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Chen X, Deng SZ, Sun Y, Bai Y, Wang Y, Yang Y. Key genes involved in nonalcoholic steatohepatitis improvement after bariatric surgery. Front Endocrinol (Lausanne) 2024; 15:1338889. [PMID: 38469144 PMCID: PMC10925704 DOI: 10.3389/fendo.2024.1338889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 01/22/2024] [Indexed: 03/13/2024] Open
Abstract
Background Nonalcoholic steatohepatitis (NASH) is the advanced stage of nonalcoholic fatty liver disease (NAFLD), one of the most prevalent chronic liver diseases. The effectiveness of bariatric surgery in treating NASH and preventing or even reversing liver fibrosis has been demonstrated in numerous clinical studies, but the underlying mechanisms and crucial variables remain unknown. Methods Using the GSE135251 dataset, we examined the gene expression levels of NASH and healthy livers. Then, the differentially expressed genes (DEGs) of patients with NASH, at baseline and one year after bariatric surgery, were identified in GSE83452. We overlapped the hub genes performed by protein-protein interaction (PPI) networks and DEGs with different expression trends in both datasets to obtain key genes. Genomic enrichment analysis (GSEA) and genomic variation analysis (GSVA) were performed to search for signaling pathways of key genes. Meanwhile, key molecules that regulate the key genes are found through the construction of the ceRNA network. NASH mice were induced by a high-fat diet (HFD) and underwent sleeve gastrectomy (SG). We then cross-linked the DEGs in clinical and animal samples using quantitative polymerase chain reaction (qPCR) and validated the key genes. Results Seven key genes (FASN, SCD, CD68, HMGCS1, SQLE, CXCL10, IGF1) with different expression trends in GSE135251 and GSE83452 were obtained with the top 30 hub genes selected by PPI. The expression of seven key genes in mice after SG was validated by qPCR. Combined with the qPCR results from NASH mice, the four genes FASN, SCD, HMGCS1, and CXCL10 are consistent with the biological analysis. The GSEA results showed that the 'cholesterol homeostasis' pathway was enriched in the FASN, SCD, HMGCS1, and SQLE high-expression groups. The high-expression groups of CD68 and CXCL10 were extremely enriched in inflammation-related pathways. The construction of the ceRNA network obtained microRNAs and ceRNAs that can regulate seven key genes expression. Conclusion In summary, this study contributes to our understanding of the mechanisms by which bariatric surgery improves NASH, and to the development of potential biomarkers for the treatment of NASH.
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Affiliation(s)
- Xiyu Chen
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi’an, China
| | - Shi-Zhou Deng
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi’an, China
| | - Yuze Sun
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi’an, China
| | - Yunhu Bai
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi’an, China
- Department of General Surgery, 988 Hospital of Joint Logistic Support Force, Zhengzhou, China
| | - Yayun Wang
- Specific Lab for Mitochondrial Plasticity Underlying Nervous System Diseases, National Demonstration Center for Experimental Preclinical Medicine Education, The Fourth Military Medical University, Xi’an, China
| | - Yanling Yang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi’an, China
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Shimizu K, Ono M, Mikamoto T, Urayama Y, Yoshida S, Hase T, Michinaga S, Nakanishi H, Iwasaki M, Terada T, Sakurai F, Mizuguchi H, Shindou H, Tomita K, Nishinaka T. Overexpression of lysophospholipid acyltransferase, LPLAT10/LPCAT4/LPEAT2, in the mouse liver increases glucose-stimulated insulin secretion. FASEB J 2024; 38:e23425. [PMID: 38226852 DOI: 10.1096/fj.202301594rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 12/22/2023] [Accepted: 12/29/2023] [Indexed: 01/17/2024]
Abstract
Postprandial hyperglycemia is an early indicator of impaired glucose tolerance that leads to type 2 diabetes mellitus (T2DM). Alterations in the fatty acid composition of phospholipids have been implicated in diseases such as T2DM and nonalcoholic fatty liver disease. Lysophospholipid acyltransferase 10 (LPLAT10, also called LPCAT4 and LPEAT2) plays a role in remodeling fatty acyl chains of phospholipids; however, its relationship with metabolic diseases has not been fully elucidated. LPLAT10 expression is low in the liver, the main organ that regulates metabolism, under normal conditions. Here, we investigated whether overexpression of LPLAT10 in the liver leads to improved glucose metabolism. For overexpression, we generated an LPLAT10-expressing adenovirus (Ad) vector (Ad-LPLAT10) using an improved Ad vector. Postprandial hyperglycemia was suppressed by the induction of glucose-stimulated insulin secretion in Ad-LPLAT10-treated mice compared with that in control Ad vector-treated mice. Hepatic and serum levels of phosphatidylcholine 40:7, containing C18:1 and C22:6, were increased in Ad-LPLAT10-treated mice. Serum from Ad-LPLAT10-treated mice showed increased glucose-stimulated insulin secretion in mouse insulinoma MIN6 cells. These results indicate that changes in hepatic phosphatidylcholine species due to liver-specific LPLAT10 overexpression affect the pancreas and increase glucose-stimulated insulin secretion. Our findings highlight LPLAT10 as a potential novel therapeutic target for T2DM.
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Affiliation(s)
- Kahori Shimizu
- Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan
| | - Moe Ono
- Laboratory of Molecular Biology, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan
| | - Takenari Mikamoto
- Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan
| | - Yuya Urayama
- Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan
| | - Sena Yoshida
- Laboratory of Molecular Biology, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan
| | - Tomomi Hase
- Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan
| | - Shotaro Michinaga
- Department of Pharmacodynamics, Meiji Pharmaceutical University, Tokyo, Japan
| | | | - Miho Iwasaki
- Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan
| | - Tomoyuki Terada
- Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan
| | - Fuminori Sakurai
- Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Hiroyuki Mizuguchi
- Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
- Global Center for Medical Engineering and Informatics, Osaka University, Osaka, Japan
- Laboratory of Functional Organoid for Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan
- Center for Infectious Disease Education and Research (CiDER), Osaka University, Osaka, Japan
| | - Hideo Shindou
- Department of Lipid Life Science, National Center for Global Health and Medicine, Tokyo, Japan
- Department of Medical Lipid Science, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Koji Tomita
- Laboratory of Molecular Biology, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan
| | - Toru Nishinaka
- Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan
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3
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Wu M, Lo TH, Li L, Sun J, Deng C, Chan KY, Li X, Yeh STY, Lee JTH, Lui PPY, Xu A, Wong CM. Amelioration of non-alcoholic fatty liver disease by targeting adhesion G protein-coupled receptor F1 ( Adgrf1). eLife 2023; 12:e85131. [PMID: 37580962 PMCID: PMC10427146 DOI: 10.7554/elife.85131] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 07/28/2023] [Indexed: 08/16/2023] Open
Abstract
Background Recent research has shown that the adhesion G protein-coupled receptor F1 (Adgrf1; also known as GPR110; PGR19; KPG_012; hGPCR36) is an oncogene. The evidence is mainly based on high expression of Adgrf1 in numerous cancer types, and knockdown Adgrf1 can reduce the cell migration, invasion, and proliferation. Adgrf1 is, however, mostly expressed in the liver of healthy individuals. The function of Adgrf1 in liver has not been revealed. Interestingly, expression level of hepatic Adgrf1 is dramatically decreased in obese subjects. Here, the research examined whether Adgrf1 has a role in liver metabolism. Methods We used recombinant adeno-associated virus-mediated gene delivery system, and antisense oligonucleotide was used to manipulate the hepatic Adgrf1 expression level in diet-induced obese mice to investigate the role of Adgrf1 in hepatic steatosis. The clinical relevance was examined using transcriptome profiling and archived biopsy specimens of liver tissues from non-alcoholic fatty liver disease (NAFLD) patients with different degree of fatty liver. Results The expression of Adgrf1 in the liver was directly correlated to fat content in the livers of both obese mice and NAFLD patients. Stearoyl-coA desaturase 1 (Scd1), a crucial enzyme in hepatic de novo lipogenesis, was identified as a downstream target of Adgrf1 by RNA-sequencing analysis. Treatment with the liver-specific Scd1 inhibitor MK8245 and specific shRNAs against Scd1 in primary hepatocytes improved the hepatic steatosis of Adgrf1-overexpressing mice and lipid profile of hepatocytes, respectively. Conclusions These results indicate Adgrf1 regulates hepatic lipid metabolism through controlling the expression of Scd1. Downregulation of Adgrf1 expression can potentially serve as a protective mechanism to stop the overaccumulation of fat in the liver in obese subjects. Overall, the above findings not only reveal a new mechanism regulating the progression of NAFLD, but also proposed a novel therapeutic approach to combat NAFLD by targeting Adgrf1. Funding This work was supported by the National Natural Science Foundation of China (81870586), Area of Excellence (AoE/M-707/18), and General Research Fund (15101520) to CMW, and the National Natural Science Foundation of China (82270941, 81974117) to SJ.
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Affiliation(s)
- Mengyao Wu
- Department of Chemistry and Chemical Engineering, Guangzhou UniversityGuangzhouChina
| | - Tak-Ho Lo
- Department of Health Technology and Informatics, Hong Kong Polytechnic UniversityHong KongHong Kong
| | - Liping Li
- Zhujiang Hospital, Southern Medical UniversityChinaChina
| | - Jia Sun
- Zhujiang Hospital, Southern Medical UniversityChinaChina
| | - Chujun Deng
- Department of Health Technology and Informatics, Hong Kong Polytechnic UniversityHong KongHong Kong
| | - Ka-Ying Chan
- Department of Health Technology and Informatics, Hong Kong Polytechnic UniversityHong KongHong Kong
| | - Xiang Li
- Department of Health Technology and Informatics, Hong Kong Polytechnic UniversityHong KongHong Kong
| | | | - Jimmy Tsz Hang Lee
- Department of Medicine, University of Hong KongHong KongHong Kong
- State Key Laboratory of Pharmaceutical Biotechnology, University of Hong KongHong KongChina
| | - Pauline Po Yee Lui
- Department of Orthopaedics and Traumatology, Chinese University of Hong KongHong KongHong Kong
| | - Aimin Xu
- Department of Medicine, University of Hong KongHong KongHong Kong
- State Key Laboratory of Pharmaceutical Biotechnology, University of Hong KongHong KongChina
| | - Chi-Ming Wong
- Department of Health Technology and Informatics, Hong Kong Polytechnic UniversityHong KongHong Kong
- State Key Laboratory of Pharmaceutical Biotechnology, University of Hong KongHong KongChina
- Hong Kong Polytechnic University, Shenzhen Research InstituteHong KongChina
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Yang Y, Fu X, Xia B, Zhou L, Zhang H, Li C, Ye X, Liu T. Glycyrrhizic acid glycosides reduces extensive tripterygium glycosides-induced lipid deposition in hepatocytes. Heliyon 2023; 9:e17891. [PMID: 37483744 PMCID: PMC10362073 DOI: 10.1016/j.heliyon.2023.e17891] [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: 02/01/2023] [Revised: 06/25/2023] [Accepted: 06/30/2023] [Indexed: 07/25/2023] Open
Abstract
Aim Tripterygium glycosides (TG) extracted from the plant Tripterygium wilfordii Hook F has been used to treat chronic kidney diseases for many years. However, hepatotoxicity limits its clinical application. Glycyrrhizic acid glycosides (GA) can reduce TG hepatotoxicity, however, further investigation into the underlying molecular mechanisms by which GA attenuates TG-induced hepatotoxicity is required. Methods Sprague‒Dawley rats were randomly divided into the control group, the TG groups (TG189 mg/kg group, TG472.5 mg/kg group), and the TG + GA groups (TG189 mg/kg + GA20.25 mg/kg group, TG472.5 mg/kg + GA20.25 mg/kg group). After 21 consecutive days of intragastric administration, structural and molecular changes in hepatocytes were detected. Results After 21 days of TG treatment, the serum level of the total bilirubin, triglyceride, total cholesterol, and low-density lipoprotein cholesterol increased in the TG189 mg/kg and TG472.5 mg/kg groups when compared to the control group. High-density lipoprotein cholesterol levels were reduced in both TG groups. The ultrastructure of hepatocytes and the structural integrity of the liver were compromised. In addition, the relevant molecular level of the peroxisome proliferators-activated receptor α (PPARα) and acyl-CoA synthetase long-chain family members (ACSLs) pathway was modulated. With the addition of 20.25 mg/kg GA, the serum biochemical indexes and liver tissue structure ultrastructure of hepatocytes were improved, and the PPARα-ACSLs pathway was corrected. Conclusion The combined application of GA and TG improved abnormal lipid metabolism, repaired liver structure, reduced lipid deposition in hepatocytes, and reduced TG-induced hepatotoxicity.
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Lu K, Fan Q, Zou X. Antisense oligonucleotide is a promising intervention for liver diseases. Front Pharmacol 2022; 13:1061842. [PMID: 36569303 PMCID: PMC9780395 DOI: 10.3389/fphar.2022.1061842] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 11/28/2022] [Indexed: 12/13/2022] Open
Abstract
As the body's critical metabolic organ, the liver plays an essential role in maintaining proper body homeostasis. However, as people's living standards have improved and the number of unhealthy lifestyles has increased, the liver has become overburdened. These have made liver disease one of the leading causes of death worldwide. Under the influence of adverse factors, liver disease progresses from simple steatosis to hepatitis, to liver fibrosis, and finally to cirrhosis and cancer, followed by increased mortality. Until now, there has been a lack of accepted effective treatments for liver disease. Based on current research, antisense oligonucleotide (ASO), as an alternative intervention for liver diseases, is expected to be an effective treatment due to its high efficiency, low toxicity, low dosage, strong specificity, and additional positive characteristics. In this review, we will first introduce the design, modification, delivery, and the mechanisms of ASO, and then summarize the application of ASO in liver disease treatment, including in non-alcoholic fatty liver disease (NAFLD), hepatitis, liver fibrosis, and liver cancer. Finally, we discuss challenges and perspectives on the transfer of ASO drugs into clinical use. This review provides a current and comprehensive understanding of the integrative and systematic functions of ASO for its use in liver disease.
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Affiliation(s)
- Kailing Lu
- College of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicinal Utilization, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Qijing Fan
- Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, Yunnan, China
| | - Xiaoju Zou
- College of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicinal Utilization, Yunnan University of Chinese Medicine, Kunming, Yunnan, China,*Correspondence: Xiaoju Zou,
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Zeng Y, Wu Y, Zhang Q, Xiao X. Non-coding RNAs: The link between maternal malnutrition and offspring metabolism. Front Nutr 2022; 9:1022784. [PMID: 36438765 PMCID: PMC9684648 DOI: 10.3389/fnut.2022.1022784] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 10/27/2022] [Indexed: 06/13/2025] Open
Abstract
Early life nutrition is associated with the development and metabolism in later life, which is known as the Developmental Origin of Health and Diseases (DOHaD). Epigenetics have been proposed as an important explanation for this link between early life malnutrition and long-term diseases. Non-coding RNAs (ncRNAs) may play a role in this epigenetic programming. The expression of ncRNAs (such as long non-coding RNA H19, microRNA-122, and circular RNA-SETD2) was significantly altered in specific tissues of offspring exposed to maternal malnutrition. Changes in these downstream targets of ncRNAs lead to abnormal development and metabolism. This review aims to summarize the existing knowledge on ncRNAs linking the maternal nutrition condition and offspring metabolic diseases, such as obesity, type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD).
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Affiliation(s)
| | | | - Qian Zhang
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xinhua Xiao
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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Katoh Y, Yaguchi T, Kubo A, Iwata T, Morii K, Kato D, Ohta S, Satomi R, Yamamoto Y, Oyamada Y, Ouchi K, Takahashi S, Ishioka C, Matoba R, Suematsu M, Kawakami Y. Inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor T cell response through regulating β-catenin signaling in cancer cells and ER stress in T cells and synergizes with anti-PD-1 antibody. J Immunother Cancer 2022; 10:jitc-2022-004616. [PMID: 35793868 PMCID: PMC9260842 DOI: 10.1136/jitc-2022-004616] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/19/2022] [Indexed: 11/26/2022] Open
Abstract
Background Understanding the mechanisms of non-T cell inflamed tumor microenvironment (TME) and their modulation are important to improve cancer immunotherapies such as immune checkpoint inhibitors. The involvement of various immunometabolisms has recently been indicated in the formation of immunosuppressive TME. In this study, we investigated the immunological roles of stearoyl-CoA desaturase 1 (SCD1), which is essential for fatty acid metabolism, in the cancer immune response. Methods We investigated the roles of SCD1 by inhibition with the chemical inhibitor or genetic manipulation in antitumor T cell responses and the therapeutic effect of anti-programmed cell death protein 1 (anti-PD-1) antibody using various mouse tumor models, and their cellular and molecular mechanisms. The roles of SCD1 in human cancers were also investigated by gene expression analyses of colon cancer tissues and by evaluating the related free fatty acids in sera obtained from patients with non-small cell lung cancer who were treated with anti-PD-1 antibody. Results Systemic administration of a SCD1 inhibitor in mouse tumor models enhanced production of CCL4 by cancer cells through reduction of Wnt/β-catenin signaling and by CD8+ effector T cells through reduction of endoplasmic reticulum stress. It in turn promoted recruitment of dendritic cells (DCs) into the tumors and enhanced the subsequent induction and tumor accumulation of antitumor CD8+ T cells. SCD1 inhibitor was also found to directly stimulate DCs and CD8+ T cells. Administration of SCD1 inhibitor or SCD1 knockout in mice synergized with an anti-PD-1 antibody for its antitumor effects in mouse tumor models. High SCD1 expression was observed in one of the non-T cell-inflamed subtypes in human colon cancer, and serum SCD1 related fatty acids were correlated with response rates and prognosis of patients with non-small lung cancer following anti-PD-1 antibody treatment. Conclusions SCD1 expressed in cancer cells and immune cells causes immunoresistant conditions, and its inhibition augments antitumor T cells and therapeutic effects of anti-PD-1 antibody. Therefore, SCD1 is an attractive target for the development of new diagnostic and therapeutic strategies to improve current cancer immunotherapies including immune checkpoint inhibitors.
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Affiliation(s)
- Yuki Katoh
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.,Division of Anatomical Science, Department of Functional Morphology, Nihon University School of Medicine, Tokyo, Japan
| | - Tomonori Yaguchi
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Akiko Kubo
- Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan
| | - Takashi Iwata
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.,Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Kenji Morii
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Daiki Kato
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.,Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Shigeki Ohta
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Ryosuke Satomi
- National Hospital Organisation Tokyo Medical Center, Tokyo, Japan
| | - Yasuhiro Yamamoto
- Department of Respiratory Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Kota Ouchi
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan.,Department of Clinical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shin Takahashi
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan.,Department of Clinical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Chikashi Ishioka
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan.,Department of Clinical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | | | - Makoto Suematsu
- Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan
| | - Yutaka Kawakami
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan .,Department of Immunology, International University of Health and Welfare, Chiba, Japan
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Jeyakumar SM, Vajreswari A. Stearoyl-CoA desaturase 1: A potential target for non-alcoholic fatty liver disease?-perspective on emerging experimental evidence. World J Hepatol 2022; 14:168-179. [PMID: 35126846 PMCID: PMC8790397 DOI: 10.4254/wjh.v14.i1.168] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/18/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a progressive disease and one of the leading causes of death. An unnamed disease has become a global epidemic disease of public health concern. This spectrum of diseases manifests itself with initial accumulation of excessive triglycerides (due to de novo lipogenesis) in the hepatocytes, leading to simple steatosis. Although its aetiology is multi-factorial, lifestyle changes (diet and physical activity) are considered to be the key thriving factors. In this context, high fructose consumption is associated with an increased risk for developing NAFLD in humans, while high-fructose feeding to experimental animals results in hepatic steatosis and non-alcoholic steatohepatitis, by increasing hepatic lipogenesis. Among several lipogenic genes, the endoplasmic reticulum-bound stearoyl-CoA desaturase 1 (SCD1) is the key determinant of triglycerides biosynthesis pathway, by providing monounsaturated fatty acids, through the incorporation of a double bond at the delta-9 position of saturated fatty acids, specifically, palmitic (C16:0) and stearic (C18:0) acids, yielding palmitoleic (C16:1) and oleic (C18:1) acids, respectively. Various experimental studies involving SCD1 gene knockout and diet-induced rodent models have demonstrated that SCD1 plays a key role in the development of NAFLD, by modulating hepatic lipogenesis and thus triglyceride accumulation in the liver. Several pharmacological and dietary intervention studies have shown the benefits of inhibiting hepatic SCD1 in the pathogenesis of NAFLD. In this review, we give an overview of SCD1 in NAFLD, based on the current experimental evidence and the translational applicability of SCD1 inhibition in human NAFLD conditions, besides discussing the limitations and way-forward.
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Affiliation(s)
- Shanmugam Murugaiha Jeyakumar
- Division of Lipid Biochemistry, National Institute of Nutrition, Hyderabad 500007, Telangana, India
- Department of Clinical Pharmacology, National Institute for Research in Tuberculosis, Chennai 600031, Tamil Nadu, India
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Hliwa A, Ramos-Molina B, Laski D, Mika A, Sledzinski T. The Role of Fatty Acids in Non-Alcoholic Fatty Liver Disease Progression: An Update. Int J Mol Sci 2021; 22:ijms22136900. [PMID: 34199035 PMCID: PMC8269415 DOI: 10.3390/ijms22136900] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/14/2021] [Accepted: 06/24/2021] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major public health problem worldwide. NAFLD (both simple steatosis and steatohepatitis) is characterized by alterations in hepatic lipid metabolism, which may lead to the development of severe liver complications including cirrhosis and hepatocellular carcinoma. Thus, an exhaustive examination of lipid disorders in the liver of NAFLD patients is much needed. Mass spectrometry-based lipidomics platforms allow for in-depth analysis of lipid alterations in a number of human diseases, including NAFLD. This review summarizes the current research on lipid alterations associated with NAFLD and related complications, with special emphasis on the changes in long-chain and short-chain fatty acids levels in both serum and liver tissue, as well as in the hepatic expression of genes encoding the enzymes catalyzing lipid interconversions.
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Affiliation(s)
- Aleksandra Hliwa
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland; (A.H.); (A.M.)
| | - Bruno Ramos-Molina
- Obesity and Metabolism Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), 30120 Murcia, Spain;
| | - Dariusz Laski
- Department of General, Endocrine and Transplant Surgery, Faculty of Medicine, Medical University of Gdansk, Smoluchowskiego 17, 80-214 Gdansk, Poland;
| | - Adriana Mika
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland; (A.H.); (A.M.)
| | - Tomasz Sledzinski
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland; (A.H.); (A.M.)
- Correspondence: ; Tel.: +48-58-3491479
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10
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Zhang E, Zhao Y, Hu H. Impact of Sodium Glucose Cotransporter 2 Inhibitors on Nonalcoholic Fatty Liver Disease Complicated by Diabetes Mellitus. Hepatol Commun 2021; 5:736-748. [PMID: 34027265 PMCID: PMC8122372 DOI: 10.1002/hep4.1611] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 08/25/2020] [Accepted: 08/30/2020] [Indexed: 02/06/2023] Open
Abstract
Sodium glucose cotransporter 2 (SGLT2), a type of membrane protein highly expressed in the kidney, can regulate plasma glucose through the glomerular filtration process by reabsorption from the kidney. SGLT2 inhibitors, which are newly developed oral antidiabetic drugs, can play a role in liver diseases by inhibiting SGLT2-mediated renal glucose reabsorption and inducing glycosuria. Nonalcoholic fatty liver disease (NAFLD) is the most common type of liver disease, resulting in severe liver dysfunction. During the progression of NAFLD, there are some hallmark complications, including lipid metabolism disorders, inflammation induction, and hepatocyte death. Herein, we review several SGLT2 inhibitors that are capable of protecting individuals with NAFLD from severe complications by inhibiting de novo lipogenesis, oxidative responses, inflammation induction, and hepatocyte death.
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Affiliation(s)
- Enxiang Zhang
- Key Laboratory of Growth Regulation and Transformation Research of Zhejiang ProvinceSchool of Life SciencesWestlake Institute for Advanced StudyWestlake UniversityShilongshanHangzhouChina.,Beijing Advanced Innovation Center for Food Nutrition and Human HealthCollege of Food Science and Nutritional EngineeringChina Agricultural UniversityBeijingChina.,Department of Biochemistry, Molecular Biology, and BiophysicsUniversity of MinnesotaMinneapolisMN
| | - Yang Zhao
- Department of CardiologyZhejiang Provincial People's HospitalHangzhouChina.,Cardiovascular DivisionDepartment of MedicineUniversity of MinnesotaMinneapolisMN
| | - Hongbo Hu
- Beijing Advanced Innovation Center for Food Nutrition and Human HealthCollege of Food Science and Nutritional EngineeringChina Agricultural UniversityBeijingChina
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11
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Huh JY, Reilly SM, Abu-Odeh M, Murphy AN, Mahata SK, Zhang J, Cho Y, Seo JB, Hung CW, Green CR, Metallo CM, Saltiel AR. TANK-Binding Kinase 1 Regulates the Localization of Acyl-CoA Synthetase ACSL1 to Control Hepatic Fatty Acid Oxidation. Cell Metab 2020; 32:1012-1027.e7. [PMID: 33152322 PMCID: PMC7710607 DOI: 10.1016/j.cmet.2020.10.010] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 08/20/2020] [Accepted: 10/12/2020] [Indexed: 12/12/2022]
Abstract
Hepatic TANK (TRAF family member associated NFκB activator)-binding kinase 1 (TBK1) activity is increased during obesity, and administration of a TBK1 inhibitor reduces fatty liver. Surprisingly, liver-specific TBK1 knockout in mice produces fatty liver by reducing fatty acid oxidation. TBK1 functions as a scaffolding protein to localize acyl-CoA synthetase long-chain family member 1 (ACSL1) to mitochondria, which generates acyl-CoAs that are channeled for β-oxidation. TBK1 is induced during fasting and maintained in the unphosphorylated, inactive state, enabling its high affinity binding to ACSL1 in mitochondria. In TBK1-deficient liver, ACSL1 is shifted to the endoplasmic reticulum to promote fatty acid re-esterification in lieu of oxidation in response to fasting, which accelerates hepatic lipid accumulation. The impaired fatty acid oxidation in TBK1-deficient hepatocytes is rescued by the expression of kinase-dead TBK1. Thus, TBK1 operates as a rheostat to direct the fate of fatty acids in hepatocytes, supporting oxidation when inactive during fasting and promoting re-esterification when activated during obesity.
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Affiliation(s)
- Jin Young Huh
- Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA
| | - Shannon M Reilly
- Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA
| | - Mohammad Abu-Odeh
- Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA
| | - Anne N Murphy
- Department of Pharmacology, University of California, San Diego, San Diego, CA 92093, USA
| | - Sushil K Mahata
- Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA; VA San Diego Healthcare System, San Diego, CA 92161, USA
| | - Jinyu Zhang
- Division of Biological Sciences, University of California, San Diego, San Diego, CA 92093, USA
| | - Yoori Cho
- Division of Biological Sciences, University of California, San Diego, San Diego, CA 92093, USA
| | - Jong Bae Seo
- Department of Biosciences, Mokpo National University, Jeonnam 58554, Republic of Korea
| | - Chao-Wei Hung
- Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA
| | - Courtney R Green
- Department of Bioengineering, University of California, San Diego, San Diego, CA 92093, USA
| | - Christian M Metallo
- Department of Bioengineering, University of California, San Diego, San Diego, CA 92093, USA
| | - Alan R Saltiel
- Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA; Department of Pharmacology, University of California, San Diego, San Diego, CA 92093, USA.
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12
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Cao B, Liu C, Zhang Q, Dong Y. Maternal High-Fat Diet Leads to Non-alcoholic Fatty Liver Disease Through Upregulating Hepatic SCD1 Expression in Neonate Rats. Front Nutr 2020; 7:581723. [PMID: 33282902 PMCID: PMC7705221 DOI: 10.3389/fnut.2020.581723] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 10/05/2020] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of liver disease in children, with evidence that the maternal diet and the early life nutritional environment are potential risk for such disease. This study was aimed to investigate the effects of maternal high-fat diet (HFD) on the occurrence of NAFLD in offspring rats and the underlying mechanisms. In this study, the incidence of NAFLD was compared in F1 offspring rats between the maternal HFD group and standard chow (SC) group. In addition, the expression levels of inflammatory cytokines in the placenta, in the umbilical cord blood, and in the livers of neonate offsprings were compared between two groups. HepG2 cells were treated with recombinant IL6 (rIL6) to assess stearoyl-CoA desaturase 1 (SCD1) expression and lipid synthesis in an inflammatory condition. Lipid accumulation was assayed in both SCD1 overexpression and interference HepG2 cells as well as in neonatal rats. Our results showed that HFD exposure before and throughout the pregnancy induced the elevated hepatic TG content of F1 neonates. The levels of inflammatory cytokines in the placenta, umbilical cord blood, and the livers of HFD F1 neonates were significantly higher than those of the SC group. In addition, rIL6 treatment led to TG accumulation accompanied by the upregulation of SCD1 in HepG2 cell lines. Overexpression of SCD1 led to the accumulation of TG contents in HepG2 cells, whereas Scd1 knockdown attenuated the effects of rIL6 treatment. Overexpression of SCD1 in F1 neonatal rats led to hepatic lipid accumulation. Our study indicated that maternal HFD led to intrauterine inflammation, which subsequently caused transgenerationally abnormal hepatic lipid metabolism of F1 neonates. This modulation might be mediated by upregulating SCD1 expression in hepatic cells.
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Affiliation(s)
- Baige Cao
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chongxiao Liu
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qianren Zhang
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Dong
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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13
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Anti-Obesity Effects of a Prunus persica and Nelumbo nucifera Mixture in Mice Fed a High-Fat Diet. Nutrients 2020; 12:nu12113392. [PMID: 33158191 PMCID: PMC7694277 DOI: 10.3390/nu12113392] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 11/02/2020] [Accepted: 11/02/2020] [Indexed: 12/13/2022] Open
Abstract
Prunus persica and Nelumbo nucifera are major crops cultivated worldwide. In East Asia, both P. persica flowers and N. nucifera leaves are traditionally used for therapeutic purposes and consumed as teas for weight loss. Herein, we investigated the anti-obesity effects of an herbal extract mixture of P. persica and N. nucifera (HT077) and the underlying mechanism using a high-fat diet (HFD)-induced obesity model. Male C57BL/6 mice were fed a normal diet, HFD, HFD containing 0.02% orlistat (positive control), or HFD containing 0.1, 0.2, or 0.4% HT077 for 12 weeks. HT077 significantly reduced final body weights, weight gain, abdominal fat weights, liver weights, and hepatic levels of triglycerides and total cholesterol. HT077 also lowered glucose, cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and leptin levels and increased AST/ALT and adiponectin/leptin ratios and adiponectin levels. Real-time polymerase chain reaction analysis showed that HT077 decreased the expression of lipogenic genes and increased the expression of fatty acid oxidation-related genes in adipose tissue. Our results indicate that HT077 exerts anti-obesity effects and prevents the development of obesity-related metabolic disorders. These beneficial effects might be partially attributed to ameliorating adipokine imbalances and regulating lipid synthesis and fatty acid oxidation in adipose tissue.
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14
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Cheng K, Ji S, Jia P, Zhang H, Wang T, Song Z, Zhang L, Wang T. Resveratrol Improves Hepatic Redox Status and Lipid Balance of Neonates with Intrauterine Growth Retardation in a Piglet Model. BIOMED RESEARCH INTERNATIONAL 2020; 2020:7402645. [PMID: 32733952 PMCID: PMC7383311 DOI: 10.1155/2020/7402645] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 06/30/2020] [Indexed: 12/20/2022]
Abstract
Abnormal lipid metabolism, oxidative stress (OS), and inflammation play a pivotal role in the increased susceptibility to neonatal fatty liver diseases associated with intrauterine growth retardation (IUGR). This study was firstly conducted to investigate whether resveratrol could alleviate IUGR-induced hepatic lipid accumulation, alteration of redox and immune status in a sucking piglet model and explore the possible mechanisms at transcriptional levels. A total of 36 pairs of 7 d old male normal birth weight (NBW) and IUGR piglets were orally fed with either 80 mg resveratrol/kg body weight/d or 0.5% carboxymethylcellulose sodium for a period of 14 days, respectively. Compared with the NBW piglets, the IUGR piglets displayed compromised growth performance and liver weight, reduced plasma free fatty acid (FFA) level, increased hepatic OS, abnormal hepatic lipid accumulation and weakened hepatic immune function, and hepatic aberrant transcriptional expression of some genes such as heme oxygenase 1, superoxide dismutase 1, sterol regulatory element-binding protein 1c, stearoyl-CoA desaturase 1, liver fatty acid-binding proteins 1, toll-like receptor 4, and tumor necrosis factor alpha (TNF-α). Oral administration of resveratrol to piglets decreased the levels of FFA and total triglycerides (TG) in the plasma and hepatic TNF-α concentration, and increased glutathione reductase activity and reduced glutathione level in the liver. Resveratrol restored the increased alanine aminotransferase activity in the plasma of IUGR piglets. Treatment with resveratrol ameliorated the increased hepatic malondialdehyde, protein carbonyl, TG, and FFA concentrations induced by IUGR. Resveratrol treatment alleviated the reduced lipoprotein lipase activity and its mRNA expression as well as TNF-α gene expression in the liver of IUGR piglets. Hepatic glutathione peroxidase 1 and monocyte chemotactic protein 1 genes expression of piglets was upregulated by oral resveratrol administration. In conclusion, resveratrol administration plays a beneficial role in hepatic redox status and lipid balance of the IUGR piglets.
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Affiliation(s)
- Kang Cheng
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Shuli Ji
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Peilu Jia
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Hao Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Ting Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Zhihua Song
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Lili Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Tian Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
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15
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Axelrod CL, King WT, Davuluri G, Noland RC, Hall J, Hull M, Dantas WS, Zunica ERM, Alexopoulos SJ, Hoehn KL, Langohr I, Stadler K, Doyle H, Schmidt E, Nieuwoudt S, Fitzgerald K, Pergola K, Fujioka H, Mey JT, Fealy C, Mulya A, Beyl R, Hoppel CL, Kirwan JP. BAM15-mediated mitochondrial uncoupling protects against obesity and improves glycemic control. EMBO Mol Med 2020; 12:e12088. [PMID: 32519812 PMCID: PMC7338798 DOI: 10.15252/emmm.202012088] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 05/15/2020] [Accepted: 05/15/2020] [Indexed: 11/09/2022] Open
Abstract
Obesity is a leading cause of preventable death worldwide. Despite this, current strategies for the treatment of obesity remain ineffective at achieving long-term weight control. This is due, in part, to difficulties in identifying tolerable and efficacious small molecules or biologics capable of regulating systemic nutrient homeostasis. Here, we demonstrate that BAM15, a mitochondrially targeted small molecule protonophore, stimulates energy expenditure and glucose and lipid metabolism to protect against diet-induced obesity. Exposure to BAM15 in vitro enhanced mitochondrial respiratory kinetics, improved insulin action, and stimulated nutrient uptake by sustained activation of AMPK. C57BL/6J mice treated with BAM15 were resistant to weight gain. Furthermore, BAM15-treated mice exhibited improved body composition and glycemic control independent of weight loss, effects attributable to drug targeting of lipid-rich tissues. We provide the first phenotypic characterization and demonstration of pre-clinical efficacy for BAM15 as a pharmacological approach for the treatment of obesity and related diseases.
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Affiliation(s)
- Christopher L Axelrod
- Integrated Physiology and Molecular Medicine LaboratoryPennington Biomedical Research CenterBaton RougeLAUSA
- Department of Translational ServicesPennington Biomedical Research CenterBaton RougeLAUSA
- Department of Inflammation and ImmunityLerner Research InstituteCleveland ClinicClevelandOHUSA
| | - William T King
- Integrated Physiology and Molecular Medicine LaboratoryPennington Biomedical Research CenterBaton RougeLAUSA
- Department of Translational ServicesPennington Biomedical Research CenterBaton RougeLAUSA
| | - Gangarao Davuluri
- Integrated Physiology and Molecular Medicine LaboratoryPennington Biomedical Research CenterBaton RougeLAUSA
- Sarcopenia and Malnutrition LaboratoryPennington Biomedical Research CenterBaton RougeLAUSA
| | - Robert C Noland
- Skeletal Muscle Metabolism LaboratoryPennington Biomedical Research CenterBaton RougeLAUSA
| | - Jacob Hall
- Integrated Physiology and Molecular Medicine LaboratoryPennington Biomedical Research CenterBaton RougeLAUSA
- Department of Translational ServicesPennington Biomedical Research CenterBaton RougeLAUSA
| | - Michaela Hull
- Department of Inflammation and ImmunityLerner Research InstituteCleveland ClinicClevelandOHUSA
| | - Wagner S Dantas
- Integrated Physiology and Molecular Medicine LaboratoryPennington Biomedical Research CenterBaton RougeLAUSA
| | - Elizabeth RM Zunica
- Integrated Physiology and Molecular Medicine LaboratoryPennington Biomedical Research CenterBaton RougeLAUSA
- Department of NutritionCase Western Reserve UniversityClevelandOHUSA
| | - Stephanie J Alexopoulos
- School of Biotechnology and Biomolecular SciencesUniversity of New South WalesSydneyNSWAustralia
| | - Kyle L Hoehn
- School of Biotechnology and Biomolecular SciencesUniversity of New South WalesSydneyNSWAustralia
| | - Ingeborg Langohr
- Department of Pathobiological SciencesLouisiana State UniversityBaton RougeLAUSA
| | - Krisztian Stadler
- Oxidative Stress and Disease LaboratoryPennington Biomedical Research CenterBaton RougeLAUSA
| | - Haylee Doyle
- Oxidative Stress and Disease LaboratoryPennington Biomedical Research CenterBaton RougeLAUSA
| | - Eva Schmidt
- Oxidative Stress and Disease LaboratoryPennington Biomedical Research CenterBaton RougeLAUSA
| | - Stephan Nieuwoudt
- Department of Inflammation and ImmunityLerner Research InstituteCleveland ClinicClevelandOHUSA
| | - Kelly Fitzgerald
- Department of Inflammation and ImmunityLerner Research InstituteCleveland ClinicClevelandOHUSA
| | - Kathryn Pergola
- Integrated Physiology and Molecular Medicine LaboratoryPennington Biomedical Research CenterBaton RougeLAUSA
- Department of Translational ServicesPennington Biomedical Research CenterBaton RougeLAUSA
| | - Hisashi Fujioka
- Cryo‐Electron Microscopy CoreCase Western Reserve UniversityClevelandOHUSA
| | - Jacob T Mey
- Integrated Physiology and Molecular Medicine LaboratoryPennington Biomedical Research CenterBaton RougeLAUSA
- Department of Inflammation and ImmunityLerner Research InstituteCleveland ClinicClevelandOHUSA
| | - Ciaran Fealy
- Department of Inflammation and ImmunityLerner Research InstituteCleveland ClinicClevelandOHUSA
| | - Anny Mulya
- Department of Inflammation and ImmunityLerner Research InstituteCleveland ClinicClevelandOHUSA
| | - Robbie Beyl
- Department of BiostatisticsPennington Biomedical Research CenterBaton RougeLAUSA
| | - Charles L Hoppel
- Integrated Physiology and Molecular Medicine LaboratoryPennington Biomedical Research CenterBaton RougeLAUSA
- Department of PharmacologyCase Western Reserve UniversityClevelandOHUSA
| | - John P Kirwan
- Integrated Physiology and Molecular Medicine LaboratoryPennington Biomedical Research CenterBaton RougeLAUSA
- Department of Inflammation and ImmunityLerner Research InstituteCleveland ClinicClevelandOHUSA
- Department of NutritionCase Western Reserve UniversityClevelandOHUSA
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16
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Korbecki J, Kojder K, Jeżewski D, Simińska D, Tarnowski M, Kopytko P, Safranow K, Gutowska I, Goschorska M, Kolasa-Wołosiuk A, Wiszniewska B, Chlubek D, Baranowska-Bosiacka I. Expression of SCD and FADS2 Is Lower in the Necrotic Core and Growing Tumor Area than in the Peritumoral Area of Glioblastoma Multiforme. Biomolecules 2020; 10:biom10050727. [PMID: 32392704 PMCID: PMC7277411 DOI: 10.3390/biom10050727] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/29/2020] [Accepted: 05/02/2020] [Indexed: 01/31/2023] Open
Abstract
The expression of desaturases is higher in many types of cancer, and despite their recognized role in oncogenesis, there has been no research on the expression of desaturases in glioblastoma multiforme (GBM). Tumor tissue samples were collected during surgery from 28 patients (16 men and 12 women) diagnosed with GBM. The effect of necrotic conditions and nutritional deficiency (mimicking conditions in the studied tumor zones) was studied in an in vitro culture of human brain (glioblastoma astrocytoma) U-87 MG cells. Analysis of desaturase expression was made by qRT-PCR and the immunohistochemistry method. In the tumor, the expression of stearoyl–coenzyme A desaturase (SCD) and fatty acid desaturases 2 (FADS2) was lower than in the peritumoral area. The expression of other desaturases did not differ in between the distinguished zones. We found no differences in the expression of SCD, fatty acid desaturases 1 (FADS1), or FADS2 between the sexes. Necrotic conditions and nutritional deficiency increased the expression of the studied desaturase in human brain (glioblastoma astrocytoma) U-87 MG cells. The obtained results suggest that (i) biosynthesis of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) in a GBM tumor is less intense than in the peritumoral area; (ii) expressions of SCD, SCD5, FADS1, and FADS2 correlate with each other in the necrotic core, growing tumor area, and peritumoral area; (iii) expressions of desaturases in a GBM tumor do not differ between the sexes; and (iv) nutritional deficiency increases the biosynthesis of MUFA and PUFA in GBM cells.
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Affiliation(s)
- Jan Korbecki
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (K.S.); (M.G.); (D.C.)
| | - Klaudyna Kojder
- Department of Anaesthesiology and Intensive Care, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1, 71-252 Szczecin, Poland;
| | - Dariusz Jeżewski
- Department of Neurosurgery and Pediatric Neurosurgery, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1, 71-252 Szczecin, Poland;
- Department of Applied Neurocognitivistics, Unii Lubelskiej 1, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland
| | - Donata Simińska
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (K.S.); (M.G.); (D.C.)
| | - Maciej Tarnowski
- Department of Physiology, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (M.T.); (P.K.)
| | - Patrycja Kopytko
- Department of Physiology, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (M.T.); (P.K.)
| | - Krzysztof Safranow
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (K.S.); (M.G.); (D.C.)
| | - Izabela Gutowska
- Department of Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland;
| | - Marta Goschorska
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (K.S.); (M.G.); (D.C.)
| | - Agnieszka Kolasa-Wołosiuk
- Department of Histology and Embryology, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (A.K.-W.); (B.W.)
| | - Barbara Wiszniewska
- Department of Histology and Embryology, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (A.K.-W.); (B.W.)
| | - Dariusz Chlubek
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (K.S.); (M.G.); (D.C.)
| | - Irena Baranowska-Bosiacka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (K.S.); (M.G.); (D.C.)
- Correspondence: ; Tel.: +48-91-466-1515; Fax: +48-91-466-1516
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17
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Iwase M, Tokiwa S, Seno S, Mukai T, Yeh YS, Takahashi H, Nomura W, Jheng HF, Matsumura S, Kusudo T, Osato N, Matsuda H, Inoue K, Kawada T, Goto T. Glycerol kinase stimulates uncoupling protein 1 expression by regulating fatty acid metabolism in beige adipocytes. J Biol Chem 2020; 295:7033-7045. [PMID: 32273338 DOI: 10.1074/jbc.ra119.011658] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 04/02/2020] [Indexed: 11/06/2022] Open
Abstract
Browning of adipose tissue is induced by specific stimuli such as cold exposure and consists of up-regulation of thermogenesis in white adipose tissue. Recently, it has emerged as an attractive target for managing obesity in humans. Here, we performed a comprehensive analysis to identify genes associated with browning in murine adipose tissue. We focused on glycerol kinase (GYK) because its mRNA expression pattern is highly correlated with that of uncoupling protein 1 (UCP1), which regulates the thermogenic capacity of adipocytes. Cold exposure-induced Ucp1 up-regulation in inguinal white adipose tissue (iWAT) was partially abolished by Gyk knockdown (KD) in vivo Consistently, the Gyk KD inhibited Ucp1 expression induced by treatment with the β-adrenergic receptors (βAR) agonist isoproterenol (Iso) in vitro and resulted in impaired uncoupled respiration. Gyk KD also suppressed Iso- and adenylate cyclase activator-induced transcriptional activation and phosphorylation of the cAMP response element-binding protein (CREB). However, we did not observe these effects with a cAMP analog. Therefore Gyk KD related to Iso-induced cAMP products. In Iso-treated Gyk KD adipocytes, stearoyl-CoA desaturase 1 (SCD1) was up-regulated, and monounsaturated fatty acids such as palmitoleic acid (POA) accumulated. Moreover, a SCD1 inhibitor treatment recovered the Gyk KD-induced Ucp1 down-regulation and POA treatment down-regulated Iso-activated Ucp1 Our findings suggest that Gyk stimulates Ucp1 expression via a mechanism that partially depends on the βAR-cAMP-CREB pathway and Gyk-mediated regulation of fatty acid metabolism.
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Affiliation(s)
- Mari Iwase
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Soshi Tokiwa
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Shigeto Seno
- Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, Suita 565-0871, Japan
| | - Takako Mukai
- Faculty of Human Sciences, Tezukayama Gakuin University, Sakai 590-0113, Japan
| | - Yu-Sheng Yeh
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Haruya Takahashi
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Wataru Nomura
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan.,Research Unit for Physiological Chemistry, Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8317, Japan
| | - Huei-Fen Jheng
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Sigenobu Matsumura
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Tatsuya Kusudo
- Faculty of Human Sciences, Tezukayama Gakuin University, Sakai 590-0113, Japan
| | - Naoki Osato
- Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, Suita 565-0871, Japan
| | - Hideo Matsuda
- Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, Suita 565-0871, Japan
| | - Kazuo Inoue
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Teruo Kawada
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan.,Research Unit for Physiological Chemistry, Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8317, Japan
| | - Tsuyoshi Goto
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan .,Research Unit for Physiological Chemistry, Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8317, Japan
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18
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Trentzsch M, Nyamugenda E, Miles TK, Griffin H, Russell S, Koss B, Cooney KA, Phelan KD, Tackett AJ, Iyer S, Boysen G, Baldini G. Delivery of phosphatidylethanolamine blunts stress in hepatoma cells exposed to elevated palmitate by targeting the endoplasmic reticulum. Cell Death Discov 2020; 6:8. [PMID: 32123584 PMCID: PMC7028721 DOI: 10.1038/s41420-020-0241-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 01/18/2020] [Accepted: 01/24/2020] [Indexed: 02/07/2023] Open
Abstract
Genetic obesity increases in liver phosphatidylcholine (PC)/phosphatidylethanolamine (PE) ratio, inducing endoplasmic reticulum (ER) stress without concomitant increase of ER chaperones. Here, it is found that exposing mice to a palm oil-based high fat (HF) diet induced obesity, loss of liver PE, and loss of the ER chaperone Grp78/BiP in pericentral hepatocytes. In Hepa1-6 cells treated with elevated concentration of palmitate to model lipid stress, Grp78/BiP mRNA was increased, indicating onset of stress-induced Unfolded Protein Response (UPR), but Grp78/BiP protein abundance was nevertheless decreased. Exposure to elevated palmitate also induced in hepatoma cells decreased membrane glycosylation, nuclear translocation of pro-apoptotic C/EBP-homologous-protein-10 (CHOP), expansion of ER-derived quality control compartment (ERQC), loss of mitochondrial membrane potential (MMP), and decreased oxidative phosphorylation. When PE was delivered to Hepa1-6 cells exposed to elevated palmitate, effects by elevated palmitate to decrease Grp78/BiP protein abundance and suppress membrane glycosylation were blunted. Delivery of PE to Hepa1-6 cells treated with elevated palmitate also blunted expansion of ERQC, decreased nuclear translocation of CHOP and lowered abundance of reactive oxygen species (ROS). Instead, delivery of the chemical chaperone 4-phenyl-butyrate (PBA) to Hepa1-6 cells treated with elevated palmitate, while increasing abundance of Grp78/BiP protein and restoring membrane glycosylation, also increased ERQC, expression and nuclear translocation of CHOP, non-mitochondrial oxygen consumption, and generation of ROS. Data indicate that delivery of PE to hepatoma cells under lipid stress recovers cell function by targeting the secretory pathway and by blunting pro-apoptotic branches of the UPR.
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Affiliation(s)
- Marcus Trentzsch
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Eugene Nyamugenda
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Tiffany K. Miles
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Haven Griffin
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Susan Russell
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Brian Koss
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Kimberly A. Cooney
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Kevin D. Phelan
- Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Alan J. Tackett
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Srividhya Iyer
- Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Gunnar Boysen
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Giulia Baldini
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR USA
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19
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Simoes IC, Janikiewicz J, Bauer J, Karkucinska-Wieckowska A, Kalinowski P, Dobrzyń A, Wolski A, Pronicki M, Zieniewicz K, Dobrzyń P, Krawczyk M, Zischka H, Wieckowski MR, Potes Y. Fat and Sugar-A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease. Nutrients 2019; 11:2871. [PMID: 31771244 PMCID: PMC6950566 DOI: 10.3390/nu11122871] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 11/20/2019] [Accepted: 11/21/2019] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common disease in Western society and ranges from steatosis to steatohepatitis to end-stage liver disease such as cirrhosis and hepatocellular carcinoma. The molecular mechanisms that are involved in the progression of steatosis to more severe liver damage in patients are not fully understood. A deeper investigation of NAFLD pathogenesis is possible due to the many different animal models developed recently. In this review, we present a comparative overview of the most common dietary NAFLD rodent models with respect to their metabolic phenotype and morphological manifestation. Moreover, we describe similarities and controversies concerning the effect of NAFLD-inducing diets on mitochondria as well as mitochondria-derived oxidative stress in the progression of NAFLD.
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Affiliation(s)
- Ines C.M. Simoes
- Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland (J.J.); (A.D.); (P.D.); (Y.P.)
| | - Justyna Janikiewicz
- Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland (J.J.); (A.D.); (P.D.); (Y.P.)
| | - Judith Bauer
- Institute of Toxicology and Environmental Hygiene, Technical University Munich, School of Medicine, Biedersteiner Strasse 29, D-80802 Munich, Germany; (J.B.); (H.Z.)
| | | | - Piotr Kalinowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; (P.K.); (K.Z.)
| | - Agnieszka Dobrzyń
- Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland (J.J.); (A.D.); (P.D.); (Y.P.)
| | - Andrzej Wolski
- Department of Interventional Radiology and Neuroradiology, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Maciej Pronicki
- Department of Pathology, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland; (A.K.-W.); (M.P.)
| | - Krzysztof Zieniewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; (P.K.); (K.Z.)
| | - Paweł Dobrzyń
- Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland (J.J.); (A.D.); (P.D.); (Y.P.)
| | - Marcin Krawczyk
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, 02-091 Warsaw, Poland;
- Department of Medicine II, Saarland University Medical Center, 66421 Homburg, Germany
| | - Hans Zischka
- Institute of Toxicology and Environmental Hygiene, Technical University Munich, School of Medicine, Biedersteiner Strasse 29, D-80802 Munich, Germany; (J.B.); (H.Z.)
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, D-85764 Neuherberg, Germany
| | - Mariusz R. Wieckowski
- Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland (J.J.); (A.D.); (P.D.); (Y.P.)
| | - Yaiza Potes
- Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland (J.J.); (A.D.); (P.D.); (Y.P.)
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20
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Piccinin E, Cariello M, De Santis S, Ducheix S, Sabbà C, Ntambi JM, Moschetta A. Role of Oleic Acid in the Gut-Liver Axis: From Diet to the Regulation of Its Synthesis via Stearoyl-CoA Desaturase 1 (SCD1). Nutrients 2019; 11:nu11102283. [PMID: 31554181 PMCID: PMC6835877 DOI: 10.3390/nu11102283] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 09/18/2019] [Accepted: 09/20/2019] [Indexed: 12/13/2022] Open
Abstract
The consumption of an olive oil rich diet has been associated with the diminished incidence of cardiovascular disease and cancer. Several studies have attributed these beneficial effects to oleic acid (C18 n-9), the predominant fatty acid principal component of olive oil. Oleic acid is not an essential fatty acid since it can be endogenously synthesized in humans. Stearoyl-CoA desaturase 1 (SCD1) is the enzyme responsible for oleic acid production and, more generally, for the synthesis of monounsaturated fatty acids (MUFA). The saturated to monounsaturated fatty acid ratio affects the regulation of cell growth and differentiation, and alteration in this ratio has been implicated in a variety of diseases, such as liver dysfunction and intestinal inflammation. In this review, we discuss our current understanding of the impact of gene-nutrient interactions in liver and gut diseases, by taking advantage of the role of SCD1 and its product oleic acid in the modulation of different hepatic and intestinal metabolic pathways.
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Affiliation(s)
- Elena Piccinin
- Clinica Medica Cesare Frugoni, Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124 Bari, Italy.
| | - Marica Cariello
- Clinica Medica Cesare Frugoni, Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124 Bari, Italy.
| | - Stefania De Santis
- Clinica Medica Cesare Frugoni, Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124 Bari, Italy.
- INBB, National Institute for Biostructures and Biosystems, 00136 Rome, Italy.
- Department of Pharmacy-Drug Science, University of Bari "Aldo Moro", 70126 Bari, Italy.
| | - Simon Ducheix
- Institut du thorax, INSERM, CNRS, University of Nantes, 44007 Nantes, France.
| | - Carlo Sabbà
- Clinica Medica Cesare Frugoni, Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124 Bari, Italy.
| | - James M Ntambi
- Departments of Biochemistry and of Nutritional Sciences, University of Wisconsin, Madison, WI 53706, USA.
| | - Antonio Moschetta
- Clinica Medica Cesare Frugoni, Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124 Bari, Italy.
- INBB, National Institute for Biostructures and Biosystems, 00136 Rome, Italy.
- IRCCS Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy.
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21
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KAMOHARA T, KOSHIGUCHI M, MAEDA-YAMAMOTO M, SHINODA Y, KAMETANI N, HIRAI S, EGASHIRA Y. The Combination of ‘Benifuuki’ with Quercetin Suppresses Hepatic Fat Accumulation in High-Fat High-Cholesterol Diet-Fed Rats. J Nutr Sci Vitaminol (Tokyo) 2019; 65:196-201. [DOI: 10.3177/jnsv.65.196] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Tomoko KAMOHARA
- Laboratory of Food and Nutrition, Graduate School of Horticulture, Chiba University
| | - Manami KOSHIGUCHI
- Laboratory of Food and Nutrition, Graduate School of Horticulture, Chiba University
| | | | - Yuki SHINODA
- Product Research & Development Headquarters, Asahi Soft Drinks Co., Ltd
| | - Norihiro KAMETANI
- Product Research & Development Headquarters, Asahi Soft Drinks Co., Ltd
| | - Shizuka HIRAI
- Laboratory of Food and Nutrition, Graduate School of Horticulture, Chiba University
| | - Yukari EGASHIRA
- Laboratory of Food and Nutrition, Graduate School of Horticulture, Chiba University
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22
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Yang B, Jiang WD, Wu P, Liu Y, Zeng YY, Jiang J, Kuang SY, Tang L, Tang WN, Wang SW, Zhou XQ, Feng L. Soybean isoflavones improve the health benefits, flavour quality indicators and physical properties of grass carp (Ctenopharygodon idella). PLoS One 2019; 14:e0209570. [PMID: 30699129 PMCID: PMC6353095 DOI: 10.1371/journal.pone.0209570] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 12/07/2018] [Indexed: 12/14/2022] Open
Abstract
Health benefits, flavour quality indicators and physical properties were analysed after feeding grass carp graded concentrations of soybean isoflavones (SIF) (0, 25, 50, 75, 100 and 125 mg/kg) for 60 days. The results demonstrated that optimal dietary SIF supplementation improved the protein and total PUFA content, especially healthcare n-3 PUFA (C18: 3n-3, EPA and DHA), and increased the flavour-related free amino acid [especially umami amino acid] and 5'-inosine monophosphate content, improving the health benefits and flavour quality indicators in the muscle of grass carp. In addition, optimal dietary SIF supplementation (25 or 50 mg SIF/kg diet) enhanced some physical properties [water-holding capacity and tenderness] and increased the collagen content; however, it reduced cathepsin activity and apoptosis. SIF supplementation enhanced the glutathione content and the activity of antioxidant enzymes (except CuZnSOD) by regulating their gene expression. The gene expression could be regulated by NF-E2-related factor 2 (Nrf2) signalling in the muscle of grass carp. We demonstrated that optimal dietary SIF supplementation elevated the health benefits, flavour quality indicators and physical properties of fish muscle.
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Affiliation(s)
- Bo Yang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Wei-Dan Jiang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
- Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Pei Wu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
- Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Yang Liu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
- Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Yun-Yun Zeng
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Jun Jiang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
| | - Sheng-Yao Kuang
- Animal Nutrition Institute, Sichuan Academy of Animal Science, Chengdu, Sichuan, China
| | - Ling Tang
- Animal Nutrition Institute, Sichuan Academy of Animal Science, Chengdu, Sichuan, China
| | - Wu-Neng Tang
- Animal Nutrition Institute, Sichuan Academy of Animal Science, Chengdu, Sichuan, China
| | | | - Xiao-Qiu Zhou
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
- Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
| | - Lin Feng
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
- Fish Nutrition and Safety Production University Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
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23
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Luo L, Fang K, Dan X, Gu M. Crocin ameliorates hepatic steatosis through activation of AMPK signaling in db/db mice. Lipids Health Dis 2019; 18:11. [PMID: 30621686 PMCID: PMC6325828 DOI: 10.1186/s12944-018-0955-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 12/26/2018] [Indexed: 01/13/2023] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is closely linked to obesity, type 2 diabetes and other metabolic disorders worldwide. Crocin is a carotenoid compound possessing various pharmacological activities. In the present study, we aimed to investigate the effect on fatty liver under diabetic and obese condition and to examine the possible role of AMP-activated protein kinase (AMPK) signaling. Methods db/db mice were administrated with crocin and injected with LV-shAMPK or its negative control lentivirus. Metabolic dysfunction, lipogenesis and fatty acid-oxidation in liver were evaluated. Results In db/db mice, we found that oral administration of crocin significantly upregulated the phosphorylation of AMPK and downregulated the phosphorylation of mTOR in liver. Crocin reduced liver weight, serum levels of alanine aminotransferase, alanine aminotransferase, and liver triglyceride content, and attenuated morphological injury of liver in db/db mice. Crocin inhibited the mRNA expression of lipogenesis-associated genes, including sterol regulatory element binding protein-1c, peroxisome proliferator-activated receptor γ, fatty acid synthase, stearoyl-CoA desaturase 1, and diacylglycerol acyltransferase 1, and increased the mRNA expression of genes involved in the regulation of β-oxidation of fatty acids, including PPARα, acyl-CoA oxidase 1, carnitine palmitoyltransferase 1, and 3-hydroxy-3-methylglutaryl-CoA synthase 2. Moreover, treatment of crocin resulted in a amelioration of general metabolic disorder, as evidenced by decreased fasting blood glucose, reduced serum levels of insulin, triglyceride, total cholesterol, and non-esterified fatty acid, and improved glucose intolerance. Crocin-induced protective effects against fatty liver and metabolic disorder were significantly blocked by lentivirus-mediated downregulation of AMPK. Conclusions The results suggest that crocin can inhibit lipogenesis and promote β-oxidation of fatty acids through activation of AMPK, leading to improvement of fatty liver and metabolic dysfunction. Therefore, crocin may be a potential promising option for the clinical treatment for NAFLD and associated metabolic diseases.
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Affiliation(s)
- Li Luo
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, NO.1277 Jiefang Avenue, Wuhan, 430022, China
| | - Kai Fang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, NO.1277 Jiefang Avenue, Wuhan, 430022, China
| | - Xiaomeng Dan
- Hubei Institute For Drug Control, Wuhan, 430075, China
| | - Ming Gu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, NO.1277 Jiefang Avenue, Wuhan, 430022, China.
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24
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Srivastava RAK. Life-style-induced metabolic derangement and epigenetic changes promote diabetes and oxidative stress leading to NASH and atherosclerosis severity. J Diabetes Metab Disord 2018; 17:381-391. [PMID: 30918873 DOI: 10.1007/s40200-018-0378-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 11/20/2018] [Indexed: 12/15/2022]
Abstract
Energy imbalance resulting from high calorie food intake and insufficient metabolic activity leads to increased body mass index (BMI) and sets the stage for metabolic derangement influencing lipid and carbohydrate metabolism and ultimately leading to insulin resistance, dyslipidemia, and type 2 diabetes. 70% of cardiovascular disease (CVD) deaths occur in patients with diabetes. Environment-induced physiological perturbations trigger epigenetic changes through chromatin modification and leads to type 2 diabetes and progression of nonalcoholic fatty liver disease (NAFLD) and CVD. Thus, in terms of disease progression and pathogenesis, energy homeostasis, metabolic dysregulation, diabetes, fatty liver, and CVD are interlinked. Since advanced glycation end products (AGEs) and low-grade inflammation in type 2 diabetes play definitive roles in the pathogenesis of liver and vascular diseases, a natural checkpoint to prevent diabetes and associated complications appears to be the identification and management of prediabetes together with weight management, since 70% of prediabetic individuals develop diabetes during their life time, and every kg of weight increase is associated with up to 9% increase in diabetes risk. A good proportion of diabetes and obesity population have fatty liver that progresses to non-alcoholic steatohepatitis (NASH) and cirrhosis, and increased risk of hepatocellular carcinoma. Diabetes and NASH both have elevated oxidative stress, impaired cholesterol elimination, and increased inflammation that leads to CVD risk. This review addresses life-style-induced metabolic pathway derangement and how it contributes to epigenetic changes, type 2 diabetes and NASH progression, which collectively lead to increased risk of CVD.
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Affiliation(s)
- Rai Ajit K Srivastava
- Integrated Pharma Solutions, Philadelphia, PA USA.,2Department of Nutrition, Wayne State University, Detroit, MI USA
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25
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Steffen BT, Duprez D, Szklo M, Guan W, Tsai MY. Circulating oleic acid levels are related to greater risks of cardiovascular events and all-cause mortality: The Multi-Ethnic Study of Atherosclerosis. J Clin Lipidol 2018; 12:1404-1412. [PMID: 30201531 PMCID: PMC6289878 DOI: 10.1016/j.jacl.2018.08.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 08/07/2018] [Accepted: 08/08/2018] [Indexed: 10/28/2022]
Abstract
BACKGROUND Limited evidence has suggested that circulating levels of the omega-9 fatty acid, oleic acid, may be related to greater risks of adverse cardiovascular outcomes. OBJECTIVE We aimed to determine whether plasma oleic acid may be independently associated with clinical and subclinical cardiovascular disease (CVD) and all-cause mortality in a large multiethnic cohort. METHODS Plasma fatty acids were measured by gas chromatography-flame ionization in 6568 participants of the Multi-Ethnic Study of Atherosclerosis. The presence of coronary artery calcium (CAC) and aortic valve calcification (AVC) was determined by computed tomography, and carotid plaque was assessed by ultrasound. Incident CVD was defined as myocardial infarction, fatal coronary heart disease, resuscitated cardiac arrest, stroke, or stroke death. Heart failure (HF) was adjudicated from clinical records. Relative risk regression estimated plasma oleic acid-related rate ratios for prevalent CAC, AVC, and carotid plaque. Cox regression estimated hazard ratios (HRs) for CVD, HF, and all-cause mortality over a median 13-year follow-up. RESULTS Individuals in top quartiles of oleic acid showed greater rate ratios of CAC, AVC, and carotid plaque (all P < .001), but associations were rendered nonsignificant after adjustment for other risk factors. By contrast, those in top quartiles of plasma oleic acid showed significantly greater risks of incident HF (HR: 2.03; P < .001), CVD (HR: 1.41; P = .008), and all-cause mortality (HR: 1.55; P < .001) than those in referent quartiles independent of typical risk factors as well as plasma omega-3 fatty acid levels. CONCLUSIONS Plasma oleic acid appears to be a risk factor for CVD events and all-cause mortality independent of typical risk factors and plasma omega-3 fatty acids. Additional studies are warranted for confirmation and to further examine whether plasma oleic acid directly contributes to, or serves as a marker of, disease pathogenesis. These findings should not be extrapolated to dietary oleic acid intake.
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Affiliation(s)
- Brian T Steffen
- Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN, USA
| | - Daniel Duprez
- Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Moyses Szklo
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Weihua Guan
- Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, MN, USA
| | - Michael Y Tsai
- Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN, USA.
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Ipsen DH, Lykkesfeldt J, Tveden-Nyborg P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci 2018; 75:3313-3327. [PMID: 29936596 PMCID: PMC6105174 DOI: 10.1007/s00018-018-2860-6] [Citation(s) in RCA: 949] [Impact Index Per Article: 135.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 06/18/2018] [Accepted: 06/20/2018] [Indexed: 12/17/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently the world's most common liver disease, estimated to affect up to one-fourth of the population. Hallmarked by hepatic steatosis, NAFLD is associated with a multitude of detrimental effects and increased mortality. This narrative review investigates the molecular mechanisms of hepatic steatosis in NAFLD, focusing on the four major pathways contributing to lipid homeostasis in the liver. Hepatic steatosis is a consequence of lipid acquisition exceeding lipid disposal, i.e., the uptake of fatty acids and de novo lipogenesis surpassing fatty acid oxidation and export. In NAFLD, hepatic uptake and de novo lipogenesis are increased, while a compensatory enhancement of fatty acid oxidation is insufficient in normalizing lipid levels and may even promote cellular damage and disease progression by inducing oxidative stress, especially with compromised mitochondrial function and increased oxidation in peroxisomes and cytochromes. While lipid export initially increases, it plateaus and may even decrease with disease progression, sustaining the accumulation of lipids. Fueled by lipo-apoptosis, hepatic steatosis leads to systemic metabolic disarray that adversely affects multiple organs, placing abnormal lipid metabolism associated with NAFLD in close relation to many of the current life-style-related diseases.
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Affiliation(s)
- David Højland Ipsen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg C, Denmark
| | - Jens Lykkesfeldt
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg C, Denmark
| | - Pernille Tveden-Nyborg
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg C, Denmark.
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27
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Wei Q, Zhou B, Yang G, Hu W, Zhang L, Liu R, Li M, Wang K, Gu HF, Guan Y, Zhu Z, Zheng H, Peng J, Li L. JAZF1 ameliorates age and diet-associated hepatic steatosis through SREBP-1c -dependent mechanism. Cell Death Dis 2018; 9:859. [PMID: 30154417 PMCID: PMC6113258 DOI: 10.1038/s41419-018-0923-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 07/19/2018] [Accepted: 07/30/2018] [Indexed: 01/07/2023]
Abstract
JAZF zinc finger 1 (JAZF1) is involved in glucose and lipid metabolisms. However, its role in aging- and nutrient-related hepatic steatosis is unclear. In the current study, we demonstrated that JAZF1 expression was markedly down-regulated in obesity-associated mice and nonalcoholic fatty liver disease (NAFLD) patients. During aging, JAZF1 expression was gradually down-regulated in both C57BL/6 J and JAZF1-Tg mice. In JAZF1-Tg mice, body fat content and hepatosteatosis were protected from HFD-induced steatosis, and accompanied by decreased lipogenesis gene expression. The inhibitory effects of hepatic steatosis in JAZF1-Tg mice, however, were disappeared during aging. In hepatocytes, over-expression of JAZF1 attenuated, while knockdown of JAZF1 enhanced the expression of lipogenesis genes. The over-expressing of JAZF1 in hepatocytes displayed the increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and decreased sterol regulatory element-binding protein 1c (SREBP-1c) expression. The roles of JAZF1 were partially attenuated by Compound C. Mechanistically, JAZF1 suppressed SREBP-1c expression through the inhibition of transcriptional activity of liver X receptor response elements (LXREs) in the SREBP-1c promoter. Data illustrate that JAZF1 may have a crucial role in the regulation of age and nutrient-associated hepatosteatosis through an AMPK/SREBP-1c-dependent mechanism.
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Affiliation(s)
- Qin Wei
- Key Laboratory of Diagnostic Medicine (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, P. R. China
| | - Baoyong Zhou
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Chongqing Medical University, Chongqing, P. R. China
| | - Gangyi Yang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, P. R. China
| | - Wenjing Hu
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, P. R. China
| | - Lili Zhang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, P. R. China
| | - Rui Liu
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, P. R. China
| | - Minyan Li
- Key Laboratory of Diagnostic Medicine (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, P. R. China
| | - Kuan Wang
- Key Laboratory of Diagnostic Medicine (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, P. R. China
| | - Harvest F Gu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China
- Department of Clinical Science, Intervention and Technology, Karolinska University Hospital, Karolinska Institutet, Huddinge, Stockholm, Sweden
| | - Youfei Guan
- Advanced Institute for Medical Sciences, Dalian Medical University, Liaoning, P. R. China
| | - Zhiming Zhu
- Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, P. R. China
| | - Hongting Zheng
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, P. R. China
| | - Jun Peng
- Advanced Institute for Medical Sciences, Dalian Medical University, Liaoning, P. R. China
| | - Ling Li
- Key Laboratory of Diagnostic Medicine (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, P. R. China.
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Xu H, Wang C, Zhang Y, Wei Y, Liang M. Moderate levels of dietary arachidonic acid reduced lipid accumulation and tended to inhibit cell cycle progression in the liver of Japanese seabass Lateolabrax japonicus. Sci Rep 2018; 8:10682. [PMID: 30013122 PMCID: PMC6048150 DOI: 10.1038/s41598-018-28867-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 07/02/2018] [Indexed: 12/14/2022] Open
Abstract
To investigate the physiological roles of dietary arachidonic acid (ARA) in fish, a feeding trial with Japanese seabass was conducted, followed by a hepatic transcriptome assay. Six experimental diets differing basically in ARA level (0.05%, 0.22%, 0.37%, 0.60%, 1.38% and 2.32% of dry matter) were used in the feeding trial. Liver samples from fish fed diets with 0.05% and 0.37% ARA were subjected to transcriptomic assay, generating a total of 139 differently expressed unigenes, which were primarily enriched in lipid metabolism and cell cycle-related signaling pathways. Then, qRT-PCR validation on lipid metabolism and cell cycle-related genes as well as corresponding enzyme-linked immunosorbent assay of selected proteins were conducted with liver samples from all six groups. Moderated ARA levels reduced lipogenesis and stimulated β-oxidation concurrently, but high ARA levels seemed to affect lipid metabolism in complicated ways. Both gene expression and protein concentration of cell cycle-related proteins were decreased by moderate levels of dietary ARA. The lipid content and fatty acid composition in fish confirmed the transcription and protein concentration results related to lipid metabolism. In conclusion, moderate levels of dietary ARA (0.37% and 0.60%) reduced lipid accumulation and tended to inhibit cell cycle progression in the liver of Japanese seabass.
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Affiliation(s)
- Houguo Xu
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao, 266071, Shandong, China
| | - Chengqiang Wang
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao, 266071, Shandong, China
| | - Yuanqin Zhang
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao, 266071, Shandong, China
| | - Yuliang Wei
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao, 266071, Shandong, China
| | - Mengqing Liang
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao, 266071, Shandong, China. .,Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, 1 Wenhai Road, Qingdao, 266237, Shandong, China.
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29
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Park JE, Lee EJ, Kim JK, Song Y, Choi JH, Kang MJ. Flightless-I Controls Fat Storage in Drosophila. Mol Cells 2018; 41:603-611. [PMID: 29890821 PMCID: PMC6030243 DOI: 10.14348/molcells.2018.0120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 04/04/2018] [Accepted: 05/21/2018] [Indexed: 01/24/2023] Open
Abstract
Triglyceride homeostasis is a key process of normal development and is essential for the maintenance of energy metabolism. Dysregulation of this process leads to metabolic disorders such as obesity and hyperlipidemia. Here, we report a novel function of the Drosophila flightless-I (fliI) gene in lipid metabolism. Drosophila fliI mutants were resistant to starvation and showed increased levels of triglycerides in the fat body and intestine, whereas fliI overexpression decreased triglyceride levels. These flies suffered from metabolic stress indicated by increased levels of trehalose in hemolymph and enhanced phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α). Moreover, upregulation of triglycerides via a knockdown of fliI was reversed by a knockdown of desat1 in the fat body of flies. These results indicate that fliI suppresses the expression of desat1, thereby inhibiting the development of obesity; fliI may, thus, serve as a novel therapeutic target in obesity and metabolic diseases.
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Affiliation(s)
- Jung-Eun Park
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505,
Korea
| | - Eun Ji Lee
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505,
Korea
| | - Jung Kwan Kim
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919,
Korea
| | - Youngsup Song
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505,
Korea
| | - Jang Hyun Choi
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919,
Korea
| | - Min-Ji Kang
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505,
Korea
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30
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Thon M, Hosoi T, Chea C, Ozawa K. Loss of Stearoyl-CoA Desaturase-1 Activity Induced Leptin Resistance in Neuronal Cells. Biol Pharm Bull 2018; 40:1161-1164. [PMID: 28768997 DOI: 10.1248/bpb.b17-00311] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The lack of response to leptin's actions in the brain, "leptin resistance," is one of the main causes of the pathogenesis of obesity. However, although high-fat diets affect sensitivity to leptin, the underlying mechanisms of leptin resistance are still an enigma. Here we examined the effect of excess saturated fatty acids (SFAs) on leptin signaling in human neuronal cells. Palmitate, the principle source of SFAs in diet, induced leptin resistance in a human neuroblastoma cell line stably transfected with the Ob-Rb leptin receptor (SH-SY5Y-ObRb). We next investigated the function of stearoyl-CoA desaturase-1 (SCD1), an enzyme which converts SFAs into monounsaturated fatty acids (MUFAs), on leptin-induced signaling. We found that reduction of SCD1 activity, through SCD1 inhibition and knockdown, impairs leptin-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in human neuronal cells. Our findings suggested that SCD1 plays a key role in the pathophysiology of leptin resistance in neuronal cells associated with obesity.
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Affiliation(s)
- Mina Thon
- Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University
| | - Toru Hosoi
- Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University
| | - Chanbora Chea
- Department of Oral & Maxillofacial Pathobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University
| | - Koichiro Ozawa
- Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University
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31
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Samuel VT, Shulman GI. Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases. Cell Metab 2018; 27:22-41. [PMID: 28867301 PMCID: PMC5762395 DOI: 10.1016/j.cmet.2017.08.002] [Citation(s) in RCA: 514] [Impact Index Per Article: 73.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 07/01/2017] [Accepted: 08/01/2017] [Indexed: 12/15/2022]
Abstract
NAFLD is closely linked with hepatic insulin resistance. Accumulation of hepatic diacylglycerol activates PKC-ε, impairing insulin receptor activation and insulin-stimulated glycogen synthesis. Peripheral insulin resistance indirectly influences hepatic glucose and lipid metabolism by increasing flux of substrates that promote lipogenesis (glucose and fatty acids) and gluconeogenesis (glycerol and fatty acid-derived acetyl-CoA, an allosteric activator of pyruvate carboxylase). Weight loss with diet or bariatric surgery effectively treats NAFLD, but drugs specifically approved for NAFLD are not available. Some new pharmacological strategies act broadly to alter energy balance or influence pathways that contribute to NAFLD (e.g., agonists for PPAR γ, PPAR α/δ, FXR and analogs for FGF-21, and GLP-1). Others specifically inhibit key enzymes involved in lipid synthesis (e.g., mitochondrial pyruvate carrier, acetyl-CoA carboxylase, stearoyl-CoA desaturase, and monoacyl- and diacyl-glycerol transferases). Finally, a novel class of liver-targeted mitochondrial uncoupling agents increases hepatocellular energy expenditure, reversing the metabolic and hepatic complications of NAFLD.
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Affiliation(s)
- Varman T Samuel
- Department of Medicine, Yale University School of Medicine, New Haven, CT 06510, USA; Veterans Affairs Medical Center, West Haven, CT 06516, USA.
| | - Gerald I Shulman
- Department of Medicine, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
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32
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Zhang M, Sun W, Zhou M, Tang Y. MicroRNA-27a regulates hepatic lipid metabolism and alleviates NAFLD via repressing FAS and SCD1. Sci Rep 2017; 7:14493. [PMID: 29101357 PMCID: PMC5670231 DOI: 10.1038/s41598-017-15141-x] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 09/22/2017] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs are implicated as crucial mediators in metabolic diseases including obesity, diabetes, and non-alcoholic fatty liver diseases (NAFLD). Here, we show miR-27a attenuated hepatic de novo lipogenesis and alleviated obesity-initiated NAFLD through inhibiting Fasn and Scd1 in liver. Hepatic levels of miR-27a were significantly augmented in HFD-fed and ob/ob mice. Further studies demonstrated that miR-27a directly interacted with 3' untranslated region (3'-UTR) of hepatic Fasn and Scd1 mRNAs and reduced their expression levels in mice. Adenovirus-mediated overexpression of miR-27a robustly blocked sodium oleate-induced triglyceride (TG) accumulation in mouse primary hepatocytes and reduced liver TG contents in mice via repressing hepatic lipogenesis. Furthermore, ectopic expression of hepatic miR-27a impaired lipid contents of livers and attenuated NAFLD development through suppressing lipogenesis in HCD-fed and ob/ob mice. Together, our results reveal a critical role of miR-27a in lipid homeostasis of liver and pathogenesis of NAFLD.
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Affiliation(s)
- Meiyuan Zhang
- Emergency Intensive Care Unit, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, 201700, China
| | - Weilan Sun
- Emergency Intensive Care Unit, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, 201700, China
| | - Minghao Zhou
- Emergency Intensive Care Unit, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, 201700, China
| | - Yan Tang
- Emergency Intensive Care Unit, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, 201700, China.
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33
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Regulation of hepatic lipogenesis by the zinc finger protein Zbtb20. Nat Commun 2017; 8:14824. [PMID: 28327662 PMCID: PMC5364431 DOI: 10.1038/ncomms14824] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 02/03/2017] [Indexed: 12/13/2022] Open
Abstract
Hepatic de novo lipogenesis (DNL) converts carbohydrates into triglycerides and is known to influence systemic lipid homoeostasis. Here, we demonstrate that the zinc finger protein Zbtb20 is required for DNL. Mice lacking Zbtb20 in the liver exhibit hypolipidemia and reduced levels of liver triglycerides, along with impaired hepatic lipogenesis. The expression of genes involved in glycolysis and DNL, including that of two ChREBP isoforms, is decreased in livers of knockout mice. Zbtb20 binds to and enhances the activity of the ChREBP-α promoter, suggesting that altered metabolic gene expression is mainly driven by ChREBP. In addition, ChREBP-β overexpression largely restores hepatic expression of genes involved in glucose and lipid metabolism, and increases plasma and liver triglyceride levels in knockout mice. Finally, we show that Zbtb20 ablation protects from diet-induced liver steatosis and improves hepatic insulin resistance. We suggest ZBTB20 is an essential regulator of hepatic lipogenesis and may be a therapeutic target for the treatment of fatty liver disease. De novo lipogenesis is tightly controlled by hormonal and nutritional signals and plays an important role in energy homoeostasis. Here, Liu et al. show that zinc finger protein ZBTB20 regulates the expression of key glycolytic and lipogenic genes by modulating ChREBP expression and transcriptional activity.
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34
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Kumazoe M, Nakamura Y, Yamashita M, Suzuki T, Takamatsu K, Huang Y, Bae J, Yamashita S, Murata M, Yamada S, Shinoda Y, Yamaguchi W, Toyoda Y, Tachibana H. Green Tea Polyphenol Epigallocatechin-3-gallate Suppresses Toll-like Receptor 4 Expression via Up-regulation of E3 Ubiquitin-protein Ligase RNF216. J Biol Chem 2017; 292:4077-4088. [PMID: 28154178 DOI: 10.1074/jbc.m116.755959] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 01/18/2017] [Indexed: 12/13/2022] Open
Abstract
Toll-like receptor 4 (TLR4) plays an essential role in innate immunity through inflammatory cytokine induction. Recent studies demonstrated that the abnormal activation of TLR4 has a pivotal role in obesity-induced inflammation, which is associated with several diseases, including hyperinsulinemia, hypertriglyceridemia, and cardiovascular disease. Here we demonstrate that (-)-epigallocatechin-3-O-gallate, a natural agonist of the 67-kDa laminin receptor (67LR), suppressed TLR4 expression through E3 ubiquitin-protein ring finger protein 216 (RNF216) up-regulation. Our data indicate cyclic GMP mediates 67LR agonist-dependent RNF216 up-regulation. Moreover, we show that the highly absorbent 67LR agonist (-)-epigallocatechin-3-O-(3-O-methyl)-gallate (EGCG3″Me) significantly attenuated TLR4 expression in the adipose tissue. EGCG3″Me completely inhibited the high-fat/high-sucrose (HF/HS)-induced up-regulation of tumor necrosis factor α in adipose tissue and serum monocyte chemoattractant protein-1 increase. Furthermore, this agonist intake prevented HF/HS-induced hyperinsulinemia and hypertriglyceridemia. Taken together, 67LR presents an attractive target for the relief of obesity-induced inflammation.
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Affiliation(s)
- Motofumi Kumazoe
- From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581 and
| | - Yuki Nakamura
- From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581 and
| | - Mai Yamashita
- From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581 and
| | - Takashi Suzuki
- From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581 and
| | - Kanako Takamatsu
- From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581 and
| | - Yuhui Huang
- From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581 and
| | - Jaehoon Bae
- From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581 and
| | - Shuya Yamashita
- From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581 and
| | - Motoki Murata
- From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581 and
| | - Shuhei Yamada
- From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581 and
| | - Yuki Shinoda
- the Products Research & Development Laboratory, Asahi Soft Drinks Co., Ltd., Ibaraki 302-0106, Japan
| | - Wataru Yamaguchi
- the Products Research & Development Laboratory, Asahi Soft Drinks Co., Ltd., Ibaraki 302-0106, Japan
| | - Yui Toyoda
- the Products Research & Development Laboratory, Asahi Soft Drinks Co., Ltd., Ibaraki 302-0106, Japan
| | - Hirofumi Tachibana
- From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581 and
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35
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da Silva-Santi LG, Antunes MM, Caparroz-Assef SM, Carbonera F, Masi LN, Curi R, Visentainer JV, Bazotte RB. Liver Fatty Acid Composition and Inflammation in Mice Fed with High-Carbohydrate Diet or High-Fat Diet. Nutrients 2016; 8:E682. [PMID: 27801862 PMCID: PMC5133070 DOI: 10.3390/nu8110682] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 10/17/2016] [Accepted: 10/24/2016] [Indexed: 02/06/2023] Open
Abstract
Both high-carbohydrate diet (HCD) and high-fat diet (HFD) modulate liver fat accumulation and inflammation, however, there is a lack of data on the potential contribution of carbohydrates and lipids separately. For this reason, the changes in liver fatty acid (FA) composition in male Swiss mice fed with HCD or HFD were compared, at the time points 0 (before starting the diets), and after 7, 14, 28 or 56 days. Activities of stearoyl-CoA desaturase-1 (SCD-1), ∆-6 desaturase (D6D), elongases and de novo lipogenesis (DNL) were estimated. Liver mRNA expression of acetyl-CoA carboxylase 1 (ACC1) was evaluated as an additional indicator of the de novo lipogenesis. Myeloperoxidase activity, nitric oxide (NO) production, and mRNA expressions of F4/80, type I collagen, interleukin (IL)-6, IL-1β, IL-10, and tumor necrosis factor-α (TNF-α) were measured as indication of the liver inflammatory state. The HCD group had more intense lipid deposition, particularly of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). This group also showed higher DNL, SCD-1, and D6D activities associated with increased NO concentration, as well as myeloperoxidase activity. Livers from the HFD group showed higher elongase activity, stored more polyunsaturated fatty acids (PUFAs) and had a lower omega-6/omega-3 fatty acid (n-6/n-3) ratio. In conclusion, liver lipid accumulation, fatty acids (FA) composition and inflammation were modulated by the dietary composition of lipids and carbohydrates. The HCD group had more potent lipogenic and inflammatory effects in comparison with HFD.
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Affiliation(s)
| | - Marina Masetto Antunes
- Department of Pharmacology and Therapeutics, State University of Maringá, Maringá 87020-900, Paraná, Brazil.
| | | | - Fabiana Carbonera
- Department of Chemistry, State University of Maringá, Maringá 87020-900, Paraná, Brazil.
| | - Laureane Nunes Masi
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, Brazil.
| | - Rui Curi
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, Brazil.
| | | | - Roberto Barbosa Bazotte
- Department of Pharmacology and Therapeutics, State University of Maringá, Maringá 87020-900, Paraná, Brazil.
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36
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Softic S, Cohen DE, Kahn CR. Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease. Dig Dis Sci 2016; 61:1282-93. [PMID: 26856717 PMCID: PMC4838515 DOI: 10.1007/s10620-016-4054-0] [Citation(s) in RCA: 470] [Impact Index Per Article: 52.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 01/21/2016] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome. Overconsumption of high-fat diet (HFD) and increased intake of sugar-sweetened beverages are major risk factors for development of NAFLD. Today the most commonly consumed sugar is high fructose corn syrup. Hepatic lipids may be derived from dietary intake, esterification of plasma free fatty acids (FFA) or hepatic de novo lipogenesis (DNL). A central abnormality in NAFLD is enhanced DNL. Hepatic DNL is increased in individuals with NAFLD, while the contribution of dietary fat and plasma FFA to hepatic lipids is not significantly altered. The importance of DNL in NAFLD is further established in mouse studies with knockout of genes involved in this process. Dietary fructose increases levels of enzymes involved in DNL even more strongly than HFD. Several properties of fructose metabolism make it particularly lipogenic. Fructose is absorbed via portal vein and delivered to the liver in much higher concentrations as compared to other tissues. Fructose increases protein levels of all DNL enzymes during its conversion into triglycerides. Additionally, fructose supports lipogenesis in the setting of insulin resistance as fructose does not require insulin for its metabolism, and it directly stimulates SREBP1c, a major transcriptional regulator of DNL. Fructose also leads to ATP depletion and suppression of mitochondrial fatty acid oxidation, resulting in increased production of reactive oxygen species. Furthermore, fructose promotes ER stress and uric acid formation, additional insulin independent pathways leading to DNL. In summary, fructose metabolism supports DNL more strongly than HFD and hepatic DNL is a central abnormality in NAFLD. Disrupting fructose metabolism in the liver may provide a new therapeutic option for the treatment of NAFLD.
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Affiliation(s)
- Samir Softic
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, One Joslin Place, Boston, MA, 02215, USA
- Department of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA
| | - David E Cohen
- Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - C Ronald Kahn
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, One Joslin Place, Boston, MA, 02215, USA.
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37
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Ding Y, Xian X, Holland WL, Tsai S, Herz J. Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis. EBioMedicine 2016; 7:135-45. [PMID: 27322467 PMCID: PMC4913705 DOI: 10.1016/j.ebiom.2016.04.002] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 03/31/2016] [Accepted: 04/01/2016] [Indexed: 11/15/2022] Open
Abstract
Low-density lipoprotein receptor-related protein-1 (LRP1) is a multifunctional uptake receptor for chylomicron remnants in the liver. In vascular smooth muscle cells LRP1 controls reverse cholesterol transport through platelet-derived growth factor receptor β (PDGFR-β) trafficking and tyrosine kinase activity. Here we show that LRP1 regulates hepatic energy homeostasis by integrating insulin signaling with lipid uptake and secretion. Somatic inactivation of LRP1 in the liver (hLRP1KO) predisposes to diet-induced insulin resistance with dyslipidemia and non-alcoholic hepatic steatosis. On a high-fat diet, hLRP1KO mice develop a severe Metabolic Syndrome secondary to hepatic insulin resistance, reduced expression of insulin receptors on the hepatocyte surface and decreased glucose transporter 2 (GLUT2) translocation. While LRP1 is also required for efficient cell surface insulin receptor expression in the absence of exogenous lipids, this latent state of insulin resistance is unmasked by exposure to fatty acids. This further impairs insulin receptor trafficking and results in increased hepatic lipogenesis, impaired fatty acid oxidation and reduced very low density lipoprotein (VLDL) triglyceride secretion.
Hepatic LRP1 deficiency in a mouse model (hLRP1KO) predisposes to diet-induced insulin resistance, dyslipidemia, and obesity. Insulin resistance in the hLRP1KO mouse results from reduced cell surface expression of insulin receptor (IR) and impaired translocation of glucose transporter 2 (GLUT2). Excess fatty acids in hLRP1KO mice shift hepatic fatty acid metabolism from an oxidative to a synthetic state, resulting in hepatic steatosis. LRP1 is a multifunctional transmembrane receptor with essential functions in lipoprotein metabolism and subcellular receptor tyrosine kinase trafficking. A mouse model of hepatic LRP1 deficiency integrates the hallmark findings in Metabolic Syndrome - insulin resistance, dyslipidemia, and hepatic steatosis - with impaired glucose metabolism and altered hepatic fatty acid metabolism as a consequence of reduced insulin receptor trafficking and signaling. These findings underscore the central role of LRP1 in overall energy homeostasis, and specifically liver glucose and fatty acid metabolism.
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Affiliation(s)
- Yinyuan Ding
- Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390, USA; Center for Translational Neurodegeneration Research, UT Southwestern Medical Center, Dallas, TX 75390, USA; Key Laboratory of Medical Electrophysiology, Ministry of Education of China, China; Institute of Cardiovascular Research, Sichuan Medical University, Luzhou 646000, China
| | - Xunde Xian
- Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390, USA; Center for Translational Neurodegeneration Research, UT Southwestern Medical Center, Dallas, TX 75390, USA.
| | - William L Holland
- Department of Internal Medicine, Touchstone Diabetes Center, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Shirling Tsai
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA; Dallas VA Medical Center, Dallas, TX 75216, USA
| | - Joachim Herz
- Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390, USA; Center for Translational Neurodegeneration Research, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX 75390, USA.
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Abstract
In the last few decades, rapid changes in lifestyle have led to an alarming increase in the prevalence of obesity and obesity-associated complications. Obese patients are at increased risk of developing hypertension, heart disease, insulin resistance, dyslipidemia, type 2 diabetes and kidney disease. The surplus of calories is normally stored as triglycerides in adipose tissue. However, excess lipids can also accumulate ectopically in other organs, including the kidney, contributing to their damage through toxic processes named lipotoxicity. The kidney is negatively affected by dyslipidemia, lipid accumulation and changes in circulating adipokines that bring about alterations in renal lipid metabolism and promote insulin resistance, generation of reactive oxygen species and endoplasmic reticulum stress, ultimately leading to alterations in the glomerular filtration barrier and renal failure. This review focuses on the pathogenic molecular mechanisms associated with renal lipotoxicity, and presents new insights about potential new therapeutic targets and biomarkers such as microRNAs and long non-coding RNAs, of relevance for the early detection of lipid-associated kidney disease.
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Feng J, Dai Z, Zhang Y, Meng L, Ye J, Ma X. Alteration of Gene Expression Profile in Kidney of Spontaneously Hypertensive Rats Treated with Protein Hydrolysate of Blue Mussel (Mytilus edulis) by DNA Microarray Analysis. PLoS One 2015; 10:e0142016. [PMID: 26517713 PMCID: PMC4627735 DOI: 10.1371/journal.pone.0142016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Accepted: 10/15/2015] [Indexed: 12/19/2022] Open
Abstract
Marine organisms are rich sources of bioactive components, which are often reported to have antihypertensive effects. However, the underlying mechanisms have yet to be fully identified. The aim of this study was to investigate the antihypertensive effect of enzymatic hydrolysis of blue mussel protein (HBMP) in rats. Peptides with in vitro ACE inhibitory activity were purified from HBMP by ultrafiltration, gel filtration chromatography and reversed-phase high performance liquid chromatography. And the amino acid sequences of isolated peptides were estimated to be Val-Trp, Leu-Gly-Trp, and Met-Val-Trp-Thr. To study its in vivo action, spontaneously hypertensive rats (SHRs) were orally administration with high- or low-dose of HBMP for 28 days. Major components of the renin-angiotensin (RAS) system in serum of SHRs from different groups were analyzed, and gene expression profiling were performed in the kidney of SHRs, using the Whole Rat Genome Oligonucleotide Microarray. Results indicated although genes involved in RAS system were not significantly altered, those related to blood coagulation system, cytokine and growth factor, and fatty acids metabolism were remarkablely changed. Several genes which were seldom reported to be implicated in pathogenesis of hypertension also showed significant expression alterations after oral administration of HBMP. These data provided valuable information for our understanding of the molecular mechanisms that underlie the potential antihypertensive activities of HBMP, and will contribute towards increased value-added utilization of blue mussel protein.
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Affiliation(s)
- Junli Feng
- Institute of Seafood, Zhejiang Gongshang University, Hangzhou, China
| | - Zhiyuan Dai
- Institute of Seafood, Zhejiang Gongshang University, Hangzhou, China
- * E-mail:
| | - Yanping Zhang
- School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, China
| | - Lu Meng
- Institute of Seafood, Zhejiang Gongshang University, Hangzhou, China
| | - Jian Ye
- Institute of Seafood, Zhejiang Gongshang University, Hangzhou, China
| | - Xuting Ma
- Institute of Seafood, Zhejiang Gongshang University, Hangzhou, China
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40
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Harding SV, Bateman KP, Kennedy BP, Rideout TC, Jones PJH. Desaturation index versus isotopically measured de novo lipogenesis as an indicator of acute systemic lipogenesis. BMC Res Notes 2015; 8:49. [PMID: 25879456 PMCID: PMC4345028 DOI: 10.1186/s13104-015-1016-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Accepted: 02/13/2015] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND High carbohydrate feeding is known to increase plasma triglycerides as well as hepatic de novo lipogenesis (DNL) and may be implicated in the development of hepatic insulin resistance and fatty liver. Unfortunately, it is technically challenging to determine what proportion of circulating plasma triglycerides have been derived from the newly synthesized fatty acids in the postprandial period. The aims of this study were to 1) characterize the changes in the plasma postprandial total fatty acid pool in beagles following the consumption of meals containing 44% (Control) and 74% (High Sucrose) carbohydrate and 2) determine if changes in plasma fatty acid concentration and delta-9 desaturation index (DI) would be useful as simple and easy to measure biomarkers of systemic DNL. FINDINGS No differences in plasma total palmitic acid (16:0), stearic acid (18:0) and oleic acid (18:1) concentrations or delta-9 DI for the total 18:0 and 18:1 pools between High Sucrose and Controls were observed. However, newly synthesized 16:0 (2.6 ± 0.2% vs. 8.8 ± 2.0%; p = 0.016), 18:0 (0.93 ± 0.2% vs. 4.1 ± 1.7%; p = 0.007) and 18:1 (0.29 ± 0.09% vs. 3.5 ± 1.2%; p = 0.017) were higher in High Sucrose versus Control animals, respectively. Also, the delta-9 DI for the newly synthesized 18:0 and 18:1 pools was higher at 2 and 6 hours postprandial, with a pattern of change which supports the increased stearoyl-CoA desaturase (SCD-1) activity following high carbohydrate feeding followed by a down regulation of this enzyme. CONCLUSIONS Our data show that high sucrose meals increase the relative contribution of systemic DNL produced fatty acids to the total postprandial plasma fatty acid pool. These data also show that a different pattern of both fatty acid synthesis and disposal occurs depending on energy and macronutrient profile of the meal. These changes are in spite of no observable changes in the plasma concentrations or ratios of the total fatty acid pool opposed to the observed changes in the newly synthesized fatty acid pool.
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Affiliation(s)
- Scott V Harding
- Diabetes and Nutritional Sciences Division, King's College London, 150 Stamford Street, London, SE1 9NH, UK.
| | - Kevin P Bateman
- Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck, One Merck Drive, Whitehouse Station, NJ, 08889, USA.
| | - Brian P Kennedy
- Kaneq Pharma, Montreal, QC, Canada. .,Previously at Department of Biochemistry and Molecular Biology at the Merck Frosst Center for Therapeutic Research, Montreal, QC, Canada.
| | - Todd C Rideout
- Department of Exercise and Nutrition Sciences, University at Buffalo, Buffalo, NY, 14214, USA.
| | - Peter J H Jones
- Richardson Centre for Functional Foods and Nutraceuticals, University of Manitoba, Winnipeg, R3T 6C5, MB, Canada.
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Samuel W, Kutty RK, Duncan T, Vijayasarathy C, Kuo BC, Chapa KM, Redmond TM. Fenretinide induces ubiquitin-dependent proteasomal degradation of stearoyl-CoA desaturase in human retinal pigment epithelial cells. J Cell Physiol 2014; 229:1028-38. [PMID: 24357007 DOI: 10.1002/jcp.24527] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 12/04/2013] [Indexed: 12/17/2022]
Abstract
Stearoyl-CoA desaturase (SCD, SCD1), an endoplasmic reticulum (ER) resident protein and a rate-limiting enzyme in monounsaturated fatty acid biosynthesis, regulates cellular functions by controlling the ratio of saturated to monounsaturated fatty acids. Increase in SCD expression is strongly implicated in the proliferation and survival of cancer cells, whereas its decrease is known to impair proliferation, induce apoptosis, and restore insulin sensitivity. We examined whether fenretinide, (N-(4-hydroxyphenyl)retinamide, 4HPR), which induces apoptosis in cancer cells and recently shown to improve insulin sensitivity, can modulate the expression of SCD. We observed that fenretinide decreased SCD protein and enzymatic activity in the ARPE-19 human retinal pigment epithelial cell line. Increased expression of BiP/GRP78, ATF4, and GADD153 implicated ER stress. Tunicamycin and thapsigargin, compounds known to induce ER stress, also decreased the SCD protein. This decrease was completely blocked by the proteasome inhibitor MG132. In addition, PYR41, an inhibitor of ubiquitin activating enzyme E1, blocked the fenretinide-mediated decrease in SCD. Immunoprecipitation analysis using anti-ubiquitin and anti-SCD antibodies and the blocking of SCD loss by PYR41 inhibition of ubiquitination further corroborate that fenretinide mediates the degradation of SCD in human RPE cells via the ubiquitin-proteasome dependent pathway. Therefore, the effect of fenretinide on SCD should be considered in its potential therapeutic role against cancer, type-2 diabetes, and retinal diseases.
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Affiliation(s)
- William Samuel
- Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland
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42
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Khandelwal P, Stryker S, Chao H, Aranibar N, Lawrence RM, Madireddi M, Zhao W, Chen L, Reily MD. 1H NMR-based lipidomics of rodent fur: species-specific lipid profiles and SCD1 inhibitor-related dermal toxicity. J Lipid Res 2014; 55:1366-74. [PMID: 24755647 PMCID: PMC4076068 DOI: 10.1194/jlr.m049155] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Revised: 04/18/2014] [Indexed: 11/20/2022] Open
Abstract
A method is described that allows noninvasive identification and quantitative assessment of lipid classes present in sebaceous excretions in rodents. The method relies on direct high-field proton NMR analysis of common group lipid protons in deuterated organic solvent extracts of fur. Extracts from as little as 15 mg of fur from rat, mouse, and hamster provided acceptable results on a 600 MHz NMR equipped with a cryogenically cooled proton-observe probe. In rats, sex- and age-related differences in lipid composition are larger than differences in fur collected from various body regions within an individual and much larger than interanimal differences in age- and sex-matched specimens. The utility of this method to noninvasively monitor drug-induced sebaceous gland atrophy in rodents is demonstrated in rats dosed with a stearoyl-CoA desaturase 1 (SCD1) inhibitor. In this model, a 35% reduction in sebum lipids, extracted from fur, was observed. Finally, structural elucidation of cholesta-7,24-dien-3β-ol ester as the most prominent, previously unidentified sebum sterol ester in male Syrian hamsters is described. The utility of this method for drug and cosmetic safety and efficacy assessment is discussed.
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Affiliation(s)
- Purnima Khandelwal
- Applied and Investigative Metabolomics Group, Bristol-Myers Squibb Company, Princeton, NJ
| | - Steven Stryker
- Applied and Investigative Metabolomics Group, Bristol-Myers Squibb Company, Princeton, NJ
| | - Hannguang Chao
- Discovery Chemistry, Bristol-Myers Squibb Company, Princeton, NJ
| | - Nelly Aranibar
- Applied and Investigative Metabolomics Group, Bristol-Myers Squibb Company, Princeton, NJ
| | | | | | - Wenjun Zhao
- Discovery Biology, Bristol-Myers Squibb Company, Princeton, NJ
| | - Luping Chen
- Discovery Biology, Bristol-Myers Squibb Company, Princeton, NJ
| | - Michael D. Reily
- Applied and Investigative Metabolomics Group, Bristol-Myers Squibb Company, Princeton, NJ
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43
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Peverill W, Powell LW, Skoien R. Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. Int J Mol Sci 2014; 15:8591-638. [PMID: 24830559 PMCID: PMC4057750 DOI: 10.3390/ijms15058591] [Citation(s) in RCA: 289] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Revised: 03/20/2014] [Accepted: 04/17/2014] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis and inflammation and, in some patients, progressive fibrosis leading to cirrhosis. An understanding of the pathogenesis of NASH is still evolving but current evidence suggests multiple metabolic factors critically disrupt homeostasis and induce an inflammatory cascade and ensuing fibrosis. The mechanisms underlying these changes and the complex inter-cellular interactions that mediate fibrogenesis are yet to be fully elucidated. Lipotoxicity, in the setting of excess free fatty acids, obesity, and insulin resistance, appears to be the central driver of cellular injury via oxidative stress. Hepatocyte apoptosis and/or senescence contribute to activation of the inflammasome via a variety of intra- and inter-cellular signalling mechanisms leading to fibrosis. Current evidence suggests that periportal components, including the ductular reaction and expansion of the hepatic progenitor cell compartment, may be involved and that the Th17 response may mediate disease progression. This review aims to provide an overview of the pathogenesis of NASH and summarises the evidence pertaining to key mechanisms implicated in the transition from steatosis and inflammation to fibrosis. Currently there are limited treatments for NASH although an increasing understanding of its pathogenesis will likely improve the development and use of interventions in the future.
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Affiliation(s)
- William Peverill
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.
| | - Lawrie W Powell
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.
| | - Richard Skoien
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.
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44
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Nesteruk M, Hennig EE, Mikula M, Karczmarski J, Dzwonek A, Goryca K, Rubel T, Paziewska A, Woszczynski M, Ledwon J, Dabrowska M, Dadlez M, Ostrowski J. Mitochondrial-related proteomic changes during obesity and fasting in mice are greater in the liver than skeletal muscles. Funct Integr Genomics 2014; 14:245-59. [PMID: 24178926 PMCID: PMC3968515 DOI: 10.1007/s10142-013-0342-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Revised: 09/24/2013] [Accepted: 09/30/2013] [Indexed: 01/19/2023]
Abstract
Although mitochondrial dysfunction is implicated in the pathogenesis of obesity, the molecular mechanisms underlying obesity-related metabolic abnormalities are not well established. We performed mitochondrial quantitative proteomic and whole transcriptome analysis followed by functional annotations within liver and skeletal muscles, using fasted and non-fasted 16- and 48-week-old high-fat diet (HFD)-fed and normal diet-fed (control group) wild-type C56BL/6J mice, and hyperphagic ob/ob and db/db obese mice. Our study identified 1,675 and 704 mitochondria-associated proteins with at least two peptides in liver and muscle, respectively. Of these, 221 liver and 44 muscle proteins were differentially expressed (adjusted p values ≤ 0.05) between control and all obese mice, while overnight fasting altered expression of 107 liver and 35 muscle proteins. In the liver, we distinguished a network of 27 proteins exhibiting opposite direction of expression changes in HFD-fed and hyperphagic mice when compared to control. The network centered on cytochromes P450 3a11 (Cyp3a11) and 4a14 (Cyp4a14), and fructose-bisphosphate aldolase B (Aldob) proteins which bridged proteins cluster involved in Metabolism of xenobiotics with proteins engaged in Fatty acid metabolism and PPAR signaling pathways. Functional annotations revealed that most of the hepatic molecular alterations, which characterized both obesity and fasting, related to different aspects of energy metabolism (such as Fatty acid metabolism, Peroxisome, and PPAR signaling); however, only a limited number of functional annotations could be selected from skeletal muscle data sets. Thus, our comprehensive molecular overview revealed that both obesity and fasting states induce more pronounced mitochondrial proteome changes in the liver than in the muscles.
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Affiliation(s)
- Monika Nesteruk
- Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Roentgena 5, 02-781 Warsaw, Poland
| | - Ewa E. Hennig
- Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Roentgena 5, 02-781 Warsaw, Poland
- Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Michal Mikula
- Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Jakub Karczmarski
- Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Artur Dzwonek
- Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Krzysztof Goryca
- Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Tymon Rubel
- Institute of Radioelectronics, Warsaw University of Technology, Warsaw, Poland
| | - Agnieszka Paziewska
- Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Roentgena 5, 02-781 Warsaw, Poland
| | - Marek Woszczynski
- Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Joanna Ledwon
- Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Roentgena 5, 02-781 Warsaw, Poland
| | - Michalina Dabrowska
- Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Michal Dadlez
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Jerzy Ostrowski
- Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Roentgena 5, 02-781 Warsaw, Poland
- Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
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45
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Monounsaturated fatty acids generated via stearoyl CoA desaturase-1 are endogenous inhibitors of fatty acid amide hydrolase. Proc Natl Acad Sci U S A 2013; 110:18832-7. [PMID: 24191036 DOI: 10.1073/pnas.1309469110] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
High-fat diet (HFD)-induced obesity and insulin resistance are associated with increased activity of the endocannabinoid/CB1 receptor (CB1R) system that promotes the hepatic expression of lipogenic genes, including stearoyl-CoA desaturase-1 (SCD1). Mice deficient in CB1R or SCD1 remain lean and insulin-sensitive on an HFD, suggesting a functional link between the two systems. The HFD-induced increase in the hepatic levels of the endocannabinoid anandamide [i.e., arachidonoylethanolamide (AEA)] has been attributed to reduced activity of the AEA-degrading enzyme fatty acid amide hydrolase (FAAH). Here we show that HFD-induced increased hepatic AEA levels and decreased FAAH activity are absent in SCD1(-/-) mice, and the monounsaturated fatty acid (MUFA) products of SCD1, palmitoleic and oleic acid, inhibit FAAH activity in vitro at low micromolar concentrations. HFD markedly increases hepatic SCD1 activity in WT mice as well as in CB1R(-/-) mice with transgenic reexpression of CB1R in hepatocytes, but not in global CB1R(-/-) mice. Treatment of HFD-fed mice with the SCD1 inhibitor A939572 prevents the diet-induced reduction of hepatic FAAH activity, normalizes hepatic AEA levels, and improves insulin sensitivity. SCD1(-/-) mice on an HFD remain insulin-sensitive, but develop glucose intolerance and insulin resistance in response to chronic treatment with the FAAH inhibitor URB597. An HFD rich in MUFA or feeding mice pure oleic acid fail to inhibit hepatic FAAH activity. We conclude that MUFAs generated via SCD1 activity, but not diet-derived MUFAs, function as endogenous FAAH inhibitors mediating the HFD-induced increase in hepatic AEA, which then activates hepatic CB1R to induce insulin resistance.
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46
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Suárez J, Rivera P, Arrabal S, Crespillo A, Serrano A, Baixeras E, Pavón FJ, Cifuentes M, Nogueiras R, Ballesteros J, Dieguez C, Rodríguez de Fonseca F. Oleoylethanolamide enhances β-adrenergic-mediated thermogenesis and white-to-brown adipocyte phenotype in epididymal white adipose tissue in rat. Dis Model Mech 2013; 7:129-41. [PMID: 24159189 PMCID: PMC3882055 DOI: 10.1242/dmm.013110] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
β-adrenergic receptor activation promotes brown adipose tissue (BAT) β-oxidation and thermogenesis by burning fatty acids during uncoupling respiration. Oleoylethanolamide (OEA) can inhibit feeding and stimulate lipolysis by activating peroxisome proliferator-activating receptor-α (PPARα) in white adipose tissue (WAT). Here we explore whether PPARα activation potentiates the effect of β3-adrenergic stimulation on energy balance mediated by the respective agonists OEA and CL316243. The effect of this pharmacological association on feeding, thermogenesis, β-oxidation, and lipid and cholesterol metabolism in epididymal (e)WAT was monitored. CL316243 (1 mg/kg) and OEA (5 mg/kg) co-administration over 6 days enhanced the reduction of both food intake and body weight gain, increased the energy expenditure and reduced the respiratory quotient (VCO2/VO2). This negative energy balance agreed with decreased fat mass and increased BAT weight and temperature, as well as with lowered plasma levels of triglycerides, cholesterol, nonessential fatty acids (NEFAs), and the adipokines leptin and TNF-α. Regarding eWAT, CL316243 and OEA treatment elevated levels of the thermogenic factors PPARα and UCP1, reduced p38-MAPK phosphorylation, and promoted brown-like features in the white adipocytes: the mitochondrial (Cox4i1, Cox4i2) and BAT (Fgf21, Prdm16) genes were overexpressed in eWAT. The enhancement of the fatty-acid β-oxidation factors Cpt1b and Acox1 in eWAT was accompanied by an upregulation of de novo lipogenesis and reduced expression of the unsaturated-fatty-acid-synthesis enzyme gene, Scd1. We propose that the combination of β-adrenergic and PPARα receptor agonists promotes therapeutic adipocyte remodelling in eWAT, and therefore has a potential clinical utility in the treatment of obesity.
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Affiliation(s)
- Juan Suárez
- Laboratorio de Medicina Regenerativa, Hospital Carlos Haya-IBIMA (Pabellón de Gobierno), Avenida, Carlos Haya 82, 29010 Málaga, Spain
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Koo SH. Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis. Clin Mol Hepatol 2013; 19:210-5. [PMID: 24133660 PMCID: PMC3796672 DOI: 10.3350/cmh.2013.19.3.210] [Citation(s) in RCA: 311] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Accepted: 08/06/2013] [Indexed: 12/21/2022] Open
Abstract
Liver plays a central role in the biogenesis of major metabolites including glucose, fatty acids, and cholesterol. Increased incidence of obesity in the modern society promotes insulin resistance in the peripheral tissues in humans, and could cause severe metabolic disorders by inducing accumulation of lipid in the liver, resulting in the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD, which is characterized by increased fat depots in the liver, could precede more severe diseases such as non-alcoholic steatohepatitis (NASH), cirrhosis, and in some cases hepatocellular carcinoma. Accumulation of lipid in the liver can be traced by increased uptake of free fatty acids into the liver, impaired fatty acid beta oxidation, or the increased incidence of de novo lipogenesis. In this review, I would like to focus on the roles of individual pathways that contribute to the hepatic steatosis as a precursor for the NAFLD.
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Affiliation(s)
- Seung-Hoi Koo
- Department of Life Sciences, Korea University, Seoul, Korea
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48
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Green tea extract containing a highly absorbent catechin prevents diet-induced lipid metabolism disorder. Sci Rep 2013; 3:2749. [PMID: 24067358 PMCID: PMC3782887 DOI: 10.1038/srep02749] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Accepted: 09/05/2013] [Indexed: 12/11/2022] Open
Abstract
We investigated the effects of extracts of Benifuuki (a tea cultivar that contains methylated catechins such as epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3”Me)) in mice fed a high-fat/high-sucrose (HF/HS) diet. This tea cultivar was then compared with an extract of Yabukita (a popular tea cultivar that lacks methylated catechins). For 6 weeks, C57BL/6J mice were fed either HF/HS diet with or without tea extracts from tea cultivars, which contained almost identical ingredients except for methylated catechins (i.e., Yabukita (0.2% and 1%) or Benifuuki (0.2% and 1%) extract powders). Supplementation with Benifuuki 0.2% markedly lowered plasma levels of TG and NEFAs compared with mice supplemented with Yabukita 0.2%. The diet containing Benifuuki 1% decreased adipose tissue weights, liver TG, and expression of lipogenic genes in the liver. These results suggested that Benifuuki had much greater lipid-lowering effects than Yabukita. Taken together, these data suggest that methylated catechins direct the strong lipid-lowering activity of Benifuuki.
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49
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Miyoshi M, Ogawa A, Higurashi S, Kadooka Y. Anti-obesity effect of Lactobacillus gasseri SBT2055 accompanied by inhibition of pro-inflammatory gene expression in the visceral adipose tissue in diet-induced obese mice. Eur J Nutr 2013; 53:599-606. [PMID: 23917447 DOI: 10.1007/s00394-013-0568-9] [Citation(s) in RCA: 101] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 07/23/2013] [Indexed: 12/17/2022]
Abstract
PURPOSE Probiotic Lactobacillus gasseri SBT2055 (LG2055) has an anti-obesity effect although it is unknown whether the effect influences inflammatory responses in adipose tissue and lipid metabolism in the liver, which are considered substantially relevant to adiposity. METHODS C57BL/6 mice were fed a 10%-fat diet containing LG2055 cells for 24 weeks. We then studied body weight, fat tissue mass, liver fat content and inflammatory genes in the adipose tissue, and lipogenic and lipolytic genes in the liver. RESULTS Consumption of LG2055 resulted in a significant reduction in body weight and fat tissue mass (epididymal and perirenal/retroperitoneal), with a lowered level of triglyceride content in the liver. DNA microarray analysis showed that LG2055 generally inhibited the up-regulation of pro-inflammatory genes, including CCL2 and CCR2, in the epididymal adipose tissue. In the liver, LG2055 tended to inhibit lipogenic gene up-regulation, including ACC1, FAS and SREBP1, but LG2055 did not markedly alter lipolytic genes. Real-time PCR analysis confirmed the DNA microarray results in part, showing a significant reduction in the mRNA expression of CCL2 in the epididymal adipose tissue, and a downward tendency in FAS mRNA expression in the liver, in the LG2055-fed group. CONCLUSIONS LG2055 significantly prevented body weight gain, fat accumulation and pro-inflammatory gene expression in the adipose tissue. Relatively lower triglyceride levels and reduced expression of lipogenic genes were also observed in the liver. It is suggested that improvement in the inflammatory state of the adipose tissue might be a possible mechanism underlying the anti-obesity effect of LG2055.
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Affiliation(s)
- Masaya Miyoshi
- Milk Science Research Institute, Megmilk Snow Brand Co. Ltd., 1-1-2 Minamidai, Kawagoe, Saitama, Japan,
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50
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Beaven SW, Matveyenko A, Wroblewski K, Chao L, Wilpitz D, Hsu TW, Lentz J, Drew B, Hevener AL, Tontonoz P. Reciprocal regulation of hepatic and adipose lipogenesis by liver X receptors in obesity and insulin resistance. Cell Metab 2013; 18:106-17. [PMID: 23823481 PMCID: PMC4089509 DOI: 10.1016/j.cmet.2013.04.021] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Revised: 03/28/2013] [Accepted: 04/26/2013] [Indexed: 12/25/2022]
Abstract
Liver X receptors (LXRs) regulate lipogenesis and inflammation, but their contribution to the metabolic syndrome is unclear. We show that LXRs modulate key aspects of the metabolic syndrome in mice. LXRαβ-deficient-ob/ob (LOKO) mice remain obese but show reduced hepatic steatosis and improved insulin sensitivity compared to ob/ob mice. Impaired hepatic lipogenesis in LOKO mice is accompanied by reciprocal increases in adipose lipid storage, reflecting tissue-selective effects on the SREBP, PPARγ, and ChREBP lipogenic pathways. LXRs are essential for obesity-driven SREBP-1c and ChREBP activity in liver, but not fat. Furthermore, loss of LXRs in obesity promotes adipose PPARγ and ChREBP-β activity, leading to improved insulin sensitivity. LOKO mice also exhibit defects in β cell mass and proliferation despite improved insulin sensitivity. Our data suggest that sterol sensing by LXRs in obesity is critically linked with lipid and glucose homeostasis and provide insight into the complex relationships between LXR and insulin signaling.
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Affiliation(s)
- Simon W Beaven
- Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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