Active p38α causes macrovesicular fatty liver in mice

Ilona Darlyuk-Saadon, Chen Bai, Chew Kiat Matthew Heng, Nechama Gilad, Wei Ping Yu, Pei Yen Lim, Amaury Cazenave-Gassiot, Yongliang Zhang, W. S. Fred Wong, David Engelberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

One third of the western population suffers from nonalcoholic fatty liver disease (NAFLD), which may ultimately develop into hepatocellular carcinoma (HCC). The molecular event(s) that triggers the disease are not clear. Current understanding, known as the multiple hits model, suggests that NAFLD is a result of diverse events at several tissues (e.g., liver, adipose tissues, and intestine) combined with changes in metabolism and microbiome. In contrast to this prevailing concept, we report that fatty liver could be triggered by a single mutated protein expressed only in the liver. We established a transgenic system that allows temporally controlled activation of the MAP kinase p38α in a tissue-specific manner by induced expression of intrinsically active p38α allele. Here we checked the effect of exclusive activation in the liver. Unexpectedly, induction of p38α alone was sufficient to cause macrovesicular fatty liver. Animals did not become overweight, showing that fatty liver can be imposed solely by a genetic modification in liver per se and can be separated from obesity. Active p38α- induced fatty liver is associated with up-regulation of MUC13, CIDEA, PPARγ, ATF3, and c-jun mRNAs, which are up-regulated in human HCC. Shutting off expression of the p38α mutant resulted in reversal of symptoms. The findings suggest that p38α plays a direct causative role in fatty liver diseases and perhaps in other chronic inflammatory diseases. As p38α activity was induced by point mutations, it could be considered a proto-inflammatory gene (proto-inflammagene).

Original languageAmerican English
Article numbere2018069118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number14
DOIs
StatePublished - 6 Apr 2021

Bibliographical note

Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.

Keywords

  • Active variants
  • Fatty liver
  • Lipidosis
  • Transgenic mice
  • p38

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