Non-alcoholic fatty liver disease in mice with hepatocyte-specific deletion of mitochondrial fission factor
| Autor: | Yukina Takeichi, Kazuhito Gotoh, Keiji Masuda, Ryuichi Sakamoto, Yuki Hanada, Lixiang Wang, Masatoshi Nomura, Shohei Sakamoto, Keiichiro Uchida, Shunsuke Katsuhara, Yoshihiro Ogawa, Takashi Miyazawa, Naotada Ishihara, Takaya Ishihara |
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| Rok vydání: | 2021 |
| Předmět: |
MFF
0301 basic medicine Mitochondrial fission factor Endocrinology Diabetes and Metabolism Mitochondrion Mitochondrial Dynamics Article Mice 03 medical and health sciences 0302 clinical medicine Non-alcoholic Fatty Liver Disease Internal Medicine medicine Animals Chemistry Endoplasmic reticulum Fatty liver NASH medicine.disease Cell biology Mice Inbred C57BL Disease Models Animal Lipid metabolism 030104 developmental biology medicine.anatomical_structure Liver 030220 oncology & carcinogenesis Hepatocyte Hepatocytes Unfolded protein response Mitochondrial fission Steatohepatitis ER stress |
| Zdroj: | Diabetologia |
| ISSN: | 1432-0428 0012-186X |
| Popis: | Aims/hypothesis Mitochondria are highly dynamic organelles continuously undergoing fission and fusion, referred to as mitochondrial dynamics, to adapt to nutritional demands. Evidence suggests that impaired mitochondrial dynamics leads to metabolic abnormalities such as non-alcoholic steatohepatitis (NASH) phenotypes. However, how mitochondrial dynamics are involved in the development of NASH is poorly understood. This study aimed to elucidate the role of mitochondrial fission factor (MFF) in the development of NASH. Methods We created mice with hepatocyte-specific deletion of MFF (MffLiKO). MffLiKO mice fed normal chow diet (NCD) or high-fat diet (HFD) were evaluated for metabolic variables and their livers were examined by histological analysis. To elucidate the mechanism of development of NASH, we examined the expression of genes related to endoplasmic reticulum (ER) stress and lipid metabolism, and the secretion of triacylglycerol (TG) using the liver and primary hepatocytes isolated from MffLiKO and control mice. Results MffLiKO mice showed aberrant mitochondrial morphologies with no obvious NASH phenotypes during NCD, while they developed full-blown NASH phenotypes in response to HFD. Expression of genes related to ER stress was markedly upregulated in the liver from MffLiKO mice. In addition, expression of genes related to hepatic TG secretion was downregulated, with reduced hepatic TG secretion in MffLiKO mice in vivo and in primary cultures of MFF-deficient hepatocytes in vitro. Furthermore, thapsigargin-induced ER stress suppressed TG secretion in primary hepatocytes isolated from control mice. Conclusions/interpretation We demonstrated that ablation of MFF in liver provoked ER stress and reduced hepatic TG secretion in vivo and in vitro. Moreover, MffLiKO mice were more susceptible to HFD-induced NASH phenotype than control mice, partly because of ER stress-induced apoptosis of hepatocytes and suppression of TG secretion from hepatocytes. This study provides evidence for the role of mitochondrial fission in the development of NASH. Graphical abstract |
| Databáze: | OpenAIRE |
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