Hepatic FASN deficiency differentially affects nonalcoholic fatty liver disease and diabetes in mouse obesity models.

Autor: Matsukawa T; Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine (NCGM), Tokyo, Japan., Yagi T; Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine (NCGM), Tokyo, Japan.; Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Kanagawa, Japan., Uchida T; Department of Nutrition Management, Faculty of Health Science, Hyogo University, Kakogawa, Hyogo, Japan., Sakai M; Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine (NCGM), Tokyo, Japan., Mitsushima M; Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine (NCGM), Tokyo, Japan., Naganuma T; Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine (NCGM), Tokyo, Japan., Yano H; Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine (NCGM), Tokyo, Japan.; Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Kanagawa, Japan., Inaba Y; Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, and.; Department of Physiology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan., Inoue H; Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, and.; Department of Physiology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan., Yanagida K; Department of Lipid Life Science, NCGM, Tokyo, Japan., Uematsu M; Department of Lipid Life Science, NCGM, Tokyo, Japan., Nakao K; Institute of Experimental Animal Sciences, Osaka University Graduate School of Medicine, Osaka, Japan., Nakao H; Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan., Aiba A; Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan., Nagashima Y; Department of Surgical Pathology, School of Medicine, Tokyo Women's Medical University, Tokyo, Japan., Kubota T; Department of Diabetes and Metabolic Diseases, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.; Division of Diabetes and Metabolism, The Institute of Medical Science, Asahi Life Foundation, Tokyo, Japan.; Department of Clinical Nutrition, National Institutes of Biomedical Innovation, Health, and Nutrition (NIBIOHN), Tokyo, Japan., Kubota N; Department of Diabetes and Metabolic Diseases, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.; Department of Clinical Nutrition Therapy, The University of Tokyo, Tokyo, Japan., Izumida Y; Department of Diabetes and Metabolic Diseases, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.; Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan., Yahagi N; Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan., Unoki-Kubota H; Department of Diabetic Complications, Diabetes Research Center, Research Institute, NCGM, Tokyo, Japan., Kaburagi Y; Department of Diabetic Complications, Diabetes Research Center, Research Institute, NCGM, Tokyo, Japan., Asahara SI; Division of Diabetes and Endocrinology, Department of Internal Medicine, and., Kido Y; Division of Diabetes and Endocrinology, Department of Internal Medicine, and.; Division of Medical Chemistry, Department of Metabolism and Disease, Kobe University Graduate School of Health Sciences, Kobe, Hyogo, Japan., Shindou H; Department of Lipid Life Science, NCGM, Tokyo, Japan.; Department of Medical Lipid Science, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Itoh M; Department of Metabolic Syndrome and Nutritional Science, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan., Ogawa Y; Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Minami S; Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Kanagawa, Japan., Terauchi Y; Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan., Tobe K; First Department of Internal Medicine, University of Toyama, Toyama-shi, Toyama, Japan., Ueki K; Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, NCGM, Tokyo, Japan., Kasuga M; The Institute of Medical Science, Asahi Life Foundation, Tokyo, Japan., Matsumoto M; Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine (NCGM), Tokyo, Japan.; Course of Advanced and Specialized Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2023 Sep 08; Vol. 8 (17). Date of Electronic Publication: 2023 Sep 08.
DOI: 10.1172/jci.insight.161282
Abstrakt: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes are interacting comorbidities of obesity, and increased hepatic de novo lipogenesis (DNL), driven by hyperinsulinemia and carbohydrate overload, contributes to their pathogenesis. Fatty acid synthase (FASN), a key enzyme of hepatic DNL, is upregulated in association with insulin resistance. However, the therapeutic potential of targeting FASN in hepatocytes for obesity-associated metabolic diseases is unknown. Here, we show that hepatic FASN deficiency differentially affects NAFLD and diabetes depending on the etiology of obesity. Hepatocyte-specific ablation of FASN ameliorated NAFLD and diabetes in melanocortin 4 receptor-deficient mice but not in mice with diet-induced obesity. In leptin-deficient mice, FASN ablation alleviated hepatic steatosis and improved glucose tolerance but exacerbated fed hyperglycemia and liver dysfunction. The beneficial effects of hepatic FASN deficiency on NAFLD and glucose metabolism were associated with suppression of DNL and attenuation of gluconeogenesis and fatty acid oxidation, respectively. The exacerbation of fed hyperglycemia by FASN ablation in leptin-deficient mice appeared attributable to impairment of hepatic glucose uptake triggered by glycogen accumulation and citrate-mediated inhibition of glycolysis. Further investigation of the therapeutic potential of hepatic FASN inhibition for NAFLD and diabetes in humans should thus consider the etiology of obesity.
Databáze: MEDLINE
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