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

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

Research output: Contribution to journalArticle

37 Scopus citations

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

All Science Journal Classification (ASJC) codes

  • Hepatology

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    Wang, L., Liu, X., Nie, J., Zhang, J., Kimball, S. R., Zhang, H., Zhang, W. J., Jefferson, L. S., Cheng, Z., Ji, Q., & Shi, Y. (2015). ALCAT1 controls mitochondrial etiology of fatty liver diseases, linking defective mitophagy to steatosis. Hepatology, 61(2), 486-496. https://doi.org/10.1002/hep.27420