Mitochondria are highly dynamic organelles continuously undergoing fission and fusion, referred as mitochondrial dynamics (MtD), to adapt to nutritional demand. Evidence suggested that impaired MtD leads to metabolic abnormalities such as nonalcoholic steatohepatitis (NASH)-like phenotypes, which are characterized by hepatic steatosis, inflammation and fibrosis. However, how MtD is involved in the development of NASH is poorly understood. In this study, we found mitochondrial fission factor (Mff), a critical mediator of mitochondrial fission, is upregulated in the liver from mice fed high-fat diet (HFD). To explore the role of Mff in the development of NASH, we generated liver-specific deletion of Mff (MffLiKO) mice. Histological analysis revealed that mitochondria are enlarged in the liver from MffLiKO mice fed normal chow diet (NCD), which is followed by hepatocyte apoptosis, slightly increased infiltration of inflammatory macrophages, and fibrosis. However, no lipid accumulation was observed in the liver from MffLiKO mice fed NCD. That is, only the impairment of Mff-regulated mitochondrial fission did not develop NASH-like phenotypes. On the other hand, the liver of MffLiKO mice fed HFD developed NASH-like phenotype with severer steatosis. Expression of mRNAs related to endoplasmic reticulum (ER) stress was markedly upregulated in the liver from MffLiKO mice. In addition, expression of genes related to hepatic triglyceride secretion was downregulated, with reduced hepatic triglyceride secretion in MffLiKO mice in vivo and in primary cultures of Mff-deficient hepatocytes in vitro. Interestingly, thapsigargin-induced ER stress suppressed triglyceride secretion in primary cultured hepatocytes in vitro. This study demonstrates that MffLiKO develop NASH-like-phenotypes in response to HFD and suggests that impaired MtD induces ER stress and thus reduces hepatic triglyceride secretion, which may play a role in the pathogenesis of NASH.
Y. Takeichi: None. T. Miyazawa: None. S. Sakamoto: None. R. Sakamoto: None. M. Nomura: None. Y. Ogawa: Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker’s Bureau; Self; Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation.