Abstract
Aims/hypothesisMitochondria 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.MethodsWe 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.ResultsMffLiKO 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/interpretationWe 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
Highlights
Non-alcoholic fatty liver disease (NAFLD) is characterised by increased accumulation of lipids in the liver without a history of excessive alcohol consumption or known liver disease
Arrows indicate injections into media of the specific stressors oligomycin (Olig.), carbonyl cyanite-4 phenylhydrazone (FCCP) and rotenone/antimycin A (R/A) (n=5 per group). (h) membrane potential (MMP) is shown by the ratio of MTR to MTG fluorescence in hepatocytes from MffLiKO and control mice (n=6 per group). (i–l) Mitochondrial respiratory rates of basal respiration (i), complex II (j), complex IV (k) and maximal respiration (l) in mitochondria isolated from MffLiKO and control mouse livers
The expression of other proteins related to mitochondrial dynamics (DRP1, MFN2, optic atrophy 1 (OPA1), and translocase of outer membrane, a protein located in mitochondrial outer membrane) showed no appreciable difference between the genotypes (Fig. 1e, Electronic supplementary material (ESM) Fig. 1b)
Summary
Non-alcoholic fatty liver disease (NAFLD) is characterised by increased accumulation of lipids in the liver without a history of excessive alcohol consumption or known liver disease. Mitochondria are unique multifunctional organelles that are critically involved in biological processes such as apoptosis, calcium signalling, ATP production and cellular metabolism [4,5,6,7]. They are highly dynamic organelles undergoing coordinated cycles of fission and fusion, known as ‘mitochondrial dynamics’; this is an adaptive response to cellular demands and the environment to maintain metabolic homeostasis [5, 8, 9]. Mitochondrial functions are regulated by the structural and functional crosstalk with other organelles, a
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