title: ALCAT1 controls mitochondrial etiology of fatty liver diseases, linking defective mitophagy to steatosis.
abstract: Defective autophagy is implicated in the pathogenesis of nonalcoholic fatty liver diseases (NAFLD) through poorly defined mechanisms. Cardiolipin is a mitochondrial phospholipid required for bioenergetics and mitophagy from yeast to mammals. Here we investigated a role for ALCAT1 in the development of NAFLD. ALCAT1 is a lysocardiolipin acyltransferase that catalyzes pathological cardiolipin remodeling in several aging-related diseases. We show that the onset of diet-induced NAFLD caused autophagic arrest in hepatocytes, leading to oxidative stress, mitochondrial dysfunction, and insulin resistance. In contrast, targeted deletion of ALCAT1 in mice prevented the onset of NAFLD. ALCAT1 deficiency also restored mitophagy, mitochondrial architecture, mitochondrial DNA (mtDNA) fidelity, and oxidative phosphorylation. In support of a causative role of the enzyme in a mitochondrial etiology of the disease, hepatic ALCAT1 expression was significantly up-regulated in mouse models of NAFLD.
  
  
  CONCLUSIONS
  Forced expression of ALCAT1 in primary hepatocytes led to multiple defects that are highly reminiscent of NAFLD, including steatosis, defective autophagy, and mitochondrial dysfunction, linking pathological cardiolipin remodeling by ALCAT1 to the pathogenesis of NAFLD.
authors.affiliation: Department of Endocrinology and Metabolism, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Liu
authors.forename: Jia
authors.initials: J
authors.lastname: Nie
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Scot R
authors.initials: SR
authors.lastname: Kimball
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.forename: Weiping J
authors.initials: WJ
authors.lastname: Zhang
authors.forename: Leonard S
authors.initials: LS
authors.lastname: Jefferson
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Cheng
authors.forename: Qiuhe
authors.initials: Q
authors.lastname: Ji
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000217:Acyltransferases / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D005355:Fibrosis; D022781:Hepatocytes / Q000502:physiology; D050155:Lipogenesis; D008099:Liver / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D063306:Mitophagy; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000473:pathology; D018384:Oxidative Stress
chemical_list: D000217:Acyltransferases; C525544:lysocardiolipin acyltransferase, mouse