The inhibition of inner mitochondrial fusion in hepatocytes reduces NAFL and improves metabolic profile during obesity by modulating bile acid conjugation

Background and aim: Mitochondria are plastic organelles that continuously undergo biogenesis, fusion, fission, and mitophagy to control cellular energy metabolism, calcium homeostasis, hormones, sterols and bile acids (BAs) synthesis. Here we evaluated how the impairment of mitochondrial fusion in hepatocytes affect diet induced liver steatosis and obesity. Methods and results: Male mice selectively lacking the key protein involved in inner mitochondrial fusion, OPA1, (OPA1ΔHep) on a High Fat Diet (HFD) for 20 weeks. OPA1ΔHep mice were protected from the development of hepatic steatosis and obesity because of reduced lipid absorption; a profile which was accompanied by increased respiratory exchange ratio in vivo, suggesting a preference for carbohydrate in OPA1ΔHep in agreement with the defect in mitochondrial fusion. At the molecular level, this phenotype emerged as a consequence of poor mitochondrial-peroxisome-ER tethering in OPA1 deficient hepatocytes thus impairing bile acid conjugation and therefore its release in the bile, thus impacting lipid absorption from the diet. Concordantly the liver of NAFLD subjects presented an increased expression of OPA1 and of the network of proteins involved in mitochondrial when compared to controls. Conclusion: Patients with NAFLD present increased expression of proteins involved in mitochondrial fusion in the liver. The selective inhibition of liver mitochondrial fusion observed in hepatocyte OPA1 deficient mice protects mice from HFD-induced metabolic dysfunction by reducing lipid dietary absorption and bile acid secretion as a consequence of reduced liver mitochondria-peroxisome-ER tethering.