/14/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Zexie Tang (ZXT), only two consists with Alismatis Rhizoma (AR) and Atractylodes macrocephala Rhizoma (AM), a classical Chinese medicine formula from Synopsis of the Golden Chamber with a history of 2000 years. Clinical observation in recent years has found that ZXT has excellent lipid-lowering effect. AIM OF THE STUDY To explore the potential mechanism of ZXT ameliorates hyperlipidemia based on FKBP38/mTOR/SREBPs pathway. MATERIALS AND METHODS WD-induced hyperlipidemia mice and oleic acid induced cell lipid accumulation model were used to investigate pharmacodynamic. The effect of ZXT on the transcriptional activity of SREBPs was detected by reporter gene assay. Proteins and downstream genes of mTOR/SREBPs pathway were detected in vivo and in vitro. Combined with network pharmacology and HPLC-Q-TOF/MS, the active ingredients were screened and identified. The interaction between active compounds of ZXT and FKBP38 protein were analyzed by docking analysis. RESULTS ZXT decreased TC, TG and LDL-c levels in blood of WD-induced hyperlipidemia mouse model, and improved insulin resistance in vivo. ZXT also reduced TC, TG and lipid accumulation in cells line, and inhibited SREBPs luciferase activity, protein and its target genes expression such as FASN, HMGCR, etc. Meanwhile, ZXT inhibited protein expression levels of p-mTOR, p-S6K, etc in vitro and in vivo. Combined with network pharmacology and HPLC-Q-TOF/MS, 16 active ingredients were screened and identified. Docking results showed that active compounds of ZXT binding to FKBP38 and formed hydrogen bond. CONCLUSION Our findings highlighted that ZXT ameliorates hyperlipidemia, in which FKBP/mTOR/SREBPs pathway might be the potential regulatory mechanism.
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Affiliation(s)
- Zhishen Xie
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Er-Wen Li
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China; College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Gai Gao
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Yueyue Du
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China; College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Mengyao Wang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China; College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Hui Wang
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Pan Wang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Yonghui Qiao
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Yunfang Su
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Jiangyan Xu
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Xiaowei Zhang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China.
| | - Zhenqiang Zhang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China.
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Mirzaei-Alamouti H, Moradi S, Patra AK, Mansouryar M. Monensin supplementation downregulated the expression signature of genes involved in cholesterol synthesis in the ruminal epithelium and adipose tissue of lambs. Trop Anim Health Prod 2022; 54:167. [PMID: 35445947 DOI: 10.1007/s11250-022-03168-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 04/07/2022] [Indexed: 11/25/2022]
Abstract
To understand the metabolic mechanisms regulating lipid metabolism by monensin, Afshari male lambs (n = 16) with 41.0 ± 2.4 kg body weight (BW, mean ± SD) at approximately 180 days of age were randomly assigned equally to two dietary treatments. After a 21-day pre-adaptation period, all animals in two groups continued to receive the basal diet, but one group received no monensin supplementation (control) while the other group received 30 mg/day of monensin per animal. Individual BW was recorded weekly to determine the average daily body weight gain (ADG). At the end of the 56-day experimental period, lambs were weighed and slaughtered. Monensin supplementation did not affect BW, ADG, and rumen fermentation characteristics. However, monensin significantly downregulated the sterol regulatory element-binding protein (SREBP)-2 gene expression in all sample tissues (p < 0.05). Also, monensin downregulated expressions of SREBP-1c and peroxisome proliferator-activated receptor (PPAR)-γ in back fat tissues. Monensin increased the expression of 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS)-2, but it decreased the mRNA abundance of HMGCS-1 in the rumen epithelial tissues (p < 0.05). Our data suggest that monensin downregulates cholesterol synthesis via inhibition of HMGCS-1 and impairment of the SREBP pathway, probably due to a crosstalk among different tissues to control energy metabolism.
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Affiliation(s)
- H Mirzaei-Alamouti
- Department of Animal Science, University of Zanjan, 45371-38791, Zanjan, Iran.
| | - S Moradi
- Department of Animal Science, University of Zanjan, 45371-38791, Zanjan, Iran
| | - A K Patra
- Department of Animal Nutrition, Bengal University of Animal and Fishery Sciences, West, Kolkata, 700037, India
| | - M Mansouryar
- Zist Dam Group, University Incubator Center, University of Zanjan, 45371-38791, Zanjan, Iran.
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Zou J, Yan C, Wan JB. Red yeast rice ameliorates non-alcoholic fatty liver disease through inhibiting lipid synthesis and NF-κB/NLRP3 inflammasome-mediated hepatic inflammation in mice. Chin Med 2022; 17:17. [PMID: 35078487 PMCID: PMC8788078 DOI: 10.1186/s13020-022-00573-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 01/12/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Red yeast rice (RYR), a nutraceutical with a profound cholesterol-lowering effect, was found to attenuate non-alcoholic fatty liver disease (NAFLD) in mice. Despite monacolin K in RYR being a specific inhibitor of hydroxymethylglutaryl-coenzyme A reductase (HMCGR), the mechanisms underlying the protective effects of RYR against NAFLD are not fully elucidated. METHODS Using a mouse model of high-fat diet (HFD) feeding and a cellular model of HepG2 cells challenged by lipopolysaccharide (LPS) and palmitic acid (PA), the possible molecular mechanisms were exploited in the aspects of NF-κB/NLRP3 inflammasome and mTORC1-SREBPs signaling pathways by examining the relevant gene/protein expressions. Subsequently, the correlation between these two signals was also verified using cellular experiments. RESULTS RYR ameliorated lipid accumulation and hepatic inflammation in vivo and in vitro. RYR improved lipid metabolism through modulating mTORC1-SREBPs and their target genes related to triglyceride and cholesterol synthesis. Furthermore, RYR suppressed hepatic inflammation by inhibiting the NF-κB/NLRP3 inflammasome signaling. Interestingly, the treatment with RYR or MCC950, a specific NLRP3 inhibitor, resulted in the reduced lipid accumulation in HepG2 cells challenged by LPS plus PA, suggesting that the inhibitory effects of RYR on NLRP3 inflammasome-mediated hepatic inflammation may partially, in turn, contribute to the lipid-lowering effect of RYR. CONCLUSIONS The modulation of NF-κB/NLRP3 inflammasome and lipid synthesis may contribute to the ameliorative effects of RYR against HFD-induced NAFLD.
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Affiliation(s)
- Jian Zou
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, Taipa, China
| | - Chunyan Yan
- School of Clinical Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
| | - Jian-Bo Wan
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, Taipa, China.
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Ma S, Murakami K, Tanaka K, Hashimoto M, Tanaka M, Kitagori K, Akizuki S, Nakashima R, Yoshifuji H, Ohmura K, Morinobu A, Mimori T. Fatostatin ameliorates inflammation without affecting cell viability. FEBS Open Bio 2022; 12:594-604. [PMID: 35015380 PMCID: PMC8886327 DOI: 10.1002/2211-5463.13364] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/07/2021] [Accepted: 01/10/2022] [Indexed: 11/10/2022] Open
Abstract
The mature form of sterol regulatory element-binding protein 1 (SREBP1) is a transcription factor involved in lipid synthesis, which participates in toll like receptor 4 (TLR4)-triggered inflammatory pathways during the resolution phase of inflammation in macrophages. SREBP1 has thus attracted interest as a candidate target molecule for ameliorating inflammation. Fatostatin is a small molecule that inhibits the maturation and function of SREBP, and its role in regulating inflammation is poorly understood. To evaluate the anti-inflammatory effect of fatostatin, we compared body weight, footpad and hock dimensions, and arthritis scores between K/BxN serum-induced arthritis mice treated with fatostatin and those treated with dimethyl sulfoxide as vehicle control. We performed hematoxylin and eosin staining of joints of distal paws to assess tissue inflammation. Moreover, inflammatory cytokine production levels and cell viability were measured in lipopolysaccharide (LPS)-responsive human embryonic kidney 293 cells (293/hTLR4A-MD2-CD14 cells) after fatostatin administration. In K/BxN serum-induced arthritis mice, fatostatin treatment significantly reduced the arthritis scores and lining hyperplasia. In vitro analysis revealed that fatostatin significantly inhibited the secretion of inflammatory cytokines from cells activated with LPS, without affecting cell viability. This is the first study to elucidate that fatostatin is an anti-inflammatory agent that modulates the processing of lipid transcription factors without affecting cell viability. Therefore, this study reveals the potential of anti-inflammatory therapeutics that link lipid regulation and inflammation.
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Affiliation(s)
- Shuhe Ma
- Kyoto University Graduate School of Medicine, Department of Rheumatology and Clinical Immunology, Kyoto, Japan
| | - Kosaku Murakami
- Kyoto University Graduate School of Medicine, Center for Cancer Immunotherapy and Immunobiology
| | - Kazune Tanaka
- Kyoto University Graduate School of Medicine, Department of Rheumatology and Clinical Immunology, Kyoto, Japan
| | - Motomu Hashimoto
- Kyoto University Graduate School of Medicine, Department for Advanced Medicine for Rheumatic Disease, Kyoto, Japan.,Osaka City University Graduate School of Medicine, Department of Clinical Immunology, Osaka, Japan
| | - Masao Tanaka
- Kyoto University Graduate School of Medicine, Department for Advanced Medicine for Rheumatic Disease, Kyoto, Japan
| | - Koji Kitagori
- Kyoto University Graduate School of Medicine, Department of Rheumatology and Clinical Immunology, Kyoto, Japan
| | - Shuji Akizuki
- Kyoto University Graduate School of Medicine, Department of Rheumatology and Clinical Immunology, Kyoto, Japan
| | - Ran Nakashima
- Kyoto University Graduate School of Medicine, Department of Rheumatology and Clinical Immunology, Kyoto, Japan
| | - Hajime Yoshifuji
- Kyoto University Graduate School of Medicine, Department of Rheumatology and Clinical Immunology, Kyoto, Japan
| | - Koichiro Ohmura
- Kyoto University Graduate School of Medicine, Department of Rheumatology and Clinical Immunology, Kyoto, Japan
| | - Akio Morinobu
- Kyoto University Graduate School of Medicine, Department of Rheumatology and Clinical Immunology, Kyoto, Japan
| | - Tsuneyo Mimori
- Kyoto University Graduate School of Medicine, Department of Rheumatology and Clinical Immunology, Kyoto, Japan.,Ijinkai Takeda General Hospital, Kyoto, Japan
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Yang D, Jeong H, Hwang SM, Kim JW, Moon HW, Lee YE, Oh HB, Park CB, Kim B. Oral administration of Jinan Red Ginseng and licorice extract mixtures ameliorates nonalcoholic steatohepatitis by modulating lipogenesis. J Ginseng Res 2022; 46:126-137. [PMID: 35058729 PMCID: PMC8753527 DOI: 10.1016/j.jgr.2021.05.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/11/2021] [Accepted: 05/12/2021] [Indexed: 12/20/2022] Open
Abstract
Background Nonalcoholic steatohepatitis (NASH) is one of the main chronic liver diseases. NASH is identified by lipid accumulation, inflammation, and fibrosis. Jinan Red Ginseng (JRG) and licorice have been widely used because of their anti-inflammatory and hepatoprotective effects. Hence, this study assessed JRG and licorice extract mixtures' effects on NASH progression. Methods Palmitic acid (PA) and the western diet (WD) plus, high glucose-fructose water were used to induce in vitro and in vivo NASH. Mice were orally administered with JRG-single (JRG-S) and JRG-mixtures (JRG-M; JRG-S + licorice) at 0, 50, 100, 200 or 400 mg/kg/day once a day during the last half-period of diet feeding. Results JRG-S and JRG-M reduced NASH-related pathologies in WD-fed mice. JRG-S and JRG-M consistently decreased the mRNA level of genes related with inflammation, fibrosis, and lipid metabolism. The treatment of JRG-S and JRG-M also diminished the SREBP-1c protein levels and the p-AMPK/AMPK ratio. The FAS protein levels were decreased by JRG-M treatment both in vivo and in vitro but not JRG-S. Conclusion JRG-M effectively reduced lipogenesis by modulating AMPK downstream signaling. Our findings suggest that this mixture can be used as a prophylactic or therapeutic alternative for the remedy of NASH.
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Affiliation(s)
- Daram Yang
- Biosafety Research Institute and Laboratory of Pathology, College of Veterinary Medicine, Jeonbuk National University, Iksan-si, Jeollabuk-do, Republic of Korea
| | - Hyuneui Jeong
- Biosafety Research Institute and Laboratory of Pathology, College of Veterinary Medicine, Jeonbuk National University, Iksan-si, Jeollabuk-do, Republic of Korea
| | - Seung-Mi Hwang
- Department of Efficacy Study, Institute of Jinan Red Ginseng, Jinan-gun, Jeollabuk-do, Republic of Korea
- Department of Food Science and Technology, Jeonbuk National University, Deokjin-gu, Jeonju-si, Jeollabuk-do, Republic of Korea
| | - Jong-Won Kim
- Biosafety Research Institute and Laboratory of Pathology, College of Veterinary Medicine, Jeonbuk National University, Iksan-si, Jeollabuk-do, Republic of Korea
| | - Hee-Won Moon
- Biosafety Research Institute and Laboratory of Pathology, College of Veterinary Medicine, Jeonbuk National University, Iksan-si, Jeollabuk-do, Republic of Korea
| | - Ye-Eun Lee
- Department of Efficacy Study, Institute of Jinan Red Ginseng, Jinan-gun, Jeollabuk-do, Republic of Korea
| | - Hyo-Bin Oh
- Department of Efficacy Study, Institute of Jinan Red Ginseng, Jinan-gun, Jeollabuk-do, Republic of Korea
- Department of Food Science and Technology, Jeonbuk National University, Deokjin-gu, Jeonju-si, Jeollabuk-do, Republic of Korea
| | - Chung-berm Park
- Department of Efficacy Study, Institute of Jinan Red Ginseng, Jinan-gun, Jeollabuk-do, Republic of Korea
- Corresponding author. Institute of Jinan Red Ginseng, 41 Hongsamhanbang-ro, Jinan-gun, Jeollabuk-do, 55442, Republic of Korea.
| | - Bumseok Kim
- Biosafety Research Institute and Laboratory of Pathology, College of Veterinary Medicine, Jeonbuk National University, Iksan-si, Jeollabuk-do, Republic of Korea
- Corresponding author. Biosafety Research Institute and Laboratory of Pathology, College of Veterinary Medicine, Jeonbuk National University, 79 Gobong-ro, Iksan-si, Jeollabukdo, 54596, Republic of Korea.
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SREBP-1c and lipogenesis in the liver: an update1. Biochem J 2021; 478:3723-3739. [PMID: 34673919 DOI: 10.1042/bcj20210071] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 09/28/2021] [Accepted: 09/30/2021] [Indexed: 12/13/2022]
Abstract
Sterol Regulatory Element Binding Protein-1c is a transcription factor that controls the synthesis of lipids from glucose in the liver, a process which is of utmost importance for the storage of energy. Discovered in the early nineties by B. Spiegelman and by M. Brown and J. Goldstein, it has generated more than 5000 studies in order to elucidate its mechanism of activation and its role in physiology and pathology. Synthetized as a precursor found in the membranes of the endoplasmic reticulum, it has to be exported to the Golgi and cleaved by a mechanism called regulated intramembrane proteolysis. We reviewed in 2002 its main characteristics, its activation process and its role in the regulation of hepatic glycolytic and lipogenic genes. We particularly emphasized that Sterol Regulatory Element Binding Protein-1c is the mediator of insulin effects on these genes. In the present review, we would like to update these informations and focus on the response to insulin and to another actor in Sterol Regulatory Element Binding Protein-1c activation, the endoplasmic reticulum stress.
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Mirzaei-Alamouti H, Elhami S, Abdollahi A, Vazirigohar M, Harakinejad T, Nielson MO, Aschenbach JR, Mansouryar M. Short communication: effect of dietary supplementation with a mixture of fish and sunflower oils on the expression of key lipogenic and cholesterologenic genes in adipose tissues with different metabolic functions. Trop Anim Health Prod 2021; 53:522. [PMID: 34697645 DOI: 10.1007/s11250-021-02972-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 10/14/2021] [Indexed: 10/20/2022]
Abstract
The present study investigated the effects of dietary fish and sunflower oils as sources of n-3, n-6 polyunsaturated fatty acids (PUFA) on the expression of key lipogenic and cholesterologenic genes in subcutaneous adipose tissue (SAT) and tail adipose tissue (TAT) of fat-tailed sheep. Twenty-six male Afshari lambs were divided into 4 groups. Three groups were fed a high concentrate basal diet plus 100 g/lamb/day oil supplement (OS; 60 g sunflower oil and 40 g fish oil) beyond a 21-day adaptation period for 10, 20, and 30 days (groups OS10, OS20, and OS30; n = 6, each) until slaughter. A control group was slaughtered at the last day of adaptation (OS0; n = 4). Expression of PPARγ, SREBP-1c, and SREBP-2 were determined in TAT and SAT. All transcription factors had lower expression in SAT than TAT. Feeding OS induced a similar pattern of SREBP-1c expression in both TAT and SAT with highest values in OS20. SREBP-2 mRNA decreased by > 50% in TAT of OS30 compared to OS0, whereas the expression of SREBP-2 mRNA did not change in SAT in the same period. PPARγ expression was not affected over time either in SAT or TAT. Plasma concentrations of cholesterol and blood urea nitrogen increased in OS20. The comparison of gene expression responses to OS in TAT vs. SAT suggest that PUFA-mediated effects on lipid metabolism differ between SAT and TAT, which may be linked to the specific role of TAT in energy and water balance under arid conditions.
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Affiliation(s)
- H Mirzaei-Alamouti
- Department of Animal Sciences, Faculty of Agriculture, University of Zanjan, 45371-38791, Zanjan, Iran.
| | - S Elhami
- Department of Animal Sciences, Faculty of Agriculture, University of Zanjan, 45371-38791, Zanjan, Iran
| | - A Abdollahi
- Department of Animal Science, Faculty of Agriculture, Shiraz University, 71441-65186, Shiraz, Iran
| | - M Vazirigohar
- Zist Dam Group, University of Zanjan Incubator Center, 45371-38791, Zanjan, Iran
| | - T Harakinejad
- Department of Animal Sciences, Faculty of Agriculture, University of Zanjan, 45371-38791, Zanjan, Iran
| | - M O Nielson
- Department of Animal Science, Faculty of Science and Technology, Aarhus University, Blichers Allé, 20, 8830, Tjele, Denmark
| | - J R Aschenbach
- Institute of Veterinary Physiology, Freie Universität Berlin, Oertzenweg 19b, 14163, Berlin, Germany
| | - M Mansouryar
- Zist Dam Group, University of Zanjan Incubator Center, 45371-38791, Zanjan, Iran.
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Lim SH, Lee HS, Han HK, Choi CI. Saikosaponin A and D Inhibit Adipogenesis via the AMPK and MAPK Signaling Pathways in 3T3-L1 Adipocytes. Int J Mol Sci 2021; 22:ijms222111409. [PMID: 34768840 PMCID: PMC8583978 DOI: 10.3390/ijms222111409] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 10/07/2021] [Accepted: 10/20/2021] [Indexed: 12/12/2022] Open
Abstract
Obesity is a lipid metabolism disorder caused by genetic, medicinal, nutritional, and other environmental factors. It is characterized by a complex condition of excess lipid accumulation in adipocytes. Adipogenesis is a differentiation process that converts preadipocytes into mature adipocytes and contributes to excessive fat deposition. Saikosaponin A (SSA) and saikosaponin D (SSD) are triterpenoid saponins separated from the root of the Bupleurum chinensis, which has long been used to treat inflammation, fever, and liver diseases. However, the effects of these constituents on lipid accumulation and obesity are poorly understood. We investigated the anti-obesity effects of SSA and SSD in mouse 3T3-L1 adipocytes. The MTT assay was performed to measure cell viability, and Oil Red O staining was conducted to determine lipid accumulation. Various adipogenic transcription factors were evaluated at the protein and mRNA levels by Western blot assay and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Here, we showed that SSA and SSD significantly inhibited lipid accumulation without affecting cell viability within the range of the tested concentrations (0.938–15 µM). SSA and SSD also dose-dependently suppressed the expression of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer binding protein alpha (C/EBPα), sterol regulatory element binding protein-1c (SREBP-1c), and adiponectin. Furthermore, the decrease of these transcriptional factors resulted in the repressed expression of several lipogenic genes including fatty acid binding protein (FABP4), fatty acid synthase (FAS), and lipoprotein lipase (LPL). In addition, SSA and SSD enhanced the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and its substrate, acetyl-CoA carboxylase (ACC), and inhibited the phosphorylation of extracellular-regulated kinase 1/2 (ERK1/2) and p38, but not c-Jun-N-terminal kinase (JNK). These results suggest that SSA and SSD inhibit adipogenesis through the AMPK or mitogen-activated protein kinase (MAPK) pathways in the early stages of adipocyte differentiation. This is the first study on the anti-adipogenic effects of SSA and SSD, and further research in animals and humans is necessary to confirm the potential of saikosaponins as therapeutic agents for obesity.
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Affiliation(s)
- Sung Ho Lim
- Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea; (S.H.L.); (H.S.L.)
| | - Ho Seon Lee
- Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea; (S.H.L.); (H.S.L.)
| | - Hyo-Kyung Han
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea;
| | - Chang-Ik Choi
- Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea; (S.H.L.); (H.S.L.)
- Correspondence: ; Tel.: +82-31-961-5230
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PARPs in lipid metabolism and related diseases. Prog Lipid Res 2021; 84:101117. [PMID: 34450194 DOI: 10.1016/j.plipres.2021.101117] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 08/10/2021] [Accepted: 08/18/2021] [Indexed: 12/28/2022]
Abstract
PARPs and tankyrases (TNKS) represent a family of 17 proteins. PARPs and tankyrases were originally identified as DNA repair factors, nevertheless, recent advances have shed light on their role in lipid metabolism. To date, PARP1, PARP2, PARP3, tankyrases, PARP9, PARP10, PARP14 were reported to have multi-pronged connections to lipid metabolism. The activity of PARP enzymes is fine-tuned by a set of cholesterol-based compounds as oxidized cholesterol derivatives, steroid hormones or bile acids. In turn, PARPs modulate several key processes of lipid homeostasis (lipotoxicity, fatty acid and steroid biosynthesis, lipoprotein homeostasis, fatty acid oxidation, etc.). PARPs are also cofactors of lipid-responsive nuclear receptors and transcription factors through which PARPs regulate lipid metabolism and lipid homeostasis. PARP activation often represents a disruptive signal to (lipid) metabolism, and PARP-dependent changes to lipid metabolism have pathophysiological role in the development of hyperlipidemia, obesity, alcoholic and non-alcoholic fatty liver disease, type II diabetes and its complications, atherosclerosis, cardiovascular aging and skin pathologies, just to name a few. In this synopsis we will review the evidence supporting the beneficial effects of pharmacological PARP inhibitors in these diseases/pathologies and propose repurposing PARP inhibitors already available for the treatment of various malignancies.
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Gamarra D, Aldai N, Arakawa A, de Pancorbo MM, Taniguchi M. Effect of a genetic polymorphism in SREBP1 on fatty acid composition and related gene expression in subcutaneous fat tissue of beef cattle breeds. Anim Sci J 2021; 92:e13521. [PMID: 33554418 DOI: 10.1111/asj.13521] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 12/25/2020] [Accepted: 01/06/2021] [Indexed: 12/14/2022]
Abstract
Sterol regulatory element-binding factor 1 (SREBP1) plays an important role in the lipogenesis which affects fatty acid (FA) composition in backfat and consequently influences beef nutritional quality. This study analyzed the association of 84 bp-indel, both short (S) and long (L) alleles in intron 5 of SREBP1, with FA composition and gene expression of SREBP1 in backfat of northern Spanish beef breeds (Pirenaica, Salers and Holstein-Friesian). Phylogenetic analysis suggests that 84 bp-indel of ruminants is a highly conserved region compared with those in the full-length sequence of intron 5 or mRNA of SREBP1 among species. Overall, higher content of polyunsaturated FAs was observed in SL genotype compared to LL genotype of 84 bp-Indel (p < .05). In particular, in Pirenaica, SL genotype was associated with a higher content of stearic (18:0), α-linolenic (18:3n-3) acid, and total n-3 content (p < .05). However, the gene expression of SREBP1 did not differ among genotypes of 84 bp-Indel (p > .05).
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Affiliation(s)
- David Gamarra
- Biomics Research Group, Lascaray Research Center, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain
| | - Noelia Aldai
- Lactiker Research Group, Pharmacy & Food Sciences Department, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain
| | - Aisaku Arakawa
- Animal Genome Unit, Institute of Livestock and Grassland Science, National Agriculture and Food Research Organization (NARO), Tsukuba, Japan
| | - Marian M de Pancorbo
- Biomics Research Group, Lascaray Research Center, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain
| | - Masaaki Taniguchi
- Animal Genome Unit, Institute of Livestock and Grassland Science, National Agriculture and Food Research Organization (NARO), Tsukuba, Japan
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Cuko L, Duniec-Dmuchowski Z, Rondini EA, Pant A, Fallon JK, Wilson EM, Peraino NJ, Westrick JA, Smith PC, Kocarek TA. Negative Regulation of Human Hepatic Constitutive Androstane Receptor by Cholesterol Synthesis Inhibition: Role of Sterol Regulatory Element Binding Proteins. Drug Metab Dispos 2021; 49:706-717. [PMID: 34011532 PMCID: PMC11025015 DOI: 10.1124/dmd.120.000341] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 04/27/2021] [Indexed: 11/22/2022] Open
Abstract
The squalene synthase inhibitor squalestatin 1 (Squal1) is a potent and efficacious inducer of CYP2B expression in primary cultured rat hepatocytes and rat liver. To determine whether Squal1 is also an inducer of human CYP2B, the effects of Squal1 treatment were evaluated in primary cultured human hepatocytes, differentiated HepaRG cells, and humanized mouse livers. Squal1 treatment did not increase CYP2B6 mRNA levels in human hepatocytes or HepaRG cells and only slightly and inconsistently increased CYP2B6 mRNA content in humanized mouse liver. However, treatment with farnesol, which mediates Squal1's effect on rat CYP2B expression, increased CYP2B6 mRNA levels in HepaRG cells expressing the constitutive androstane receptor (CAR), but not in cells with knocked-down CAR. To determine the impact of cholesterol biosynthesis inhibition on CAR activation, the effects of pravastatin (Prava) were determined on CITCO-mediated gene expression in primary cultured human hepatocytes. Prava treatment abolished CITCO-inducible CYP2B6 expression, but had less effect on rifampicin-mediated CYP3A4 induction, and CITCO treatment did not affect Prava-inducible HMG-CoA reductase (HMGCR) expression. Treatment with inhibitors of different steps of cholesterol biosynthesis attenuated CITCO-mediated CYP2B6 induction in HepaRG cells, and Prava treatment increased HMGCR expression and inhibited CYP2B6 induction with comparable potency. Transfection of HepG2 cells with transcriptionally active sterol regulatory element binding proteins (SREBPs) reduced CAR-mediated transactivation, and inducible expression of transcriptionally active SREBP2 attenuated CITCO-inducible CYP2B6 expression in HepaRG cells. These findings suggest that Squal1 does not induce CYP2B6 in human hepatocytes because Squal1's inhibitory effect on cholesterol biosynthesis interferes with CAR activation. SIGNIFICANCE STATEMENT: The cholesterol biosynthesis inhibitor squalestatin 1 induces rat hepatic CYP2B expression indirectly by causing accumulation of an endogenous isoprenoid that activates the constitutive androstane receptor (CAR). This study demonstrates that squalestatin 1 does not similarly induce CYP2B6 expression in human hepatocytes. Rather, inhibition of cholesterol biosynthesis interferes with CAR activity, likely by activating sterol regulatory element binding proteins. These findings increase our understanding of the endogenous processes that modulate human drug-metabolizing gene expression.
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Affiliation(s)
- Liberta Cuko
- Institute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.)
| | - Zofia Duniec-Dmuchowski
- Institute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.)
| | - Elizabeth A Rondini
- Institute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.)
| | - Asmita Pant
- Institute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.)
| | - John K Fallon
- Institute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.)
| | - Elizabeth M Wilson
- Institute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.)
| | - Nicholas J Peraino
- Institute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.)
| | - Judy A Westrick
- Institute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.)
| | - Philip C Smith
- Institute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.)
| | - Thomas A Kocarek
- Institute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.)
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Nguyen-Lefebvre AT, Selzner N, Wrana JL, Bhat M. The hippo pathway: A master regulator of liver metabolism, regeneration, and disease. FASEB J 2021; 35:e21570. [PMID: 33831275 DOI: 10.1096/fj.202002284rr] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 03/04/2021] [Accepted: 03/18/2021] [Indexed: 12/13/2022]
Abstract
The liver is the only visceral organ in the body with a tremendous capacity to regenerate in response to insults that induce inflammation, cell death, and injury. Liver regeneration is a complicated process involving a well-orchestrated activation of non-parenchymal cells in the injured area and proliferation of undamaged hepatocytes. Furthermore, the liver has a Hepatostat, defined as adjustment of its volume to that required for homeostasis. Understanding the mechanisms that control different steps of liver regeneration is critical to informing therapies for liver repair, to help patients with liver disease. The Hippo signaling pathway is well known for playing an essential role in the control and regulation of liver size, regeneration, stem cell self-renewal, and liver cancer. Thus, the Hippo pathway regulates dynamic cell fates in liver, and in absence of its downstream effectors YAP and TAZ, liver regeneration is severely impaired, and the proliferative expansion of liver cells blocked. We will mainly review upstream mechanisms activating the Hippo signaling pathway following partial hepatectomy in mouse model and patients, its roles during different steps of liver regeneration, metabolism, and cancer. We will also discuss how targeting the Hippo signaling cascade might improve liver regeneration and suppress liver tumorigenesis.
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Affiliation(s)
- Anh Thu Nguyen-Lefebvre
- Department of Medicine, Multi-Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada.,Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada
| | - Nazia Selzner
- Department of Medicine, Multi-Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada
| | | | - Mamatha Bhat
- Department of Medicine, Multi-Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada
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Chen L, Lengi AJ, Corl BA. The inhibitory effect of trans-10,cis-12 conjugated linoleic acid on sterol regulatory element binding protein-1 activation in bovine mammary epithelial cells involved reduced proteasomal degradation of insulin-induced gene-1. J Dairy Sci 2021; 104:11306-11316. [PMID: 34275626 DOI: 10.3168/jds.2021-20544] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 05/31/2021] [Indexed: 11/19/2022]
Abstract
Trans 10,cis-12 conjugated linoleic acid (t10,c12 CLA) is well recognized as a key CLA isomer responsible for the reduction in milk fat synthesis that leads to milk fat depression in dairy cows. Sterol regulatory element binding protein-1 (SREBP1) is a key transcription factor in bovine mammary gland coordinating transcription of the genes for fatty acid synthesis. SREBP1 activation requires the removal of insulin-induced gene-1 (Insig1) that serves as a repressor of SREBP1 in the endoplasmic reticulum (ER). We hypothesized that t10,c12 CLA reduced SREBP1 activation by delaying Insig1 degradation. In the present study, we used undifferentiated bovine mammary epithelial cells (MAC-T cells) and treated them with t10,c12 CLA for 6 h. We found that SREBP1 protein expression declined over 56% when cells were treated with 60 µM or greater concentration of t10,c12 CLA. Such inhibitory effects were also observed in the mRNA expression of SREBP1-regulated genes including SREBP1, fatty acid synthetase, stearoyl-CoA desaturase, and Insig1. Compared with no CLA group, 60 µM or higher concentration of t10,c12 CLA increased Insig1 protein expression over 2-fold in cells transfected with FLAG-tagged Insig1. This stimulatory effect was not specific to t10,c12 CLA but also other polyunsaturated fatty acids including cis-9,trans-11 CLA and linoleic acid. Oleic acid had no effect on Insig1 protein expression, whereas palmitic acid decreased Insig1 protein expression. Further investigation revealed that increased abundance of FLAG-Insig1 with t10,c12 CLA was due to the inhibition of the proteasomal degradation of Insig1. The t10,c12 CLA delayed the Insig1 decay when protein synthesis was blocked. Immunoprecipitation also confirmed that the interaction between ubiquitin-like domain-containing protein 8 and Insig1, the key step of removing Insig1 from ER and freeing SREBP1 for proteolytic processing, was inhibited by t10,c12 CLA, but not palmitic acid. These findings suggested that t10,c12 CLA played a role in regulating SREBP1 activation by reducing proteasomal degradation of Insig1. We concluded that stabilized Insig1 retained SREBP1 in the ER from activation, thus reducing lipogenic gene transcription.
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Affiliation(s)
- Liang Chen
- Department of Dairy Science, Virginia Tech, Blacksburg 24061
| | - Andrea J Lengi
- Department of Dairy Science, Virginia Tech, Blacksburg 24061
| | - Benjamin A Corl
- Department of Dairy Science, Virginia Tech, Blacksburg 24061.
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SREBP-1c Deficiency Affects Hippocampal Micromorphometry and Hippocampus-Dependent Memory Ability in Mice. Int J Mol Sci 2021; 22:ijms22116103. [PMID: 34198910 PMCID: PMC8201143 DOI: 10.3390/ijms22116103] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/28/2021] [Accepted: 06/04/2021] [Indexed: 11/18/2022] Open
Abstract
Changes in structural and functional neuroplasticity have been implicated in various neurological disorders. Sterol regulatory element-binding protein (SREBP)-1c is a critical regulatory molecule of lipid homeostasis in the brain. Recently, our findings have shown the potential involvement of SREBP-1c deficiency in the alteration of novel modulatory molecules in the hippocampus and occurrence of schizophrenia-like behaviors in mice. However, the possible underlying mechanisms, related to neuronal plasticity in the hippocampus, are yet to be elucidated. In this study, we investigated the hippocampus-dependent memory function and neuronal architecture of hippocampal neurons in SREBP-1c knockout (KO) mice. During the passive avoidance test, SREBP-1c KO mice showed memory impairment. Based on Golgi staining, the dendritic complexity, length, and branch points were significantly decreased in the apical cornu ammonis (CA) 1, CA3, and dentate gyrus (DG) subregions of the hippocampi of SREBP-1c KO mice, compared with those of wild-type (WT) mice. Additionally, significant decreases in the dendritic diameters were detected in the CA3 and DG subregions, and spine density was also significantly decreased in the apical CA3 subregion of the hippocampi of KO mice, compared with that of WT mice. Alterations in the proportions of stubby and thin-shaped dendritic spines were observed in the apical subcompartments of CA1 and CA3 in the hippocampi of KO mice. Furthermore, the corresponding differential decreases in the levels of SREBP-1 expression in the hippocampal subregions (particularly, a significant decrease in the level in the CA3) were detected by immunofluorescence. This study suggests that the contributions of SREBP-1c to the structural plasticity of the mouse hippocampus may have underlain the behavioral alterations. These findings offer insights into the critical role of SREBP-1c in hippocampal functioning in mice.
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Lasunción MA, Martínez-Botas J, Martín-Sánchez C, Busto R, Gómez-Coronado D. Cell cycle dependence on the mevalonate pathway: Role of cholesterol and non-sterol isoprenoids. Biochem Pharmacol 2021; 196:114623. [PMID: 34052188 DOI: 10.1016/j.bcp.2021.114623] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/25/2021] [Accepted: 05/25/2021] [Indexed: 12/16/2022]
Abstract
The mevalonate pathway is responsible for the synthesis of isoprenoids, including sterols and other metabolites that are essential for diverse biological functions. Cholesterol, the main sterol in mammals, and non-sterol isoprenoids are in high demand by rapidly dividing cells. As evidence of its importance, many cell signaling pathways converge on the mevalonate pathway and these include those involved in proliferation, tumor-promotion, and tumor-suppression. As well as being a fundamental building block of cell membranes, cholesterol plays a key role in maintaining their lipid organization and biophysical properties, and it is crucial for the function of proteins located in the plasma membrane. Importantly, cholesterol and other mevalonate derivatives are essential for cell cycle progression, and their deficiency blocks different steps in the cycle. Furthermore, the accumulation of non-isoprenoid mevalonate derivatives can cause DNA replication stress. Identification of the mechanisms underlying the effects of cholesterol and other mevalonate derivatives on cell cycle progression may be useful in the search for new inhibitors, or the repurposing of preexisting cholesterol biosynthesis inhibitors to target cancer cell division. In this review, we discuss the dependence of cell division on an active mevalonate pathway and the role of different mevalonate derivatives in cell cycle progression.
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Affiliation(s)
- Miguel A Lasunción
- Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, Madrid, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Spain.
| | - Javier Martínez-Botas
- Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, Madrid, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Spain
| | - Covadonga Martín-Sánchez
- Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, Madrid, Spain
| | - Rebeca Busto
- Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, Madrid, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Spain
| | - Diego Gómez-Coronado
- Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, Madrid, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Spain.
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Park G, Jung S, Wellen KE, Jang C. The interaction between the gut microbiota and dietary carbohydrates in nonalcoholic fatty liver disease. Exp Mol Med 2021; 53:809-822. [PMID: 34017059 PMCID: PMC8178320 DOI: 10.1038/s12276-021-00614-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 03/24/2021] [Indexed: 02/04/2023] Open
Abstract
Imbalance between fat production and consumption causes various metabolic disorders. Nonalcoholic fatty liver disease (NAFLD), one such pathology, is characterized by abnormally increased fat synthesis and subsequent fat accumulation in hepatocytes1,2. While often comorbid with obesity and insulin resistance, this disease can also be found in lean individuals, suggesting specific metabolic dysfunction2. NAFLD has become one of the most prevalent liver diseases in adults worldwide, but its incidence in both children and adolescents has also markedly increased in developed nations3,4. Progression of this disease into nonalcoholic steatohepatitis (NASH), cirrhosis, liver failure, and hepatocellular carcinoma in combination with its widespread incidence thus makes NAFLD and its related pathologies a significant public health concern. Here, we review our understanding of the roles of dietary carbohydrates (glucose, fructose, and fibers) and the gut microbiota, which provides essential carbon sources for hepatic fat synthesis during the development of NAFLD.
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Affiliation(s)
- Grace Park
- Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
| | - Sunhee Jung
- Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
| | - Kathryn E Wellen
- Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Cholsoon Jang
- Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA.
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Shin HS, Lee Y, Shin MH, Cho SI, Zouboulis CC, Kim MK, Lee DH, Chung JH. Histone Deacetylase 1 Reduces Lipogenesis by Suppressing SREBP1 Transcription in Human Sebocyte Cell Line SZ95. Int J Mol Sci 2021; 22:ijms22094477. [PMID: 33922983 PMCID: PMC8123291 DOI: 10.3390/ijms22094477] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/16/2021] [Accepted: 04/23/2021] [Indexed: 01/19/2023] Open
Abstract
Proper regulation of sebum production is important for maintaining skin homeostasis in humans. However, little is known about the role of epigenetic regulation in sebocyte lipogenesis. We investigated histone acetylation changes and their role in key lipogenic gene regulation during sebocyte lipogenesis using the human sebaceous gland cell line SZ95. Sebocyte lipogenesis is associated with a significant increase in histone acetylation. Treatment with anacardic acid (AA), a p300 histone acetyltransferase inhibitor, significantly decreased the lipid droplet number and the expression of key lipogenic genes, including sterol regulatory-binding protein 1 (SREBP1), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). In contrast, treatment with trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, increased the expression of these genes. Global HDAC enzyme activity was decreased, and HDAC1 and HDAC2 expression was downregulated during sebaceous lipogenesis. Interestingly, HDAC1 knockdown increased lipogenesis through SREBP1 induction, whereas HDAC1 overexpression decreased lipogenesis and significantly suppressed SREBP1 promoter activity. HDAC1 and SREBP1 levels were inversely correlated in human skin sebaceous glands as demonstrated in immunofluorescence images. In conclusion, HDAC1 plays a critical role in reducing SREBP1 transcription, leading to decreased sebaceous lipogenesis. Therefore, HDAC1 activation could be an effective therapeutic strategy for skin diseases related to excessive sebum production.
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Affiliation(s)
- Hye Sun Shin
- Department of Dermatology, Seoul National University College of Medicine, Seoul 03080, Korea; (H.S.S.); (Y.L.); (M.H.S.); (S.I.C.)
- Department of Biomedical Sciences, Graduate School, Seoul National University, Seoul 03080, Korea
- Medical Research Center, Institute of Human-Environment Interface Biology, Seoul National University, Seoul 03080, Korea
| | - Yuri Lee
- Department of Dermatology, Seoul National University College of Medicine, Seoul 03080, Korea; (H.S.S.); (Y.L.); (M.H.S.); (S.I.C.)
- Department of Biomedical Sciences, Graduate School, Seoul National University, Seoul 03080, Korea
- Medical Research Center, Institute of Human-Environment Interface Biology, Seoul National University, Seoul 03080, Korea
| | - Mi Hee Shin
- Department of Dermatology, Seoul National University College of Medicine, Seoul 03080, Korea; (H.S.S.); (Y.L.); (M.H.S.); (S.I.C.)
- Medical Research Center, Institute of Human-Environment Interface Biology, Seoul National University, Seoul 03080, Korea
| | - Soo Ick Cho
- Department of Dermatology, Seoul National University College of Medicine, Seoul 03080, Korea; (H.S.S.); (Y.L.); (M.H.S.); (S.I.C.)
- Medical Research Center, Institute of Human-Environment Interface Biology, Seoul National University, Seoul 03080, Korea
| | - Christos C. Zouboulis
- Dessau Medical Center, Departments of Dermatology, Venereology, Allergology and Immunology, Faculty of Health Sciences Brandenburg, Brandenburg Medical School Theodor Fontane, 06847 Dessau, Germany;
| | - Min Kyoung Kim
- Department of Dermatology, Seoul National University College of Medicine, Seoul 03080, Korea; (H.S.S.); (Y.L.); (M.H.S.); (S.I.C.)
- Medical Research Center, Institute of Human-Environment Interface Biology, Seoul National University, Seoul 03080, Korea
- Correspondence: (M.-K.K.); (D.H.L.); (J.H.C.)
| | - Dong Hun Lee
- Department of Dermatology, Seoul National University College of Medicine, Seoul 03080, Korea; (H.S.S.); (Y.L.); (M.H.S.); (S.I.C.)
- Medical Research Center, Institute of Human-Environment Interface Biology, Seoul National University, Seoul 03080, Korea
- Correspondence: (M.-K.K.); (D.H.L.); (J.H.C.)
| | - Jin Ho Chung
- Department of Dermatology, Seoul National University College of Medicine, Seoul 03080, Korea; (H.S.S.); (Y.L.); (M.H.S.); (S.I.C.)
- Department of Biomedical Sciences, Graduate School, Seoul National University, Seoul 03080, Korea
- Medical Research Center, Institute of Human-Environment Interface Biology, Seoul National University, Seoul 03080, Korea
- Institute on Aging, Seoul National University, Seoul 03080, Korea
- Correspondence: (M.-K.K.); (D.H.L.); (J.H.C.)
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Martinat M, Rossitto M, Di Miceli M, Layé S. Perinatal Dietary Polyunsaturated Fatty Acids in Brain Development, Role in Neurodevelopmental Disorders. Nutrients 2021; 13:1185. [PMID: 33918517 PMCID: PMC8065891 DOI: 10.3390/nu13041185] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/30/2021] [Accepted: 03/30/2021] [Indexed: 12/26/2022] Open
Abstract
n-3 and n-6 polyunsaturated fatty acids (PUFAs) are essential fatty acids that are provided by dietary intake. Growing evidence suggests that n-3 and n-6 PUFAs are paramount for brain functions. They constitute crucial elements of cellular membranes, especially in the brain. They are the precursors of several metabolites with different effects on inflammation and neuron outgrowth. Overall, long-chain PUFAs accumulate in the offspring brain during the embryonic and post-natal periods. In this review, we discuss how they accumulate in the developing brain, considering the maternal dietary supply, the polymorphisms of genes involved in their metabolism, and the differences linked to gender. We also report the mechanisms linking their bioavailability in the developing brain, their transfer from the mother to the embryo through the placenta, and their role in brain development. In addition, data on the potential role of altered bioavailability of long-chain n-3 PUFAs in the etiologies of neurodevelopmental diseases, such as autism, attention deficit and hyperactivity disorder, and schizophrenia, are reviewed.
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