ALCAT1 controls mitochondrial etiology of fatty liver diseases, linking defective mitophagy to steatosis

Li Wang, Xiaolei Liu, Jia Nie, Jun Zhang, Scot Kimball, Hai Zhang, Weiping J. Zhang, Leonard "Jim" Jefferson, Zeneng Cheng, Qiuhe Ji, Yuguang Shi

Research output: Contribution to journalArticle

28 Citations (Scopus)

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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)486-496
Number of pages11
JournalHepatology
Volume61
Issue number2
DOIs
StatePublished - Feb 1 2015

Fingerprint

Mitochondrial Degradation
Fatty Liver
Liver Diseases
Cardiolipins
Autophagy
Hepatocytes
Acyltransferases
Mitochondrial Diseases
Oxidative Phosphorylation
Non-alcoholic Fatty Liver Disease
Mitochondrial DNA
Energy Metabolism
Insulin Resistance
Mammals
Phospholipids
Oxidative Stress
Yeasts
Diet
Liver

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Wang, Li ; Liu, Xiaolei ; Nie, Jia ; Zhang, Jun ; Kimball, Scot ; Zhang, Hai ; Zhang, Weiping J. ; Jefferson, Leonard "Jim" ; Cheng, Zeneng ; Ji, Qiuhe ; Shi, Yuguang. / ALCAT1 controls mitochondrial etiology of fatty liver diseases, linking defective mitophagy to steatosis. In: Hepatology. 2015 ; Vol. 61, No. 2. pp. 486-496.
@article{e8bb0dd4a39e434db333e8aad05e55b2,
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. Conclusion: 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.",
author = "Li Wang and Xiaolei Liu and Jia Nie and Jun Zhang and Scot Kimball and Hai Zhang and Zhang, {Weiping J.} and Jefferson, {Leonard {"}Jim{"}} and Zeneng Cheng and Qiuhe Ji and Yuguang Shi",
year = "2015",
month = "2",
day = "1",
doi = "10.1002/hep.27420",
language = "English (US)",
volume = "61",
pages = "486--496",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "2",

}

Wang, L, Liu, X, Nie, J, Zhang, J, Kimball, S, Zhang, H, Zhang, WJ, Jefferson, LJ, Cheng, Z, Ji, Q & Shi, Y 2015, 'ALCAT1 controls mitochondrial etiology of fatty liver diseases, linking defective mitophagy to steatosis', Hepatology, vol. 61, no. 2, pp. 486-496. https://doi.org/10.1002/hep.27420

ALCAT1 controls mitochondrial etiology of fatty liver diseases, linking defective mitophagy to steatosis. / Wang, Li; Liu, Xiaolei; Nie, Jia; Zhang, Jun; Kimball, Scot; Zhang, Hai; Zhang, Weiping J.; Jefferson, Leonard "Jim"; Cheng, Zeneng; Ji, Qiuhe; Shi, Yuguang.

In: Hepatology, Vol. 61, No. 2, 01.02.2015, p. 486-496.

Research output: Contribution to journalArticle

TY - JOUR

T1 - ALCAT1 controls mitochondrial etiology of fatty liver diseases, linking defective mitophagy to steatosis

AU - Wang, Li

AU - Liu, Xiaolei

AU - Nie, Jia

AU - Zhang, Jun

AU - Kimball, Scot

AU - Zhang, Hai

AU - Zhang, Weiping J.

AU - Jefferson, Leonard "Jim"

AU - Cheng, Zeneng

AU - Ji, Qiuhe

AU - Shi, Yuguang

PY - 2015/2/1

Y1 - 2015/2/1

N2 - 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. Conclusion: 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.

AB - 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. Conclusion: 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.

UR - http://www.scopus.com/inward/record.url?scp=84921448245&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84921448245&partnerID=8YFLogxK

U2 - 10.1002/hep.27420

DO - 10.1002/hep.27420

M3 - Article

VL - 61

SP - 486

EP - 496

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 2

ER -