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Rashidpour A, Wu Y, Almajano MP, Fàbregas A, Metón I. Chitosan-Based Sustained Expression of Sterol Regulatory Element-Binding Protein 1a Stimulates Hepatic Glucose Oxidation and Growth in Sparus aurata. Mar Drugs 2023; 21:562. [PMID: 37999386 PMCID: PMC10672111 DOI: 10.3390/md21110562] [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: 10/06/2023] [Revised: 10/18/2023] [Accepted: 10/25/2023] [Indexed: 11/25/2023] Open
Abstract
The administration of a single dose of chitosan nanoparticles driving the expression of sterol regulatory element-binding protein 1a (SREBP1a) was recently associated with the enhanced conversion of carbohydrates into lipids. To address the effects of the long-lasting expression of SREBP1a on the growth and liver intermediary metabolism of carnivorous fish, chitosan-tripolyphosphate (TPP) nanoparticles complexed with a plasmid expressing the N terminal active domain of hamster SREBP1a (pSG5-SREBP1a) were injected intraperitoneally every 4 weeks (three doses in total) to gilthead sea bream (Sparus aurata) fed high-protein-low-carbohydrate and low-protein-high-carbohydrate diets. Following 70 days of treatment, chitosan-TPP-pSG5-SREBP1a nanoparticles led to the sustained upregulation of SREBP1a in the liver of S. aurata. Independently of the diet, SREBP1a overexpression significantly increased their weight gain, specific growth rate, and protein efficiency ratio but decreased their feed conversion ratio. In agreement with an improved conversion of dietary carbohydrates into lipids, SREBP1a expression increased serum triglycerides and cholesterol as well as hepatic glucose oxidation via glycolysis and the pentose phosphate pathway, while not affecting gluconeogenesis and transamination. Our findings support that the periodical administration of chitosan-TPP-DNA nanoparticles to overexpress SREBP1a in the liver enhanced the growth performance of S. aurata through a mechanism that enabled protein sparing by enhancing dietary carbohydrate metabolisation.
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Affiliation(s)
- Ania Rashidpour
- Secció de Bioquímica i Biologia Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Joan XXIII 27-31, 08028 Barcelona, Spain
| | - Yuanbing Wu
- Secció de Bioquímica i Biologia Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Joan XXIII 27-31, 08028 Barcelona, Spain
| | - María Pilar Almajano
- Departament d'Enginyeria Química, Universitat Politècnica de Catalunya, Diagonal 647, 08028 Barcelona, Spain
| | - Anna Fàbregas
- Departament de Farmàcia i Tecnologia Farmacèutica, i Fisicoquímica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Joan XXIII 27-31, 08028 Barcelona, Spain
| | - Isidoro Metón
- Secció de Bioquímica i Biologia Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Joan XXIII 27-31, 08028 Barcelona, Spain
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Jeon YG, Kim YY, Lee G, Kim JB. Physiological and pathological roles of lipogenesis. Nat Metab 2023; 5:735-759. [PMID: 37142787 DOI: 10.1038/s42255-023-00786-y] [Citation(s) in RCA: 75] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 03/15/2023] [Indexed: 05/06/2023]
Abstract
Lipids are essential metabolites, which function as energy sources, structural components and signalling mediators. Most cells are able to convert carbohydrates into fatty acids, which are often converted into neutral lipids for storage in the form of lipid droplets. Accumulating evidence suggests that lipogenesis plays a crucial role not only in metabolic tissues for systemic energy homoeostasis but also in immune and nervous systems for their proliferation, differentiation and even pathophysiological roles. Thus, excessive or insufficient lipogenesis is closely associated with aberrations in lipid homoeostasis, potentially leading to pathological consequences, such as dyslipidaemia, diabetes, fatty liver, autoimmune diseases, neurodegenerative diseases and cancers. For systemic energy homoeostasis, multiple enzymes involved in lipogenesis are tightly controlled by transcriptional and post-translational modifications. In this Review, we discuss recent findings regarding the regulatory mechanisms, physiological roles and pathological importance of lipogenesis in multiple tissues such as adipose tissue and the liver, as well as the immune and nervous systems. Furthermore, we briefly introduce the therapeutic implications of lipogenesis modulation.
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Affiliation(s)
- Yong Geun Jeon
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, South Korea
| | - Ye Young Kim
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, South Korea
| | - Gung Lee
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, South Korea
| | - Jae Bum Kim
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, South Korea.
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Jing Y, Hu T, Yuan J, Liu Z, Tao M, Ou M, Cheng X, Cheng W, Yi Y, Xiong Q. Resveratrol protects against postmenopausal atherosclerosis progression through reducing PCSK9 expression via the regulation of the ERα-mediated signaling pathway. Biochem Pharmacol 2023; 211:115541. [PMID: 37030661 DOI: 10.1016/j.bcp.2023.115541] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/28/2023] [Accepted: 03/30/2023] [Indexed: 04/10/2023]
Abstract
Elevated circulating proprotein convertase subtilisin/kexin 9 (PCSK9) levels are an important contributor to postmenopausal atherosclerosis (AS). We have previously reported that resveratrol (RSV), as a phytoestrogen, reduces hepatocyte steatosis and PCSK9 expression in L02 cells. This study aimed to investigate how RSV reduces PCSK9 expression to inhibit postmenopausal AS progression. Here, we found that treatment of Ovx/ApoE -/- mice with RSV significantly reduced dyslipidemia, plasma PCSK9 concentration and aortic plaque area. In addition, RSV significantly inhibited liver fat accumulation and improved the hepatocyte ultrastructure. Further studies showed that RSV upregulated estrogen receptor α (ERα) expression, while reduced the liver X receptor α (LXRα) expression and sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity. In vitro, RSV inhibited insulin-induced elevated intracellular/extracellular PCSK9 levels, enhanced receptor-mediated uptake of low-density lipoproteins in HepG2 cells. Furthermore, RSV attenuated the activity of the SRE-dependent PCSK9 promoter. However, these effects can be partially reversed by the antiestrogen ICI 182,780. Attenuation of these changes with ERα inhibition suggest that RSV may prevent the progression of postmenopausal AS by reducing PCSK9 expression in hepatocytes through ERα-mediated signaling.
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Affiliation(s)
- Yi Jing
- Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huai'an 223003, China.
| | - Tianhui Hu
- Traditional Chinese Medicine Department, Huai'an Maternal and Child Health-Care Center, Huai'an 2230003, China
| | - Jun Yuan
- Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huai'an 223003, China
| | - Zhikun Liu
- Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huai'an 223003, China
| | - Mingtao Tao
- Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huai'an 223003, China
| | - Mingyu Ou
- Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huai'an 223003, China
| | - Xinru Cheng
- Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huai'an 223003, China
| | - Wei Cheng
- Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huai'an 223003, China
| | - Yuanyuan Yi
- The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China
| | - Qingping Xiong
- Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huai'an 223003, China
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Effects of Amino Acids Supplementation on Lipid and Glucose Metabolism in HepG2 Cells. Nutrients 2022; 14:nu14153050. [PMID: 35893906 PMCID: PMC9332103 DOI: 10.3390/nu14153050] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 01/22/2023] Open
Abstract
Non-alcoholic fatty liver disease and type 2 diabetes are representing symptoms of metabolic syndrome, which is often accompanied with hepatic fat accumulation and insulin resistance. Since liver is the major site of glucose and lipid metabolism, this study aimed to understand the effects of SCAAs and BCAAs supplementations on glucose and lipid metabolism in HepG2 cells. These cells were pretreated with SAMe, betaine, taurine, and BCAA for 24 h, followed by treatments of a high concentration of glucose (50 mM) or palmitic acid (PA, 0.5 mM) for 48 h to simulate high-glucose and high-fat environments. Pretreatment of BCAA and SCAAs inhibited the fat accumulation. At the transcriptional level, glucose and PA treatment led to significant increase of mRNA gluconeogenic enzyme. The mRNA expression level of GLUT2 was decreased by 20% in the SAMe-treated group and inhibited glucose synthesis by reducing the level of gluconeogenic enzyme. After SAMe or BCAA pretreatment, the mRNA expression of lipogenic enzymes was decreased. The PPAR-γ expression was increased after BCAA pretreatment, but SAMe not only downregulated the expression of PPAR-γ, but also inhibited the expression of ChREBP approximately 20% and SREBP-1c decreased by about 15%. Taken together, the effect of SAMe on glucose and lipid metabolism is significant especially on inhibiting hepatic lipogenesis and gluconeogenesis under the metabolic syndrome environment.
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Choi Y, Song MJ, Jung WJ, Jeong H, Park S, Yang B, Lee EC, Joo JS, Choi D, Koo SH, Kim EK, Nam KT, Kim HP. Liver-Specific Deletion of Mouse CTCF Leads to Hepatic Steatosis via Augmented PPARγ Signaling. Cell Mol Gastroenterol Hepatol 2021; 12:1761-1787. [PMID: 34358714 PMCID: PMC8551791 DOI: 10.1016/j.jcmgh.2021.07.016] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The liver is the major organ for metabolizing lipids, and malfunction of the liver leads to various diseases. Nonalcoholic fatty liver disease is rapidly becoming a major health concern worldwide and is characterized by abnormal retention of excess lipids in the liver. CCCTC-binding factor (CTCF) is a highly conserved zinc finger protein that regulates higher-order chromatin organization and is involved in various gene regulation processes. Here, we sought to determine the physiological role of CTCF in hepatic lipid metabolism. METHODS We generated liver-specific, CTCF-ablated and/or CD36 whole-body knockout mice. Overexpression or knockdown of peroxisome proliferator-activated receptor (PPAR)γ in the liver was achieved using adenovirus. Mice were examined for development of hepatic steatosis and inflammation. RNA sequencing was performed to identify genes affected by CTCF depletion. Genome-wide occupancy of H3K27 acetylation, PPARγ, and CTCF were analyzed by chromatin immunoprecipitation sequencing. Genome-wide chromatin interactions were analyzed by in situ Hi-C. RESULTS Liver-specific, CTCF-deficient mice developed hepatic steatosis and inflammation when fed a standard chow diet. Global analysis of the transcriptome and enhancer landscape revealed that CTCF-depleted liver showed enhanced accumulation of PPARγ in the nucleus, which leads to increased expression of its downstream target genes, including fat storage-related gene CD36, which is involved in the lipid metabolic process. Hepatic steatosis developed in liver-specific, CTCF-deficient mice was ameliorated by repression of PPARγ via pharmacologic blockade or adenovirus-mediated knockdown, but hardly rescued by additional knockout of CD36. CONCLUSIONS Our data indicate that liver-specific deletion of CTCF leads to hepatosteatosis through augmented PPARγ DNA-binding activity, which up-regulates its downstream target genes associated with the lipid metabolic process.
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Affiliation(s)
- Yeeun Choi
- Department of Environmental Medical Biology, Institute of Tropical Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Seoul, Korea
| | - Min-Ji Song
- Department of Environmental Medical Biology, Institute of Tropical Medicine, Seoul, Korea
| | - Woong-Jae Jung
- Department of Environmental Medical Biology, Institute of Tropical Medicine, Seoul, Korea; Department of Bioinformatics, Graduate School of Soongsil University, Seoul, Korea
| | - Haengdueng Jeong
- Brain Korea 21 Plus Project for Medical Science, Seoul, Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Seokjae Park
- Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea; Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea
| | - Bobae Yang
- Department of Environmental Medical Biology, Institute of Tropical Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Seoul, Korea
| | - Eun-Chong Lee
- Department of Environmental Medical Biology, Institute of Tropical Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Seoul, Korea
| | - Jung-Sik Joo
- Department of Environmental Medical Biology, Institute of Tropical Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Seoul, Korea
| | - Dahee Choi
- Division of Life Sciences, Korea University, Seoul, Korea
| | - Seung-Hoi Koo
- Division of Life Sciences, Korea University, Seoul, Korea
| | - Eun-Kyoung Kim
- Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea; Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea
| | - Ki Taek Nam
- Brain Korea 21 Plus Project for Medical Science, Seoul, Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Hyoung-Pyo Kim
- Department of Environmental Medical Biology, Institute of Tropical Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Seoul, Korea.
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Ham JR, Lee MJ, Lee HI, Lee HJ, Kim HY, Seo WD, Son YJ, Lee MK. Anti-Diabetic Activity of Heuksoojeongchal Bran Prethanol Extract in HFD/STZ-Induced Diabetic Mice. JOURNAL OF THE KOREAN SOCIETY OF FOOD SCIENCE AND NUTRITION 2021; 50:655-663. [DOI: 10.3746/jkfn.2021.50.7.655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/09/2021] [Accepted: 04/16/2021] [Indexed: 04/21/2025]
Affiliation(s)
- Ju Ri Ham
- Mokpo Marine Food-Industry Research Center
| | - Mi Ja Lee
- Crop Foundation Division, National Institute of Crop Science
| | - Hae-In Lee
- Department of Food & Nutrition, Sunchon National University
| | - Hyun-Jin Lee
- Crop Foundation Division, National Institute of Crop Science
| | - Hyun Young Kim
- Crop Foundation Division, National Institute of Crop Science
| | - Woo Duck Seo
- Crop Foundation Division, National Institute of Crop Science
| | | | - Mi-Kyung Lee
- Department of Food & Nutrition, Sunchon National University
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Ge Y, Li B, Yang Y, Feng C, Tang X, Shi Y, Le G, Sun J. Oxidized Pork Induces Disorders of Glucose Metabolism in Mice. Mol Nutr Food Res 2021; 65:e2000859. [PMID: 33502107 DOI: 10.1002/mnfr.202000859] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 12/21/2020] [Indexed: 02/27/2024]
Abstract
SCOPE Consumption of red meat, particularly processed red meat, has been reported to be associated with type 2 diabetes risk, and oxidized proteins and amino acids may be involved in this process. This study explores the effects of pork with varying degrees of oxidative injury caused by cooking on glucose metabolism in mice. METHODS AND RESULTS Cooked pork is freeze-dried to prepare animal feed. Mice are fed either a control diet (CON), a low- (LOP), or a high-oxidative injury pork diet (HOP) for 12 weeks. Intake of HOP causes hyperglycemia, hypoinsulinemia, and impaired glucose tolerance, indicating a glucose metabolism disorder. Accumulation of oxidation products increases oxidative stress and inflammatory response, which impairs pancreatic islet β cells function and reduces insulin secretion. Moreover, HOP-mediated hyperglycemia can be partly attributed to elevated hepatic glucose output, as indicated by increased gluconeogenesis and glycogenolysis, and decreased glycolysis and glycogen content. Changes in these processes may be regulated by reduced insulin levels and suppression of the insulin receptor substrate-1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway and its downstream signaling molecules. CONCLUSION HOP intake induces disorders of glucose metabolism by impairing pancreatic insulin secretion and increasing hepatic glucose output. Protein oxidation plays a key role in abnormal glucose metabolism induced by HOP.
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Affiliation(s)
- Yueting Ge
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
- Center for Food Nutrition and Functional Food Engineering, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Bowen Li
- Center for Food Nutrition and Functional Food Engineering, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Yuhui Yang
- College of Grain and Food Science, Henan University of Technology, Zhengzhou, 450001, China
| | - Chuanxing Feng
- Center for Food Nutrition and Functional Food Engineering, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Xue Tang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
- Center for Food Nutrition and Functional Food Engineering, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Yonghui Shi
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
- Center for Food Nutrition and Functional Food Engineering, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Guowei Le
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
- Center for Food Nutrition and Functional Food Engineering, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Jin Sun
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
- Institute of Nutrition and Health, Qingdao University, Qingdao, 266071, China
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Low Molecular Weight Barley β-Glucan Affects Glucose and Lipid Metabolism by Prebiotic Effects. Nutrients 2020; 13:nu13010130. [PMID: 33396447 PMCID: PMC7823751 DOI: 10.3390/nu13010130] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/29/2020] [Accepted: 12/29/2020] [Indexed: 12/14/2022] Open
Abstract
We investigated the effect of low molecular weight barley β-glucan (LMW-BG) on cecal fermentation, glucose, and lipid metabolism through comparisons to high molecular weight β-glucan (HMW-BG). C57BL/6J male mice were fed a moderate-fat diet for 61 days. LMW-BG or HMW-BG was added to the diet corresponding to 4% β-glucan. We measured the apparent absorption of fat, serum biomarkers, the expression levels of genes involved in glucose and lipid metabolism in the liver and ileum, and bacterial counts of the major microbiota groups using real time PCR. The concentration of short-chain fatty acids (SCFAs) in the cecum was analyzed by GC/MS. Significant reductions in serum leptin, total- and LDL-cholesterol concentrations, and mRNA expression levels of sterol regulatory element-binding protein-1c (SREBP-1c) were observed in both BG groups. HMW-BG specific effects were observed in inhibiting fat absorption and reducing abdominal deposit fat, whereas LMW-BG specific effects were observed in increasing bacterial counts of Bifidobacterium and Bacteroides and cecal total SCFAs, acetate, and propionate. mRNA expression of neurogenin 3 was increased in the LMW-BG group. We report that LMW-BG affects glucose and lipid metabolism via a prebiotic effect, whereas the high viscosity of HMW-BG in the digestive tract is responsible for its specific effects.
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Li YZ, Di Cristofano A, Woo M. Metabolic Role of PTEN in Insulin Signaling and Resistance. Cold Spring Harb Perspect Med 2020; 10:a036137. [PMID: 31964643 PMCID: PMC7397839 DOI: 10.1101/cshperspect.a036137] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Phosphatase and tensin homolog (PTEN) is most prominently known for its function in tumorigenesis. However, a metabolic role of PTEN is emerging as a result of its altered expression in type 2 diabetes (T2D), which results in impaired insulin signaling and promotion of insulin resistance during the pathogenesis of T2D. PTEN functions in regulating insulin signaling across different organs have been identified. Through the use of a variety of models, such as tissue-specific knockout (KO) mice and in vitro cell cultures, PTEN's role in regulating insulin action has been elucidated across many cell types. Herein, we will review the recent advancements in the understanding of PTEN's metabolic functions in each of the tissues and cell types that contribute to regulating systemic insulin sensitivity and discuss how PTEN may represent a promising therapeutic strategy for treatment or prevention of T2D.
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Affiliation(s)
- Yu Zhe Li
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario M5G 2M9, Canada
| | - Antonio Di Cristofano
- Department of Developmental and Molecular Biology and Medicine (Oncology), Albert Einstein College of Medicine and Albert Einstein Cancer Center, Bronx, New York 10461, USA
| | - Minna Woo
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario M5G 2M9, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario M5G 2M9, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, University Health Network/Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 2C4, Canada
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Aweya JJ, Zheng X, Zheng Z, Wang W, Fan J, Yao D, Li S, Zhang Y. The sterol regulatory element binding protein homolog of Penaeus vannamei modulates fatty acid metabolism and immune response. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158757. [PMID: 32544537 DOI: 10.1016/j.bbalip.2020.158757] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 06/04/2020] [Accepted: 06/07/2020] [Indexed: 01/28/2023]
Abstract
The sterol regulatory element binding proteins (SREBPs) transcription factors family, which regulate the expression of genes involved in cellular lipid metabolism and homeostasis, have recently been implicated in various physiological and pathophysiological processes such as immune regulation and inflammation in vertebrates. Consistent with other invertebrates, we identified a single SREBP ortholog in Penaeus vannamei (designated PvSREBP) with transcripts ubiquitously expressed in tissues and induced by lipopolysaccharide (LPS), Vibrio parahaemolyticus and Streptococcus iniae. In vivo RNA interference (RNAi) of PvSREBP attenuated the expression of several fatty acid metabolism-related genes (i.e., cyclooxygenase (PvCOX), lipoxygenase (PvLOX), fatty acid binding protein (PvFABP) and fatty acid synthase (PvFASN)), which consequently decreased the levels of total polyunsaturated fatty acids (ΣPUFAs). In addition, PvSREBP silencing decreased transcript levels of several immune-related genes such as hemocyanin (PvHMC) and trypsin (PvTrypsin), as well as genes encoding for heat-shock proteins (i.e., PvHSP60, PvHSP70 and PvHSP90). Moreover, in silico analysis revealed the presence of SREBP binding motifs on the promoters of most of the dysregulated genes, while shrimp depleted of PvSREBP were more susceptible to V. parahaemolyticus infection. Collectively, we demonstrated the involvement of shrimp SREBP in fatty acids metabolism and immune response, and propose that PvSREBP and PvHMC modulate each other through a feedback mechanism to establish homeostasis. The current study is the first to show the dual role of SREBP in fatty acid metabolism and immune response in invertebrates and crustaceans.
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Affiliation(s)
- Jude Juventus Aweya
- Institute of Marine Sciences, Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou 515063, China
| | - Xiaoyu Zheng
- Institute of Marine Sciences, Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou 515063, China
| | - Zhihong Zheng
- Institute of Marine Sciences, Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou 515063, China
| | - Wei Wang
- Institute of Marine Sciences, Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou 515063, China
| | - Jiaohong Fan
- Institute of Marine Sciences, Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou 515063, China
| | - Defu Yao
- Institute of Marine Sciences, Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou 515063, China
| | - Shengkang Li
- Institute of Marine Sciences, Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou 515063, China
| | - Yueling Zhang
- Institute of Marine Sciences, Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou 515063, China.
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Nam SJ, Chung SI, Kang MY. Acidic-Treated Acorn Pollen as Health Functional Food Materials for Improvement of Post-Menopausal Glucose Metabolism. Prev Nutr Food Sci 2020; 25:50-57. [PMID: 32292755 PMCID: PMC7143018 DOI: 10.3746/pnf.2020.25.1.50] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 01/17/2020] [Indexed: 11/14/2022] Open
Abstract
Pollen has high physiological value because it contains protein, essential amino acids, and 16 vitamins. However, pollen is difficult to absorb because of its hard form. This study explores the use of the acid-treated acorn pollen (acorn pollen deposited in apple vinegar for 30 days). The health functions of acid-treated acorn pollen on post-menopausal metabolism was tested by analyzing in vitro and in vivo biomarkers for glucose metabolism, by using the acid-treated acorn pollen and its residues, respectively. In vitro experiments showed high activity after measuring the low potency of glucose-related enzymes. In vivo experiments showed reduced blood glucose and insulin levels after consuming pollen. Pollen also increased the concentration of glucokinase, a glucose-regulating enzyme in hepatic and nephritic tissue, and lowered the concentration of glucose-6-phosphatase. These results are encouraging in showing that acid pollen can be used as a functional health food for treatment of post-menopausal metabolism.
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Affiliation(s)
- Su Jin Nam
- Department of Food Sciences and Nutrition, Kyungpook National University, Daegu 41566, Korea
| | - Soo Im Chung
- International Agricultural Training Center, Kyungpook National University, Daegu 41566, Korea
| | - Mi Young Kang
- Department of Food Sciences and Nutrition, Kyungpook National University, Daegu 41566, Korea
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Effect of acrylamide on glucose homeostasis in female rats and its mechanisms. Food Chem Toxicol 2020; 135:110894. [DOI: 10.1016/j.fct.2019.110894] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 10/12/2019] [Accepted: 10/16/2019] [Indexed: 12/20/2022]
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13
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Silva-Marrero JI, Villasante J, Rashidpour A, Palma M, Fàbregas A, Almajano MP, Viegas I, Jones JG, Miñarro M, Ticó JR, Baanante IV, Metón I. The Administration of Chitosan-Tripolyphosphate-DNA Nanoparticles to Express Exogenous SREBP1a Enhances Conversion of Dietary Carbohydrates into Lipids in the Liver of Sparus aurata. Biomolecules 2019; 9:biom9080297. [PMID: 31344838 PMCID: PMC6724022 DOI: 10.3390/biom9080297] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 07/16/2019] [Accepted: 07/19/2019] [Indexed: 12/12/2022] Open
Abstract
In addition to being essential for the transcription of genes involved in cellular lipogenesis, increasing evidence associates sterol regulatory element binding proteins (SREBPs) with the transcriptional control of carbohydrate metabolism. The aim of this study was to assess the effect of overexpression SREBP1a, a potent activator of all SREBP-responsive genes, on the intermediary metabolism of Sparus aurata, a glucose-intolerant carnivorous fish. Administration of chitosan-tripolyphosphate nanoparticles complexed with a plasmid driving expression of the N-terminal transactivation domain of SREBP1a significantly increased SREBP1a mRNA and protein in the liver of S. aurata. Overexpression of SREBP1a enhanced the hepatic expression of key genes in glycolysis-gluconeogenesis (glucokinase and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase), fatty acid synthesis (acetyl-CoA carboxylase 1 and acetyl-CoA carboxylase 2), elongation (elongation of very long chain fatty acids protein 5) and desaturation (fatty acid desaturase 2) as well as reduced nicotinamide adenine dinucleotide phosphate production (glucose-6-phosphate 1-dehydrogenase) and cholesterol synthesis (3-hydroxy-3-methylglutaryl-coenzyme A reductase), leading to increased blood triglycerides and cholesterol levels. Beyond reporting the first study addressing in vivo effects of exogenous SREBP1a in a glucose-intolerant model, our findings support that SREBP1a overexpression caused multigenic effects that favoured hepatic glycolysis and lipogenesis and thus enabled protein sparing by improving dietary carbohydrate conversion into fatty acids and cholesterol.
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Affiliation(s)
- Jonás I Silva-Marrero
- Secció de Bioquímica i Biologia Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Joan XXIII 27-31, 08028 Barcelona, Spain
| | - Juliana Villasante
- Secció de Bioquímica i Biologia Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Joan XXIII 27-31, 08028 Barcelona, Spain
- Departament d'Enginyeria Química, Universitat Politècnica de Catalunya, Diagonal 647, 08028 Barcelona, Spain
| | - Ania Rashidpour
- Secció de Bioquímica i Biologia Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Joan XXIII 27-31, 08028 Barcelona, Spain
| | - Mariana Palma
- Center for Functional Ecology (CFE), Department Life Sciences, University of Coimbra, Calçada Martins de Freitas, 3000-456 Coimbra, Portugal
| | - Anna Fàbregas
- Departament de Farmàcia i Tecnologia Farmacèutica, i Fisicoquímica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Joan XXIII 27-31, 08028 Barcelona, Spain
| | - María Pilar Almajano
- Departament d'Enginyeria Química, Universitat Politècnica de Catalunya, Diagonal 647, 08028 Barcelona, Spain
| | - Ivan Viegas
- Center for Functional Ecology (CFE), Department Life Sciences, University of Coimbra, Calçada Martins de Freitas, 3000-456 Coimbra, Portugal
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal
| | - John G Jones
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal
| | - Montserrat Miñarro
- Departament de Farmàcia i Tecnologia Farmacèutica, i Fisicoquímica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Joan XXIII 27-31, 08028 Barcelona, Spain
| | - Josep R Ticó
- Departament de Farmàcia i Tecnologia Farmacèutica, i Fisicoquímica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Joan XXIII 27-31, 08028 Barcelona, Spain
| | - Isabel V Baanante
- Secció de Bioquímica i Biologia Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Joan XXIII 27-31, 08028 Barcelona, Spain
| | - Isidoro Metón
- Secció de Bioquímica i Biologia Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Joan XXIII 27-31, 08028 Barcelona, Spain.
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14
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Regulation of liver receptor homologue-1 by DDB2 E3 ligase activity is critical for hepatic glucose metabolism. Sci Rep 2019; 9:5304. [PMID: 30923324 PMCID: PMC6438966 DOI: 10.1038/s41598-019-41411-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 02/07/2019] [Indexed: 02/07/2023] Open
Abstract
Liver receptor homologue-1 (LRH-1) plays a critical role in hepatic metabolism and disease. Here we show that LRH-1 protein stability is regulated by the cullin 4 (CUL4) E3 ubiquitin ligase complex. We found that DNA damage-binding protein 2 (DDB2) directly interacts with LRH-1 and functions as a substrate recognition component of CUL4-DDB1 to promote LRH-1 ubiquitination and proteasomal degradation. In human hepatoma (HepG2) cells, we observed that protein levels of endogenous LRH-1 are increased by insulin without a change in mRNA levels of LRH-1. However, overexpression of DDB2 impaired the insulin-stimulated increase in LRH-1 levels. In addition, DDB2 overexpression decreased LRH-1 transcriptional activation and expression of target genes, such as glucokinase, whereas knockdown of DDB2 increased the expression of glucokinase. Finally, we demonstrated that DDB2 knockdown increases glucose uptake and intracellular levels of glucose-6-phosphate in HepG2 cells. Our study reveals a novel regulatory mechanism of LRH-1 activity and suggests a role for DDB2 in hepatic glucose metabolism.
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15
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Ontawong A, Boonphang O, Pasachan T, Duangjai A, Pongchaidecha A, Phatsara M, Jinakote M, Amornlerdpison D, Srimaroeng C. Hepatoprotective effect of coffee pulp aqueous extract combined with simvastatin against hepatic steatosis in high-fat diet-induced obese rats. J Funct Foods 2019. [DOI: 10.1016/j.jff.2019.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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16
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Beddow SA, Gattu AK, Vatner DF, Paolella L, Alqarzaee A, Tashkandi N, Popov VB, Church CD, Rodeheffer MS, Cline GW, Geisler JG, Bhanot S, Samuel VT. PEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed Rats. Endocrinology 2019; 160:205-219. [PMID: 30445425 PMCID: PMC6307100 DOI: 10.1210/en.2018-00630] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 11/06/2018] [Indexed: 11/19/2022]
Abstract
The increased hepatic gluconeogenesis in type 2 diabetes mellitus has often been ascribed to increased transcription of phosphoenolpyruvate carboxykinase 1, cystolic form (PEPCK1), although recent evidence has questioned this attribution. To assess the metabolic role of PEPCK1, we treated regular chow fed and high-fat fed (HFF) male Sprague-Dawley rats with a 2'-O-methoxyethyl chimeric antisense oligonucleotide (ASO) against PEPCK1 and compared them with control ASO-treated rats. PEPCK1 ASO effectively decreased PEPCK1 expression in the liver and white adipose tissue. In chow fed rats, PEPCK1 ASO did not alter adiposity, plasma glucose, or insulin. In contrast, PEPCK1 ASO decreased the white adipose tissue mass in HFF rats but without altering basal rates of lipolysis, de novo lipogenesis, or glyceroneogenesis in vivo. Despite the protection from adiposity, hepatic insulin sensitivity was impaired in HFF PEPCK1 ASO-treated rats. PEPCK1 ASO worsened hepatic steatosis, although without additional impairments in hepatic insulin signaling or activation of inflammatory signals in the liver. Instead, the development of hepatic insulin resistance and the decrease in hepatic glycogen synthesis during a hyperglycemic clamp was attributed to a decrease in hepatic glucokinase (GCK) expression and decreased synthesis of glycogen via the direct pathway. The decrease in GCK expression was associated with increased expression of activating transcription factor 3, a negative regulator of GCK transcription. These studies have demonstrated that PEPCK1 is integral to coordinating cellular metabolism in the liver and adipose tissue, although it does not directly effect hepatic glucose production or adipose glyceroneogenesis.
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Affiliation(s)
- Sara A Beddow
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
- West Haven Veterans Affairs Medical Center, West Haven, Connecticut
| | - Arijeet K Gattu
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
- West Haven Veterans Affairs Medical Center, West Haven, Connecticut
| | - Daniel F Vatner
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Lauren Paolella
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
- West Haven Veterans Affairs Medical Center, West Haven, Connecticut
| | | | - Nedda Tashkandi
- West Haven Veterans Affairs Medical Center, West Haven, Connecticut
| | - Violeta B Popov
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Christopher D Church
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Matthew S Rodeheffer
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Gary W Cline
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | | | | | - Varman T Samuel
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
- West Haven Veterans Affairs Medical Center, West Haven, Connecticut
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17
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Ahn YH. A Journey to Understand Glucose Homeostasis: Starting from Rat Glucose Transporter Type 2 Promoter Cloning to Hyperglycemia. Diabetes Metab J 2018; 42:465-471. [PMID: 30398040 PMCID: PMC6300444 DOI: 10.4093/dmj.2018.0116] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 08/08/2018] [Indexed: 12/24/2022] Open
Abstract
My professional journey to understand the glucose homeostasis began in the 1990s, starting from cloning of the promoter region of glucose transporter type 2 (GLUT2) gene that led us to establish research foundation of my group. When I was a graduate student, I simply thought that hyperglycemia, a typical clinical manifestation of type 2 diabetes mellitus (T2DM), could be caused by a defect in the glucose transport system in the body. Thus, if a molecular mechanism controlling glucose transport system could be understood, treatment of T2DM could be possible. In the early 70s, hyperglycemia was thought to develop primarily due to a defect in the muscle and adipose tissue; thus, muscle/adipose tissue type glucose transporter (GLUT4) became a major research interest in the diabetology. However, glucose utilization occurs not only in muscle/adipose tissue but also in liver and brain. Thus, I was interested in the hepatic glucose transport system, where glucose storage and release are the most actively occurring.
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Affiliation(s)
- Yong Ho Ahn
- Department of Biochemistry and Molecular Biology, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.
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18
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Bifari F, Manfrini R, Dei Cas M, Berra C, Siano M, Zuin M, Paroni R, Folli F. Multiple target tissue effects of GLP-1 analogues on non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Pharmacol Res 2018; 137:219-229. [PMID: 30359962 DOI: 10.1016/j.phrs.2018.09.025] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Revised: 09/11/2018] [Accepted: 09/24/2018] [Indexed: 12/12/2022]
Abstract
Accumulating experimental and clinical evidences over the last decade indicate that GLP-1 analogues have a series of central nervous system and peripheral target tissues actions which are able to significantly influence the liver metabolism. GLP-1 analogues pleiotropic effects proved to be efficacious in T2DM subjects not only reducing liver steatosis and ameliorating NAFLD and NASH, but also in lowering plasma glucose and liver inflammation, improving cardiac function and protecting from kidney dysfunction. While the experimental and clinical data are robust, the precise mechanisms of action potentially involved in these protective multi-target effects need further investigation. Here we present a systematic review of the most recent literature data on the multi-target effects of GLP-1 analogues on the liver, on adipose and muscular tissue and on the nervous system, all capable of influencing significant aspects of the fatty liver disease physiopathology. From this analysis, we can conclude that the multi-target beneficial action of the GLP-1 analogues could explain the positive effects observed in animal and human models on progression of NAFLD to NASH.
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Affiliation(s)
- Francesco Bifari
- Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Roberto Manfrini
- Department of Internal Medicine ASST Santi Paolo e Carlo, Milan, Italy
| | - Michele Dei Cas
- Laboratory of Clinical Biochemistry and Mass Spectrometry, Department of Health Science, University of Milan, Milan, Italy
| | - Cesare Berra
- Metabolic Disease and Diabetes, Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Matteo Siano
- Department of Internal Medicine ASST Santi Paolo e Carlo, Milan, Italy
| | - Massimo Zuin
- Unit of Medicine, Gastroenterology and Hepatology, Milan, Italy
| | - Rita Paroni
- Laboratory of Clinical Biochemistry and Mass Spectrometry, Department of Health Science, University of Milan, Milan, Italy
| | - Franco Folli
- Unit of Endocrinology and Metabolism ASST Santi Paolo e Carlo, Department of Health Science, University of Milan, Milan, Italy.
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19
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Abstract
PURPOSE OF REVIEW Insulin resistance (IR) is recognized to play an important role in the pathogenesis of dyslipidemia. This review summarizes the complex interplay between IR and dyslipidemia in people with and without diabetes. RECENT FINDINGS IR impacts the metabolism of triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and very low-density lipoprotein cholesterol (VLDL-C) by several mechanisms. Trials with insulin sensitizing therapies, including biguanides and thiazolidinediones, have provided inconsistent results on lipid lowering in people with and without diabetes. In this review, we focus on the pathophysiological interplay between IR and dyslipidemia and recapitulate lipid and lipoprotein data from insulin-sensitizing trials. Further research elucidating the reciprocal relationship between IR and dyslipidemia is needed to better target these important risk factors for cardiovascular disease.
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Affiliation(s)
- Petter Bjornstad
- Department of Pediatrics, Division of Endocrinology, University of Colorado School of Medicine, 13123 East 16th Ave, Box B26, Aurora, CO, 80045, USA.
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, CO, USA.
| | - Robert H Eckel
- Department of Medicine, Division of Endocrinology and Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA.
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20
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Pérez-García A, Dongil P, Hurtado-Carneiro V, Blazquez E, Sanz C, Alvarez E. PAS Kinase deficiency alters the glucokinase function and hepatic metabolism. Sci Rep 2018; 8:11091. [PMID: 30038292 PMCID: PMC6056484 DOI: 10.1038/s41598-018-29234-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 07/03/2018] [Indexed: 12/15/2022] Open
Abstract
The liver controls metabolic homeostasis in response to fasting and refeeding periods. Glucokinase (GCK) adjusts hepatic glucose phosphorylation to blood glucose levels, acting as a glucose sensor. Our objective was to determine whether PAS kinase (PASK), a nutrient sensor, could be affecting the expression or activity of liver GCK and the response to fasting and refeeding states of key hepatic metabolic pathways. PASK-deficient mice have impaired insulin signaling (AKT overactivation). Furthermore, PASK deficiency modified the expression of several transcription factors involved in the adjustment to fasting and refeeding. Foxo1 decreased under fasting conditions, while Ppara and Pparg were overexpressed in PASK-deficient mice. However, PEPCK protein levels were similar or higher, while the expression of Cpt1a decreased in PASK-deficient mice. By contrast, Lxra and Chrebp were overexpressed after refeeding, while the expression of Acc and Fas decreased in PASK-deficient mice. Likewise, with a decreased expression of Gck and increased nuclear location of the complex GCK-GCKR, GCK activity decreased in PASK-deficient mice. Therefore, PASK regulated some of the genes and proteins responsible for glucose sensing, such as glucokinase, and for insulin signalling, affecting glucose and lipid metabolism and consequently certain critical hepatic functions.
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Affiliation(s)
- A Pérez-García
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University of Madrid, Institute of Medical Research at the Hospital Clínico San Carlos (IdISSC), Ciudad Universitaria, s/n, 28040, Madrid, Spain.,Department of Cell Biology, Faculty of Medicine, Complutense University of Madrid, Madrid, Spain
| | - P Dongil
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University of Madrid, Institute of Medical Research at the Hospital Clínico San Carlos (IdISSC), Ciudad Universitaria, s/n, 28040, Madrid, Spain.,Department of Cell Biology, Faculty of Medicine, Complutense University of Madrid, Madrid, Spain
| | - V Hurtado-Carneiro
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University of Madrid, Institute of Medical Research at the Hospital Clínico San Carlos (IdISSC), Ciudad Universitaria, s/n, 28040, Madrid, Spain.,Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - E Blazquez
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University of Madrid, Institute of Medical Research at the Hospital Clínico San Carlos (IdISSC), Ciudad Universitaria, s/n, 28040, Madrid, Spain.,Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - C Sanz
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain. .,Department of Cell Biology, Faculty of Medicine, Complutense University of Madrid, Madrid, Spain.
| | - E Alvarez
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University of Madrid, Institute of Medical Research at the Hospital Clínico San Carlos (IdISSC), Ciudad Universitaria, s/n, 28040, Madrid, Spain.,Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
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21
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Zhang D, Yan Y, Tian H, Jiang G, Li X, Liu W. Resveratrol supplementation improves lipid and glucose metabolism in high-fat diet-fed blunt snout bream. FISH PHYSIOLOGY AND BIOCHEMISTRY 2018; 44:163-173. [PMID: 28891024 DOI: 10.1007/s10695-017-0421-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 08/28/2017] [Indexed: 06/07/2023]
Abstract
Here, we aimed to investigate whether resveratrol (RSV) can ameliorate high-fat diet (HFD)-induced metabolic disorder in fish. Blunt snout bream (Megalobrama amblycephala) with average weight 27.99 ± 0.56 g were fed a normal fat diet (NFD, 5% fat, w/w), a HFD (11% fat), or a HFD supplemented with 0.04, 0.36, or 1.08% RSV for 10 weeks. As expected, fish fed a HFD developed hepatic steatosis, as shown by elevated hepatic and plasma triglycerides, raised whole body fat, intraperitoneal fat ratio and hepatosomatic index, and increased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST). RSV supplementation lessened increases in body mass, whole body fat, and intraperitoneal fat, and alleviated development of hepatic steatosis, elevations of plasma triglyceride and glucose, and abnormalities of ALT and AST in HFD-fed fish. RSV supplementation increased SIRT1 messenger RNA (mRNA) expression and consequently hepatic mRNA expression of adipose triglyceride lipase (ATGL), carnitine palmitoyltransferase (CPT1a), and microsomal triglyceride transfer protein (MTTP), implying upregulation of lipolysis, β-oxidation, and lipid transport, respectively, in the liver. Conversely, hepatic lipoprotein lipase (LPL), sterol regulatory element-binding protein 1 (SREBP-1c), peroxisome proliferator-activated receptor γ (PPARγ), and ATP citrate lyase (ACLY) mRNA expression were decreased, implying suppression of fatty acid uptake, lipogenesis, and fatty acid synthesis. Additionally, RSV downregulated glucokinase (GCK) and sodium-dependent glucose cotransporter 1 (SGLT1) and upregulated glucose transporter 2 (GLUT2) mRNA expression, thus restoring normal glucose fluxes. Thus, RSV improves lipid and glucose metabolisms in blunt snout bream, which are potentially mediated by activation of SIRT1.
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Affiliation(s)
- Dingdong Zhang
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
| | - Yanan Yan
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Hongyan Tian
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Guangzhen Jiang
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Xiangfei Li
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Wenbin Liu
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
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22
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Sosa-Larios TC, A Miliar-Garcia A, Reyes-Castro LA, Morimoto S, Jaramillo-Flores ME. Alterations in lipid metabolism due to a protein-restricted diet in rats during gestation and/or lactation. Food Funct 2017. [PMID: 29099131 DOI: 10.1039/c7fo01513e] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Perinatal malnutrition affects not only fetal and neonatal growth, but also the health of offspring in adulthood, as suggested by the concept of metabolic programming. The impact of maternal protein malnutrition on the metabolism of offspring is demonstrated with the current data. One group of pregnant/lactating female rats was fed with an isocaloric diet having normal protein content. Three other groups were provided 50% of this protein level during pregnancy and/or lactation. The growth and metabolic state of the offspring was monitored. The expression of genes regulating lipid metabolism was determined, including SREBP-1c and SIRT-1 in liver and retroperitoneal adipose tissue. Blood cholesterol and triglycerides were higher in the adult offspring (at 110 days of age) fed a protein-restricted diet than in the adult offspring fed a normal diet. Protein restriction likely leads to inadequate detection of glucose levels, as suggested by the reduced expression of the gene for GCK, the sensor of glucose in the liver. The effects of a protein-restricted diet were highly dependent on the window in which this limitation occurred. There was a more adverse effect when the rats underwent protein restriction during gestation than lactation, leading to lower body weight and alterations in lipid metabolism in adult offspring.
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Affiliation(s)
- T C Sosa-Larios
- Departamento de Ing, Bioquímica, Escuela Nacional de Ciencias Biológica, Instituto Politécnico Nacional, Ciudad de México 07738, México.
| | - A A Miliar-Garcia
- Departamento de Ing, Bioquímica, Escuela Nacional de Ciencias Biológica, Instituto Politécnico Nacional, Ciudad de México 07738, México.
| | - L A Reyes-Castro
- Departamento de Ing, Bioquímica, Escuela Nacional de Ciencias Biológica, Instituto Politécnico Nacional, Ciudad de México 07738, México.
| | - S Morimoto
- Departamento de Ing, Bioquímica, Escuela Nacional de Ciencias Biológica, Instituto Politécnico Nacional, Ciudad de México 07738, México.
| | - M E Jaramillo-Flores
- Departamento de Ing, Bioquímica, Escuela Nacional de Ciencias Biológica, Instituto Politécnico Nacional, Ciudad de México 07738, México.
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23
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Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling. Cell 2017; 171:824-835.e18. [PMID: 29056338 DOI: 10.1016/j.cell.2017.09.045] [Citation(s) in RCA: 151] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 07/26/2017] [Accepted: 09/25/2017] [Indexed: 01/08/2023]
Abstract
Insulin resistance is a hallmark of diabetes and an unmet clinical need. Insulin inhibits hepatic glucose production and promotes lipogenesis by suppressing FOXO1-dependent activation of G6pase and inhibition of glucokinase, respectively. The tight coupling of these events poses a dual conundrum: mechanistically, as the FOXO1 corepressor of glucokinase is unknown, and clinically, as inhibition of glucose production is predicted to increase lipogenesis. Here, we report that SIN3A is the insulin-sensitive FOXO1 corepressor of glucokinase. Genetic ablation of SIN3A abolishes nutrient regulation of glucokinase without affecting other FOXO1 target genes and lowers glycemia without concurrent steatosis. To extend this work, we executed a small-molecule screen and discovered selective inhibitors of FOXO-dependent glucose production devoid of lipogenic activity in hepatocytes. In addition to identifying a novel mode of insulin action, these data raise the possibility of developing selective modulators of unliganded transcription factors to dial out adverse effects of insulin sensitizers.
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24
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Martinez-Gamboa M, Cruz-Vega DE, Moreno-Cuevas J, Gonzalez-Garza MT. Induction of Nestin Early Expression as a Hallmark for Mesenchymal Stem Cells Expression of PDX-1 as a Pre-disposing Factor for Their Conversion into Insulin Producing Cells. Int J Stem Cells 2017; 10:76-82. [PMID: 28024317 PMCID: PMC5488779 DOI: 10.15283/ijsc16040] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2016] [Indexed: 12/18/2022] Open
Abstract
Diabetes constitutes a worldwide epidemic that affects all ethnic groups. Cell therapy is one of the best alternatives of treatment, by providing an effective way to regenerate insulin-producing cells lost during the course of the disease, but many issues remain to be solved. Several groups have been working in the development of a protocol capable of differentiating Mesenchymal Stem Cells (MSCs) into physiologically sound Insulin Producing Cells (IPCs). In order to obtain a simple, fast and direct method, we propose in this manuscript the induction of MSCs to express NESTIN in a short time period (2 h), proceeded by incubation in a low glucose induced medium (24 h) and lastly by incubation in a high glucose medium. Samples from cell cultures incubated in high glucose medium from 12 to 168 h were obtained to detect the expression of INSULIN-1, INSULIN -2, PDX-1 and GLUT-2 genes. Induced cells were exposed to a glucose challenge, in order to assess the production of insulin. This method allowed us to obtain cells expressing PDX-1, which resembles a progenitor insulin-producing cell.
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Affiliation(s)
- Marisela Martinez-Gamboa
- Escuela De Ciencias De La Salud, Valle de las Palmas, Universidad Autónoma de Baja California, Tijuana, B.C, CP 22263, México.,Cell Therapy Group, Escuela Nacional De Medicina, Tecnológico de Monterrey, Monterrey, CP 64710, NL, México
| | - Delia Elba Cruz-Vega
- Cell Therapy Group, Escuela Nacional De Medicina, Tecnológico de Monterrey, Monterrey, CP 64710, NL, México
| | - Jorge Moreno-Cuevas
- Cell Therapy Group, Escuela Nacional De Medicina, Tecnológico de Monterrey, Monterrey, CP 64710, NL, México
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The transcription factor carbohydrate-response element-binding protein (ChREBP): A possible link between metabolic disease and cancer. Biochim Biophys Acta Mol Basis Dis 2016; 1863:474-485. [PMID: 27919710 DOI: 10.1016/j.bbadis.2016.11.029] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 11/24/2016] [Accepted: 11/29/2016] [Indexed: 12/19/2022]
Abstract
Carbohydrate-response element-binding protein (ChREBP) has been identified as a transcription factor that binds to carbohydrate response element in the promoter of pyruvate kinase, liver and red blood cells. ChREBP is activated by metabolites derived from glucose and suppressed by adenosine monophosphate (AMP), ketone bodies and cyclic cAMP. ChREBP regulates gene transcription related to glucose and lipid metabolism. Findings from knockout mice and human subjects suggest that ChREBP helps to induce hepatic steatosis, dyslipidemia, and glucose intolerance. Moreover, in tumor cells, ChREBP promotes aerobic glycolysis through p53 inhibition, resulting in tumor cell proliferation. Anti-diabetic and anti-lipidemic drugs such as atorvastatin, metformin, bile acid sequestrants, docosahexaenoic acid and eicosapentaenoic acid may affect ChREBP transactivity. Secretory proteins such as fibroblast growth factor 21 and ANGPTL8 (Betatrophin) may be promising candidates for biologic markers reflecting ChREBP transactivity. Thus, ChREBP is associated with metabolic diseases and cancers, and may be a link between them.
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Valenti L, Bugianesi E, Pajvani U, Targher G. Nonalcoholic fatty liver disease: cause or consequence of type 2 diabetes? Liver Int 2016; 36:1563-1579. [PMID: 27276701 DOI: 10.1111/liv.13185] [Citation(s) in RCA: 111] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Accepted: 06/06/2016] [Indexed: 02/13/2023]
Abstract
Growing epidemiological evidence suggests that nonalcoholic fatty liver disease (NAFLD) is an early predictor of and determinant for the development of type 2 diabetes and other features of the metabolic syndrome. This finding may have important clinical implications for the diagnosis, prevention and treatment of type 2 diabetes and its chronic complications. However, given the complex and bi-directional relationships between NAFLD, insulin resistance and chronic hyperglycaemia, it is extremely difficult to distinguish whether NAFLD is a cause or a consequence of insulin resistance and type 2 diabetes. Indeed, at the molecular level, hepatic lipogenesis and hepatic glucose production depend on differentially regulated branches of the insulin signalling pathway. Furthermore, genetic studies suggest that excess hepatic fat is associated with progressive liver disease, but does not always increase the risk of incident type 2 diabetes. Here, we will briefly review the epidemiological, pathophysiological and molecular evidence linking NAFLD to the development of type 2 diabetes. We will also discuss some recent genetic and therapeutic advances that seem to challenge a causal role of NAFLD in the pathogenesis type 2 diabetes, and propose a working hypothesis to explain this apparent conundrum. In conclusion, progressive liver disease and type 2 diabetes are divergent though inter-related consequences of insulin resistance and the metabolic syndrome.
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Affiliation(s)
- Luca Valenti
- Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy. .,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.
| | - Elisabetta Bugianesi
- Division of Gastroenterology, Department of Medical Sciences, A.O.U. Città della Salute e della Scienza, Università di Torino, Torino, Italy
| | - Utpal Pajvani
- Division of Endocrinology, Columbia University, New York, NY, USA
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
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Affiliation(s)
- Loranne Agius
- Institutes of Cellular Medicine and Ageing and Health, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH United Kingdom;
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Röder PV, Wu B, Liu Y, Han W. Pancreatic regulation of glucose homeostasis. Exp Mol Med 2016; 48:e219. [PMID: 26964835 PMCID: PMC4892884 DOI: 10.1038/emm.2016.6] [Citation(s) in RCA: 519] [Impact Index Per Article: 57.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 12/03/2015] [Accepted: 12/06/2015] [Indexed: 12/11/2022] Open
Abstract
In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed.
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Affiliation(s)
- Pia V Röder
- Metabolism in Human Diseases Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Metabolism in Human Diseases Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore. E-mail: or
| | - Bingbing Wu
- Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore, Singapore
| | - Yixian Liu
- Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore, Singapore
| | - Weiping Han
- Metabolism in Human Diseases Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore, Singapore
- Metabolism in Human Diseases Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore. E-mail: or
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Ou Y, Ren Z, Wang J, Yang X. Phycocyanin ameliorates alloxan-induced diabetes mellitus in mice: Involved in insulin signaling pathway and GK expression. Chem Biol Interact 2016; 247:49-54. [DOI: 10.1016/j.cbi.2016.01.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Revised: 01/14/2016] [Accepted: 01/22/2016] [Indexed: 11/16/2022]
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Park JM, Jo SH, Kim MY, Kim TH, Ahn YH. Role of transcription factor acetylation in the regulation of metabolic homeostasis. Protein Cell 2015; 6:804-13. [PMID: 26334401 PMCID: PMC4624674 DOI: 10.1007/s13238-015-0204-y] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 07/24/2015] [Indexed: 12/23/2022] Open
Abstract
Post-translational modifications (PTMs) of transcription factors play a crucial role in regulating metabolic homeostasis. These modifications include phosphorylation, methylation, acetylation, ubiquitination, SUMOylation, and O-GlcNAcylation. Recent studies have shed light on the importance of lysine acetylation at nonhistone proteins including transcription factors. Acetylation of transcription factors affects subcellular distribution, DNA affinity, stability, transcriptional activity, and current investigations are aiming to further expand our understanding of the role of lysine acetylation of transcription factors. In this review, we summarize recent studies that provide new insights into the role of protein lysine-acetylation in the transcriptional regulation of metabolic homeostasis.
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Affiliation(s)
- Joo-Man Park
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Seong-Ho Jo
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Mi-Young Kim
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Tae-Hyun Kim
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Yong-Ho Ahn
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea. .,Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
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Lee HI, Lee MK. Effects of Scopoletin Supplementation on Insulin Resistance and Antioxidant Defense System in Chronic Alcohol-Fed Rats. JOURNAL OF THE KOREAN SOCIETY OF FOOD SCIENCE AND NUTRITION 2015; 44:173-181. [DOI: 10.3746/jkfn.2015.44.2.173] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/21/2025]
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Kim JY, Lee DY, Lee YJ, Park KJ, Kim KH, Kim JW, Kim WH. Chronic alcohol consumption potentiates the development of diabetes through pancreatic β-cell dysfunction. World J Biol Chem 2015; 6:1-15. [PMID: 25717351 PMCID: PMC4317634 DOI: 10.4331/wjbc.v6.i1.1] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Revised: 10/29/2014] [Accepted: 12/10/2014] [Indexed: 02/05/2023] Open
Abstract
Chronic ethanol consumption is well established as a major risk factor for type-2 diabetes (T2D), which is evidenced by impaired glucose metabolism and insulin resistance. However, the relationships between alcohol consumption and the development of T2D remain controversial. In particular, the direct effects of ethanol consumption on proliferation of pancreatic β-cell and the exact mechanisms associated with ethanol-mediated β-cell dysfunction and apoptosis remain elusive. Although alcoholism and alcohol consumption are prevalent and represent crucial public health problems worldwide, many people believe that low-to-moderate ethanol consumption may protect against T2D and cardiovascular diseases. However, the J- or U-shaped curves obtained from cross-sectional and large prospective studies have not fully explained the relationship between alcohol consumption and T2D. This review provides evidence for the harmful effects of chronic ethanol consumption on the progressive development of T2D, particularly with respect to pancreatic β-cell mass and function in association with insulin synthesis and secretion. This review also discusses a conceptual framework for how ethanol-produced peroxynitrite contributes to pancreatic β-cell dysfunction and metabolic syndrome.
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Ha AW, Ying T, Kim WK. The effects of black garlic (Allium satvium) extracts on lipid metabolism in rats fed a high fat diet. Nutr Res Pract 2015; 9:30-6. [PMID: 25671065 PMCID: PMC4317477 DOI: 10.4162/nrp.2015.9.1.30] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2014] [Revised: 12/30/2014] [Accepted: 01/07/2015] [Indexed: 11/08/2022] Open
Abstract
BACKGROUD/OBEJECTIVES The mechanism of how black garlic effects lipid metabolism remains unsolved. Therefore, the objectives of this study were to determine the effects of black garlic on lipid profiles and the expression of related genes in rats fed a high fat diet. MATERIALS/METHODS Thirty-two male Sqrague-Dawley rats aged 4 weeks were randomly divided into four groups (n=8) and fed the following diets for 5 weeks: normal food diet, (NF); a high-fat diet (HF); and a high-fat diet + 0.5% or 1.5% black garlic extract (HFBG0.5 or HFBG1.5). Body weights and blood biochemical parameters, including lipid profiles, and expressions of genes related to lipid metabolism were determined. RESULTS Significant differences were observed in the final weights between the HFBG1.5 and HF groups. All blood biochemical parameters measured in the HFBG1.5 group showed significantly lower values than those in the HF group. Significant improvements of the plasama lipid profiles as well as fecal excretions of total lipids and triglyceride (TG) were also observed in the HFBG1.5 group, when compared to the HF diet group. There were significant differences in the levels of mRNA of sterol regulatory element binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and glucose-6-phosphate dehydrogenase (G6PDH) in the HFBG1.5 group compared to the HF group. In addition, the hepatic expression of (HMG-CoA) reductase and Acyl-CoA cholesterol acyltransferase (ACAT) mRNA was also significantly lower than the HF group. CONCLUSIONS Consumption of black garlic extract lowers SREBP-1C mRNA expression, which causes downregulation of lipid and cholestrol metahbolism. As a result, the blood levels of total lipids, TG, and cholesterol were decreased.
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Affiliation(s)
- Ae Wha Ha
- Department of Food Science and Nutrition, Dankook University, 152 Jukjeon-Ro, Suji-Gu, Yongin-Si, Gyunggi, 448-701, Korea
| | - Tian Ying
- Department of Food Science and Nutrition, Dankook University, 152 Jukjeon-Ro, Suji-Gu, Yongin-Si, Gyunggi, 448-701, Korea
| | - Woo Kyoung Kim
- Department of Food Science and Nutrition, Dankook University, 152 Jukjeon-Ro, Suji-Gu, Yongin-Si, Gyunggi, 448-701, Korea
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Kim JY, Hwang JY, Lee DY, Song EH, Park KJ, Kim GH, Jeong EA, Lee YJ, Go MJ, Kim DJ, Lee SS, Kim BJ, Song J, Roh GS, Gao B, Kim WH. Chronic ethanol consumption inhibits glucokinase transcriptional activity by Atf3 and triggers metabolic syndrome in vivo. J Biol Chem 2014; 289:27065-27079. [PMID: 25074928 PMCID: PMC4175344 DOI: 10.1074/jbc.m114.585653] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Chronic ethanol consumption induces pancreatic β-cell dysfunction through glucokinase (Gck) nitration and down-regulation, leading to impaired glucose tolerance and insulin resistance, but the underlying mechanism remains largely unknown. Here, we demonstrate that Gck gene expression and promoter activity in pancreatic β-cells were suppressed by chronic ethanol exposure in vivo and in vitro, whereas expression of activating transcription factor 3 (Atf3) and its binding to the putative Atf/Creb site (from −287 to −158 bp) on the Gck promoter were up-regulated. Furthermore, in vitro ethanol-induced Atf3 inhibited the positive effect of Pdx-1 on Gck transcriptional regulation, enhanced recruitment of Hdac1/2 and histone H3 deacetylation, and subsequently augmented the interaction of Hdac1/Pdx-1 on the Gck promoter, which were diminished by Atf3 siRNA. In vivo Atf3-silencing reversed ethanol-mediated Gck down-regulation and β-cell dysfunction, followed by the amelioration of impaired glucose tolerance and insulin resistance. Together, we identified that ethanol-induced Atf3 fosters β-cell dysfunction via Gck down-regulation and that its loss ameliorates metabolic syndrome and could be a potential therapeutic target in treating type 2 diabetes. The Atf3 gene is associated with the induction of type 2 diabetes and alcohol consumption-induced metabolic impairment and thus may be the major negative regulator for glucose homeostasis.
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Affiliation(s)
- Ji Yeon Kim
- Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea
| | - Joo-Yeon Hwang
- Division of Structural and Functional Genomics, Center for Genomic Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea
| | - Dae Yeon Lee
- Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea; Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea
| | - Eun Hyun Song
- Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea
| | - Keon Jae Park
- Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea; Division of Cardiology, Department of Internal Medicine, Chungbuk National University School of Medicine, Cheongju 361-763, Korea, and
| | - Gyu Hee Kim
- Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea
| | - Eun Ae Jeong
- Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea
| | - Yoo Jeong Lee
- Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea
| | - Min Jin Go
- Division of Structural and Functional Genomics, Center for Genomic Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea
| | - Dae Jin Kim
- Departments of Psychiatry and College of Medicine, Catholic University, Bucheon 420-743, Korea
| | - Seong Su Lee
- Departments of Endocrinology, College of Medicine, Catholic University, Bucheon 420-743, Korea
| | - Bong-Jo Kim
- Division of Structural and Functional Genomics, Center for Genomic Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea
| | - Jihyun Song
- Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea
| | - Gu Seob Roh
- Department of Anatomy and Neurobiology, Institute of Health Sciences, Gyeongsang National University, Jinju, Gyeongnam 660-751, Korea
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892
| | - Won-Ho Kim
- Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea.
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Ryll A, Bucher J, Bonin A, Bongard S, Gonçalves E, Saez-Rodriguez J, Niklas J, Klamt S. A model integration approach linking signalling and gene-regulatory logic with kinetic metabolic models. Biosystems 2014; 124:26-38. [PMID: 25063553 DOI: 10.1016/j.biosystems.2014.07.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Revised: 07/11/2014] [Accepted: 07/18/2014] [Indexed: 12/16/2022]
Abstract
Systems biology has to increasingly cope with large- and multi-scale biological systems. Many successful in silico representations and simulations of various cellular modules proved mathematical modelling to be an important tool in gaining a solid understanding of biological phenomena. However, models spanning different functional layers (e.g. metabolism, signalling and gene regulation) are still scarce. Consequently, model integration methods capable of fusing different types of biological networks and various model formalisms become a key methodology to increase the scope of cellular processes covered by mathematical models. Here we propose a new integration approach to couple logical models of signalling or/and gene-regulatory networks with kinetic models of metabolic processes. The procedure ends up with an integrated dynamic model of both layers relying on differential equations. The feasibility of the approach is shown in an illustrative case study integrating a kinetic model of central metabolic pathways in hepatocytes with a Boolean logical network depicting the hormonally induced signal transduction and gene regulation events involved. In silico simulations demonstrate the integrated model to qualitatively describe the physiological switch-like behaviour of hepatocytes in response to nutritionally regulated changes in extracellular glucagon and insulin levels. A simulated failure mode scenario addressing insulin resistance furthermore illustrates the pharmacological potential of a model covering interactions between signalling, gene regulation and metabolism.
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Affiliation(s)
- A Ryll
- Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstraße 1, D-39106 Magdeburg, Germany.
| | - J Bucher
- Insilico Biotechnology AG, Meitnerstraße 8, D-70563 Stuttgart, Germany
| | - A Bonin
- Insilico Biotechnology AG, Meitnerstraße 8, D-70563 Stuttgart, Germany
| | - S Bongard
- Insilico Biotechnology AG, Meitnerstraße 8, D-70563 Stuttgart, Germany
| | - E Gonçalves
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, Cambridge, United Kingdom
| | - J Saez-Rodriguez
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, Cambridge, United Kingdom
| | - J Niklas
- Insilico Biotechnology AG, Meitnerstraße 8, D-70563 Stuttgart, Germany
| | - S Klamt
- Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstraße 1, D-39106 Magdeburg, Germany.
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Wade NM, Skiba-Cassy S, Dias K, Glencross BD. Postprandial molecular responses in the liver of the barramundi, Lates calcarifer. FISH PHYSIOLOGY AND BIOCHEMISTRY 2014; 40:427-43. [PMID: 23990285 DOI: 10.1007/s10695-013-9854-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Accepted: 08/21/2013] [Indexed: 05/25/2023]
Abstract
The regulation of gene expression by nutrients is an important mechanism governing energy storage and growth in most animals, including fish. At present, very few genes that regulate intermediary metabolism have been identified in barramundi, nor is there any understanding of their nutritional regulation. In this study, a partial barramundi liver transcriptome was assembled from next-generation sequencing data and published barramundi EST sequences. A large number of putative metabolism genes were identified in barramundi, and the changes in the expression of 24 key metabolic regulators of nutritional pathways were investigated in barramundi liver over a time series immediately after a meal of a nutritionally optimised diet for this species. Plasma glucose and free amino acid levels showed a mild postprandial elevation which peaked 2 h after feeding, and had returned to basal levels within 4 or 8 h, respectively. Significant activation or repression of metabolic nuclear receptor regulator genes were observed, in combination with activation of glycolytic and lipogenic pathways, repression of the final step of gluconeogenesis and activation of the Akt-mTOR pathway. Strong correlations were identified between a number of different metabolic genes, and the coordinated co-regulation of these genes may underlie the ability of this fish to utilise dietary nutrients. Overall, these data clearly demonstrate a number of unique postprandial responses in barramundi compared with other fish species and provide a critical step in defining the response to different dietary nutrient sources.
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Affiliation(s)
- Nicholas M Wade
- Division of Marine and Atmospheric Research, Ecosciences Precinct, CSIRO Food Futures Flagship, Dutton Park, QLD, 4102, Australia,
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Liquid fructose downregulates Sirt1 expression and activity and impairs the oxidation of fatty acids in rat and human liver cells. Biochim Biophys Acta Mol Cell Biol Lipids 2014; 1841:514-24. [DOI: 10.1016/j.bbalip.2014.01.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 12/13/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023]
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Abstract
INTRODUCTION Retinoid X receptors (RXRs) are nuclear receptors that act as ligand-dependent transcription factors. RXRs function as homodimers or as heterodimers with other nuclear receptors, such as retinoic acid receptors, PPARs, liver X receptors, farnesoid X receptor, vitamin D receptor or thyroid hormone receptors. RXR ligands (agonists or antagonists) show various physiological effects, depending on their partner receptors. RXR agonist bexarotene (Targretin®) is used for the treatment of cutaneous T-cell lymphoma in clinical practice. RXR agonists were also reported to be useful for treatment of type 2 diabetes, autoimmune disease and Alzheimer's disease. RXR antagonists were also reported to be effective in type 2 diabetes treatment. AREAS COVERED Here patent applications (2007 - 2013) concerning RXR ligands are summarized, and the usefulness of RXR ligands as pharmaceutical agents is discussed. EXPERT OPINION RXR agonists show a wide variety of biological effects. However, they cause serious side effects, such as blood triglyceride elevation, hypothyroidism and others. Thus, for clinical application of RXR agonists, abrogation of these side effects is required. RXR heterodimer-selective agonists and RXR partial agonists exhibiting desired effects without side effects are expected to find clinical application.
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Affiliation(s)
- Shoya Yamada
- Okayama University Graduate School of Medicine, Division of Pharmaceutical Sciences, Dentistry and Pharmaceutical Sciences , 1-1-1, Tsushima-Naka, Kita-Ku, Okayama 700-8530 , Japan +81 086 251 7963 ; +81 086 251 7963 ;
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Guan HP, Chen G. Factors affecting insulin-regulated hepatic gene expression. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2014; 121:165-215. [PMID: 24373238 DOI: 10.1016/b978-0-12-800101-1.00006-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Obesity has become a major concern of public health. A common feature of obesity and related metabolic disorders such as noninsulin-dependent diabetes mellitus is insulin resistance, wherein a given amount of insulin produces less than normal physiological responses. Insulin controls hepatic glucose and fatty acid metabolism, at least in part, via the regulation of gene expression. When the liver is insulin-sensitive, insulin can stimulate the expression of genes for fatty acid synthesis and suppress those for gluconeogenesis. When the liver becomes insulin-resistant, the insulin-mediated suppression of gluconeogenic gene expression is lost, whereas the induction of fatty acid synthetic gene expression remains intact. In the past two decades, the mechanisms of insulin-regulated hepatic gene expression have been studied extensively and many components of insulin signal transduction pathways have been identified. Factors that alter these pathways, and the insulin-regulated hepatic gene expression, have been revealed and the underlying mechanisms have been proposed. This chapter summarizes the recent progresses in our understanding of the effects of dietary factors, drugs, bioactive compounds, hormones, and cytokines on insulin-regulated hepatic gene expression. Given the large amount of information and progresses regarding the roles of insulin, this chapter focuses on findings in the liver and hepatocytes and not those described for other tissues and cells. Typical insulin-regulated hepatic genes, such as insulin-induced glucokinase and sterol regulatory element-binding protein-1c and insulin-suppressed cytosolic phosphoenolpyruvate carboxyl kinase and insulin-like growth factor-binding protein 1, are used as examples to discuss the mechanisms such as insulin regulatory element-mediated transcriptional regulation. We also propose the potential mechanisms by which these factors affect insulin-regulated hepatic gene expression and discuss potential future directions of the area of research.
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Affiliation(s)
- Hong-Ping Guan
- Department of Diabetes, Merck Research Laboratories, Kenilworth, New Jersey, USA
| | - Guoxun Chen
- Department of Nutrition, University of Tennessee at Knoxville, Knoxville, Tennessee, USA
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Li W, Bu D, Wang J, Nan X, Sun P, Zhou L. Effect of two different diets on liver gene expression associated with glucose metabolism in dairy cows. Livest Sci 2013. [DOI: 10.1016/j.livsci.2013.08.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Rajesh P, Sathish S, Srinivasan C, Selvaraj J, Balasubramanian K. Phthalate is associated with insulin resistance in adipose tissue of male rat: role of antioxidant vitamins. J Cell Biochem 2013; 114:558-69. [PMID: 22991202 DOI: 10.1002/jcb.24399] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2012] [Accepted: 09/06/2012] [Indexed: 01/11/2023]
Abstract
Diethyl hexyl phthalate (DEHP) is a plasticizer, commonly used in a variety of products, including lubricants, perfumes, hairsprays and cosmetics, construction materials, wood finishers, adhesives, floorings and paints. DEHP is an endocrine disruptor and it has a continuum of influence on various organ systems in human beings and experimental animals. However, specific effects of DEHP on insulin signaling in adipose tissue are not known. Adult male albino rats of Wistar strain were divided into four groups. Control, DEHP treated (dissolved in olive oil at a dose of 10, and 100 mg/kg body weight, respectively, once daily through gastric intubations for 30 days) and DEHP + vitamin E (50 mg/kg body weight) and C (100 mg/kg body weight) dissolved in olive oil and distilled water, respectively, once daily through gastric intubations for 30 days. After the completion of treatment, adipose tissue was dissected out to assess various parameters. DEHP treatment escalated H(2)O(2) and hydroxyl radical levels as well as lipid peroxidation in the adipose tissue. DEHP impaired the expression of insulin signaling molecules and their phosphorelay pathways leading to diminish plasma membrane GLUT4 level and thus decreased glucose uptake and oxidation. Blood glucose level was elevated as a result of these changes. Supplementation of vitamins (C & E) prevented the DEHP-induced changes. It is concluded that DEHP-induced ROS and lipid peroxidation disrupts the insulin signal transduction in adipose tissue and favors glucose intolerance. Antioxidant vitamins have a protective role against the adverse effect of DEHP.
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Affiliation(s)
- Parsanathan Rajesh
- Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Sekkizhar Campus, Taramani, Chennai 600113, India
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Ren W, Sun Y, Cheema S, Du K. Interaction of constitutive photomorphogenesis 1 protein with protein-tyrosine phosphatase 1B suppresses protein-tyrosine phosphatase 1B activity and enhances insulin signaling. J Biol Chem 2013; 288:10902-13. [PMID: 23439647 PMCID: PMC3624470 DOI: 10.1074/jbc.m112.369371] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Indexed: 11/06/2022] Open
Abstract
Recent studies reveal that COP1 suppresses the expression of gluconeogenetic genes and prohibits hepatic glucose production. To get more insight into COP1 in hepatic cells, we examined the impact of COP1 on insulin-responsive genes and insulin signaling. We found that COP1 increased the responsiveness of insulin-modulated genes to insulin in that it promoted the expression of insulin-induced genes and inhibited that of insulin-suppressed genes and that COP1 enhanced insulin signaling as it promoted phosphorylation of Akt and ERK as well as tyrosine phosphorylation of IRβ induced by insulin. To delineate the mechanism under which COP1 modulates insulin signaling, we examined the possibility that COP1 modulates the activity of PTP1B, the major insulin receptor tyrosine phosphatase. The results indicated that COP1 physically interacted with PTP1B and suppressed PTP1B phosphatase activity as well as the association of PTP1B with IRβ. We suggest that COP1 is a positive regulator of hepatic insulin signaling.
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Affiliation(s)
- Wenying Ren
- From the Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111
| | - Yingmin Sun
- From the Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111
| | - Sarwat Cheema
- From the Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111
| | - Keyong Du
- From the Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111
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Bischoff SR, Tsai SQ, Hardison NE, Motsinger-Reif AA, Freking BA, Nonneman DJ, Rohrer GA, Piedrahita JA. Differences in X-chromosome transcriptional activity and cholesterol metabolism between placentae from swine breeds from Asian and Western origins. PLoS One 2013; 8:e55345. [PMID: 23383161 PMCID: PMC3561265 DOI: 10.1371/journal.pone.0055345] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2012] [Accepted: 12/21/2012] [Indexed: 12/19/2022] Open
Abstract
To gain insight into differences in placental physiology between two swine breeds noted for their dissimilar reproductive performance, that is, the Chinese Meishan and white composite (WC), we examined gene expression profiles of placental tissues collected at 25, 45, 65, 85, and 105 days of gestation by microarrays. Using a linear mixed model, a total of 1,595 differentially expressed genes were identified between the two pig breeds using a false-discovery rate q-value ≤0.05. Among these genes, we identified breed-specific isoforms of XIST, a long non-coding RNA responsible X-chromosome dosage compensation in females. Additionally, we explored the interaction of placental gene expression and chromosomal location by DIGMAP and identified three Sus scrofa X chromosomal bands (Xq13, Xq21, Xp11) that represent transcriptionally active clusters that differ between Meishan and WC during placental development. Also, pathway analysis identified fundamental breed differences in placental cholesterol trafficking and its synthesis. Direct measurement of cholesterol confirmed that the cholesterol content was significantly higher in the Meishan versus WC placentae. Taken together, this work identifies key metabolic pathways that differ in the placentae of two swine breeds noted for differences in reproductive prolificacy.
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Affiliation(s)
- Steve R. Bischoff
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America
- USDA, ARS, U.S. Meat Animal Research Center, Clay Center, Nebraska, United States of America
- Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, North Carolina, United States of America
| | - Shengdar Q. Tsai
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America
- Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, North Carolina, United States of America
| | - Nicholas E. Hardison
- Program in Statistical Genetics, Department of Statistics, North Carolina State University, Raleigh, North Carolina, United States of America
| | - Alison A. Motsinger-Reif
- Program in Statistical Genetics, Department of Statistics, North Carolina State University, Raleigh, North Carolina, United States of America
| | - Bradley A. Freking
- USDA, ARS, U.S. Meat Animal Research Center, Clay Center, Nebraska, United States of America
| | - Dan J. Nonneman
- USDA, ARS, U.S. Meat Animal Research Center, Clay Center, Nebraska, United States of America
| | - Gary A. Rohrer
- USDA, ARS, U.S. Meat Animal Research Center, Clay Center, Nebraska, United States of America
| | - Jorge A. Piedrahita
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America
- Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, North Carolina, United States of America
- * E-mail:
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Increased insulin receptor substrate 2 expression is associated with steatohepatitis and altered lipid metabolism in obese subjects. Int J Obes (Lond) 2012; 37:986-92. [DOI: 10.1038/ijo.2012.181] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Revised: 09/27/2012] [Accepted: 10/07/2012] [Indexed: 01/01/2023]
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Wang Y, Guo T, Zhao S, Li Z, Mao Y, Li H, Wang X, Wang R, Xu W, Song R, Jin L, Li X, Irwin DM, Niu G, Tan H. Expression of the human glucokinase gene: important roles of the 5' flanking and intron 1 sequences. PLoS One 2012; 7:e45824. [PMID: 23029263 PMCID: PMC3447760 DOI: 10.1371/journal.pone.0045824] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2012] [Accepted: 08/24/2012] [Indexed: 02/07/2023] Open
Abstract
Background Glucokinase plays important tissue-specific roles in human physiology, where it acts as a sensor of blood glucose levels in the pancreas, and a few other cells of the gut and brain, and as the rate-limiting step in glucose metabolism in the liver. Liver-specific expression is driven by one of the two tissue-specific promoters, and has an absolute requirement for insulin. The sequences that mediate regulation by insulin are incompletely understood. Methodology/Principal Findings To better understand the liver-specific expression of the human glucokinase gene we compared the structures of this gene from diverse mammals. Much of the sequence located between the 5′ pancreatic beta-cell-specific and downstream liver-specific promoters of the glucokinase genes is composed of repetitive DNA elements that were inserted in parallel on different mammalian lineages. The transcriptional activity of the liver-specific promoter 5′ flanking sequences were tested with and without downstream intronic sequences in two human liver cells lines, HepG2 and L-02. While glucokinase liver-specific 5′ flanking sequences support expression in liver cell lines, a sequence located about 2000 bases 3′ to the liver-specific mRNA start site represses gene expression. Enhanced reporter gene expression was observed in both cell lines when cells were treated with fetal calf serum, but only in the L-02 cells was expression enhanced by insulin. Conclusions/Significance Our results suggest that the normal liver L-02 cell line may be a better model to understand the regulation of the liver-specific expression of the human glucokinase gene. Our results also suggest that sequences downstream of the liver-specific mRNA start site have important roles in the regulation of liver-specific glucokinase gene expression.
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Affiliation(s)
- Yi Wang
- Department of Pharmacology, Peking University, Health Science Center, Beijing, China
| | - Tingting Guo
- Department of Pharmacology, Peking University, Health Science Center, Beijing, China
| | - Shuyong Zhao
- Department of Pharmacology, Peking University, Health Science Center, Beijing, China
| | - Zhixin Li
- Department of Pharmacology, Peking University, Health Science Center, Beijing, China
| | - Yiqing Mao
- Department of Pharmacology, Peking University, Health Science Center, Beijing, China
| | - Hui Li
- Department of Pharmacology, Peking University, Health Science Center, Beijing, China
| | - Xi Wang
- Department of Pharmacology, Peking University, Health Science Center, Beijing, China
| | - Rong Wang
- Department of Pharmacology, Peking University, Health Science Center, Beijing, China
| | - Wei Xu
- Department of Pharmacology, Peking University, Health Science Center, Beijing, China
| | - Rongjing Song
- Department of Pharmacology, Peking University, Health Science Center, Beijing, China
| | - Ling Jin
- Department of Pharmacology, Peking University, Health Science Center, Beijing, China
| | - Xiuli Li
- Department of Pharmacology, Chifeng College, Chifeng, China
| | - David M. Irwin
- Department of Pharmacology, Peking University, Health Science Center, Beijing, China
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- * E-mail: (HT); (DMI)
| | - Gang Niu
- Beijing N&N Genetech Company, Beijing, China
| | - Huanran Tan
- Department of Pharmacology, Peking University, Health Science Center, Beijing, China
- * E-mail: (HT); (DMI)
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Kakuta H, Yakushiji N, Shinozaki R, Ohsawa F, Yamada S, Ohta Y, Kawata K, Nakayama M, Hagaya M, Fujiwara C, Makishima M, Uno S, Tai A, Maehara A, Nakayama M, Oohashi T, Yasui H, Yoshikawa Y. RXR Partial Agonist CBt-PMN Exerts Therapeutic Effects on Type 2 Diabetes without the Side Effects of RXR Full Agonists. ACS Med Chem Lett 2012; 3:427-32. [PMID: 24900488 DOI: 10.1021/ml300055n] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2012] [Accepted: 04/08/2012] [Indexed: 01/26/2023] Open
Abstract
Treating insulin resistance and type 2 diabetes in rodents, currently known retinoid X receptor (RXR) agonists induce significant adverse effects. Here we introduce a novel RXR partial agonist CBt-PMN (11b), which shows a potent glucose-lowering effect and improvements of insulin secretion and glucose tolerance without the serious adverse effects caused by RXR full agonists. We suggest that RXR partial agonists may be a new class of antitype 2 diabetes drug candidates.
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Affiliation(s)
- Hiroki Kakuta
- Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1 Tsushima-Naka, Okayama 700-8530, Japan
| | - Nobumasa Yakushiji
- Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1 Tsushima-Naka, Okayama 700-8530, Japan
| | - Ryosuke Shinozaki
- Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1 Tsushima-Naka, Okayama 700-8530, Japan
| | - Fuminori Ohsawa
- Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1 Tsushima-Naka, Okayama 700-8530, Japan
| | - Shoya Yamada
- Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1 Tsushima-Naka, Okayama 700-8530, Japan
| | - Yui Ohta
- Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1 Tsushima-Naka, Okayama 700-8530, Japan
| | - Kohei Kawata
- Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1 Tsushima-Naka, Okayama 700-8530, Japan
| | - Mariko Nakayama
- Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1 Tsushima-Naka, Okayama 700-8530, Japan
| | - Manabu Hagaya
- Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1 Tsushima-Naka, Okayama 700-8530, Japan
| | - Chisa Fujiwara
- Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1 Tsushima-Naka, Okayama 700-8530, Japan
| | - Makoto Makishima
- Division of Biochemistry, Department
of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Shigeyuki Uno
- Division of Biochemistry, Department
of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Akihiro Tai
- Faculty of Life and Environmental
Sciences, Prefectural University of Hiroshima, 562 Nanatsuka-Cho,
Shobara, Hiroshima 727-0023, Japan
| | - Ami Maehara
- Division of Medical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama 700-8558,
Japan
| | - Masaru Nakayama
- Division of Medical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama 700-8558,
Japan
| | - Toshitaka Oohashi
- Division of Medical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama 700-8558,
Japan
| | - Hiroyuki Yasui
- Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku,
Kyoto 607-8414, Japan
| | - Yutaka Yoshikawa
- Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku,
Kyoto 607-8414, Japan
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Lee FT, Kuo TY, Liou SY, Chien CT. Chronic Rhodiola rosea Extract Supplementation Enforces Exhaustive Swimming Tolerance. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2012; 37:557-72. [DOI: 10.1142/s0192415x09007053] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
We explored the effects and mechanisms of Rhodiola rosea extract supplementation on swimming-induced fatigue in rats. The concentrations of active components in Rhodiola rosea have been determined by high performance liquid chromatography-mass spectrometer. The Rhodiola rosea extract supplementation in water for 2–4 weeks was evaluated in male Wistar rats with 90-min unloaded swimming exercise and 5% body weight loaded swimming up to fatigue. We measured the fatigue biomarkers, including blood urea nitrogen (BUN), glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT), lactate dehydrogenase (LDH), hepatic glycogen content, the activity of fat metabolism enzymes, sterol regulatory element-binding protein-1 (SREBP-1) and fatty acid synthase (FAS), the tissue oxygen content and ratio of red and white skeletal muscle fibers in rats. Rhodiola rosea significantly increased liver glycogen, SREBP-1, FAS, heat shock protein 70 expression, Bcl-2/Bax ratio and oxygen content before swimming. Rhodiola rosea supplementation significantly increased the swimming time in a dose-dependent manner and reduced swimming-enhanced serum BUN, GOT and GPT levels. The ratio of red and white muscle fibers was not altered after chronic Rhodiola rosea extract supplementation. Chronic Rhodiola rosea supplementation significantly improved exhaustive swimming-induced fatigue by the increased glycogen content, energy supply of lipogenic enzyme expressions and protective defense mechanisms.
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Affiliation(s)
- Fang-Tsai Lee
- Department of Orthopaedic Surgery, Kuang-Tien General Hospital, Taichung, Taiwan
| | - Tz-Yin Kuo
- Department of Food Science, Nutrition, and Nutraceutical Biotechnology, Shih-Chien University College of Human Ecology, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Shaw-Yih Liou
- Formosan Blood Purification Foundation, Taipei, Taiwan
| | - Chiang-Ting Chien
- Department of Medical Research, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
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Inoue J, Yamasaki K, Ikeuchi E, Satoh SI, Fujiwara Y, Nishimaki-Mogami T, Shimizu M, Sato R. Identification of MIG12 as a mediator for stimulation of lipogenesis by LXR activation. Mol Endocrinol 2011; 25:995-1005. [PMID: 21474539 DOI: 10.1210/me.2011-0070] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Liver X receptor (LXR)α and LXRβ belong to the nuclear receptor superfamily and play central roles in the transcriptional control of lipid metabolism. We describe a novel LXR target, midline-1-interacting G12-like protein (MIG12), which has been recently identified as an acetyl-coenzyme A carboxylase-binding protein. The binding causes the induction of de novo fatty acid (FA) synthesis through the activation of acetyl-coenzyme A carboxylase (a rate-limiting enzyme for de novo FA synthesis). Luciferase reporter gene assays using the MIG12 gene promoter revealed the existence of a LXR-responsive element (LXRE) and carbohydrate-responsive element-binding protein (ChREBP)-responsive element named LXRE3 and carbohydrate response element 1, respectively. Deletion and mutation of LXRE3 and carbohydrate response element 1 abolished LXR and ChREBP responsiveness, respectively. Electrophoretic mobility shift assays demonstrated that the LXRα/retinoid X receptor α complex was bound to LXRE3. Treatment with high glucose concentration, which leads ChREBP activation, or LXR activator stimulated MIG12 expression in rat primary hepatocytes, and combined treatment further stimulated MIG12 expression. Furthermore, hepatic expression of MIG12 in mice was induced by refeeding. Overexpression of MIG12 stimulated and knockdown of MIG12 attenuated LXR ligand-stimulated de novo FA synthesis and triacylglycerol accumulation. These results indicate that MIG12 is a mediator for stimulation of lipogenesis by LXR activation in the liver.
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Affiliation(s)
- Jun Inoue
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan
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Dietary lipid-dependent regulation of de novo lipogenesis and lipid partitioning by ketogenic essential amino acids in mice. Nutr Diabetes 2011; 1:e5. [PMID: 23154504 PMCID: PMC3302132 DOI: 10.1038/nutd.2011.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background: We have previously reported that dietary ketogenic amino acids (KAAs) modulate hepatic de novo lipogenesis (DNL) and prevent hepatic steatosis in mice. However, the dependence of the metabolic phenotypes generated by KAA on the type of dietary lipid source remains unclear. Objective: The aim of this study was to assess the effect of KAA combined with different dietary lipid sources on hepatic DNL and tissue lipid partitioning in mice. Design: We compared three different KAA-supplemented diets, in which a portion of the dietary protein was replaced by five major essential amino acids (Leu, Ile, Val, Lys and Thr) in high-fat diets based on palm oil (PO), high-oleic safflower oil (FO) or soy oil (SO). To compare the effects of these diets in C57B6 mice, the differential regulation of DNL and dietary lipid partitioning due to KAA was assessed using stable isotopic flux analysis. Results: The different dietary oils showed strikingly different patterns of lipid partitioning and accumulation in tissues. High-PO diets increased both hepatic and adipose triglycerides (TG), whereas high-FO and high-SO diets increased hepatic and adipose TG, respectively. Stable isotopic flux analysis revealed high rates of hepatic DNL in high-PO and high-FO diets, whereas it was reduced in the high-SO diet. KAA supplementation in high-PO and high-FO diets reduced hepatic TG by reducing the DNL of palmitate and the accumulation of dietary oleate. However, KAA supplementation in the high-SO diet failed to reduce hepatic DNL and TG. Interestingly, KAA reduced SO-induced accumulation of hepatic linoleate and enhanced SO-induced accumulation of dietary oleate. Conclusions: Overall, the reduction of hepatic TG by KAA is dependent on dietary lipid sources and occurs through the modulation of DNL and altered partitioning of dietary lipids. The current results provide further insight into the underlying mechanisms of hepatic lipid reduction by amino acids.
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Vilà L, Roglans N, Perna V, Sánchez RM, Vázquez-Carrera M, Alegret M, Laguna JC. Liver AMP/ATP ratio and fructokinase expression are related to gender differences in AMPK activity and glucose intolerance in rats ingesting liquid fructose. J Nutr Biochem 2010; 22:741-51. [PMID: 21115336 DOI: 10.1016/j.jnutbio.2010.06.005] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2010] [Revised: 04/30/2010] [Accepted: 06/01/2010] [Indexed: 12/21/2022]
Abstract
Women, but not men, show an association between fructose consumption and an increased risk of Type 2 diabetes mellitus. As rats are considered a model for human fructose metabolism, we sought to determine whether such a gender-related difference is present in Sprague-Dawley rats and to analyze the molecular mechanism behind. Male and female Sprague-Dawley rats had free access to water or to a 10% w/v fructose solution for 14 days. Plasma analytes, liver triglycerides and enzyme activities and the expression of enzymes and transcription factors related to fatty acid metabolism, insulin signaling and glucose tolerance were determined. Fructose-fed rats had hypertriglyceridemia, steatosis and reduced fatty acid oxidation activity, although the metabolic pattern of fructose-fed female rats was different to that observed for male rats. Fructose-fed female, but not male rats, showed no change in plasma leptin; they had hyperinsulinemia, an altered glucose tolerance test and less liver insulin receptor substrate-2. Further, only fructose-fed female rats had increased adenosine 5'-monophosphate (AMP)-activated protein kinase activity, resulting in a decreased expression of hepatic nuclear factor 4 and sterol response element binding protein 1. These differences were related to the fact that liver expression of the enzyme fructokinase, controlling fructose metabolism, was markedly induced by fructose ingestion in female, but not in male rats, resulting in a significant increase in the AMP/adenosine 5'-triphosphate (ATP) ratio and, thus, AMP-activated protein kinase activation, in female rats only. The difference in fructokinase induction could explain the higher metabolic burden produced by fructose ingestion in the livers of female Sprague-Dawley rats.
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Affiliation(s)
- Laia Vilà
- Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, IBUB (Institute of Biomedicine University of Barcelona),and CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona 08028, Spain
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