The inhibition of inner mitochondrial fusion in hepatocytes reduces non-alcoholic fatty liver and improves metabolic profile during obesity by modulating bile acid conjugation

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 affects diet-induced liver steatosis and obesity.Male mice selectively lacking the key protein involved in inner mitochondrial fusion, optic atrophy 1 (OPA1) (OPA1ΔHep) were fed 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 carbohydrates in OPA1ΔHep compared to controls. At the molecular level, this phenotype emerged as a consequence of poor mitochondria-peroxisome- endoplasmic reticulum (ER) tethering in OPA1 deficient hepatocytes, which impaired BAs conjugation and release in the bile, thus impacting lipid absorption from the diet. Concordantly, the liver of subjects with non-alcoholic fatty liver disease (NAFLD) presented an increased expression of OPA1 and of the network of proteins involved in mitochondrial function when compared with controls.Patients with NAFLD present increased expression of proteins involved in mitochondrial fusion in the liver. The selective deficency of OPA1 in hepatocytes protects mice from HFD-induced metabolic dysfunction by reducing BAs secretion and dietary lipids absorption as a consequence of reduced liver mitochondria-peroxisome-ER tethering.