Defective Phosphatidylglycerol Remodeling Causes Hepatopathy, Linking Mitochondrial Dysfunction to Hepatosteatosis

Xiaoyang Zhang, Jun Zhang, Haoran Sun, Xueling Liu, Yue Zheng, Dan Xu, Jianing Wang, Dandan Jia, Xianlin Han, Feng Liu, Jia Nie, Yuguang Shi

Research output: Contribution to journalArticlepeer-review

Abstract

Background & Aims: Obesity promotes the development of nonalcoholic fatty liver diseases (NAFLDs), yet not all obese patients develop NAFLD. The underlying causes for this discrepancy remain elusive. LPGAT1 is an acyltransferase that catalyzes the remodeling of phosphatidylglycerol (PG), a mitochondrial phospholipid implicated in various metabolic diseases. Here, we investigated the role of LPGAT1 in regulating the onset of diet-induced obesity and its related hepatosteatosis because polymorphisms of the LPGAT1 gene promoter were strongly associated with susceptibility to obesity in Pima Indians. Methods: Mice with whole-body knockout of LPGAT1 were generated to investigate the role of PG remodeling in NAFLD. Results: LPGAT1 deficiency protected mice from diet-induced obesity, but led to hepatopathy, insulin resistance, and NAFLD as a consequence of oxidative stress, mitochondrial DNA depletion, and mitochondrial dysfunction. Conclusions: This study identified an unexpected role of PG remodeling in obesity, linking mitochondrial dysfunction to NAFLD.

Original languageEnglish (US)
Pages (from-to)763-781
Number of pages19
JournalCMGH
Volume7
Issue number4
DOIs
StatePublished - Jan 1 2019

Keywords

  • Cardiolipin
  • LPGAT1
  • MEGDEL Syndrome
  • Mitochondrial Dysfunction
  • NAFLD

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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