Please use this identifier to cite or link to this item: https://doi.org/10.1073/pnas.2018069118
Title: Active p38 alpha causes macrovesicular fatty liver in mice
Authors: Darlyuk-Saadon, Ilona
Bai, Chen 
Heng, Chew Kiat Matthew
Gilad, Nechama
Yu, Wei-Ping
Lim, Pei Yen 
Cazenave-Gassiot, Amaury
Zhang, Yongliang
Wong, WS Fred 
Engelberg, David
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
p38
active variants
transgenic mice
lipidosis
fatty liver
Issue Date: 6-Apr-2021
Publisher: NATL ACAD SCIENCES
Citation: Darlyuk-Saadon, Ilona, Bai, Chen, Heng, Chew Kiat Matthew, Gilad, Nechama, Yu, Wei-Ping, Lim, Pei Yen, Cazenave-Gassiot, Amaury, Zhang, Yongliang, Wong, WS Fred, Engelberg, David (2021-04-06). Active p38 alpha causes macrovesicular fatty liver in mice. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 118 (14). ScholarBank@NUS Repository. https://doi.org/10.1073/pnas.2018069118
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).
Source Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
URI: https://scholarbank.nus.edu.sg/handle/10635/205810
ISSN: 00278424
10916490
DOI: 10.1073/pnas.2018069118
Appears in Collections:Staff Publications
Elements

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
pnas.202018069.pdf2.33 MBAdobe PDF

CLOSED

Published

SCOPUSTM   
Citations

3
checked on Aug 15, 2022

Page view(s)

82
checked on Aug 4, 2022

Download(s)

1
checked on Aug 4, 2022

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.