Hepatic Phospholipid Remodeling Modulates Insulin Sensitivity and Systemic Metabolism

Ye Tian, Kritika Mehta, Matthew J. Jellinek, Hao Sun, Wei Lu, Ruicheng Shi, Kevin Ingram, Randall H. Friedline, Jason K. Kim, Jongsook Kim Kemper, David A. Ford, Kai Zhang, Bo Wang

Research output: Contribution to journalArticlepeer-review

Abstract

The liver plays a central role in regulating glucose and lipid metabolism. Aberrant insulin action in the liver is a major driver of selective insulin resistance, in which insulin fails to suppress glucose production but continues to activate lipogenesis in the liver, resulting in hyperglycemia and hypertriglyceridemia. The underlying mechanisms of selective insulin resistance are not fully understood. Here It is shown that hepatic membrane phospholipid composition controlled by lysophosphatidylcholine acyltransferase 3 (LPCAT3) regulates insulin signaling and systemic glucose and lipid metabolism. Hyperinsulinemia induced by high-fat diet (HFD) feeding augments hepatic Lpcat3 expression and membrane unsaturation. Loss of Lpcat3 in the liver improves insulin resistance and blunts lipogenesis in both HFD-fed and genetic ob/ob mouse models. Mechanistically, Lpcat3 deficiency directly facilitates insulin receptor endocytosis, signal transduction, and hepatic glucose production suppression and indirectly enhances fibroblast growth factor 21 (FGF21) secretion, energy expenditure, and glucose uptake in adipose tissue. These findings identify hepatic LPCAT3 and membrane phospholipid composition as a novel regulator of insulin sensitivity and provide insights into the pathogenesis of selective insulin resistance.

Original languageEnglish (US)
Article number2300416
JournalAdvanced Science
Volume10
Issue number18
DOIs
StatePublished - Jun 23 2023

Keywords

  • FGF21
  • LPCAT3
  • insulin signaling transduction
  • phospholipid remodeling
  • selective insulin resistance

ASJC Scopus subject areas

  • General Engineering
  • General Chemical Engineering
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • General Materials Science
  • General Physics and Astronomy
  • Medicine (miscellaneous)

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