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Hepatocytic Activating Transcription Factor 3 Protects Against Steatohepatitis via Hepatocyte Nuclear Factor 4α

Authors :
Yanqiao Zhang
Yanyong Xu
Yingdong Zhu
Xiaoli Pan
Shuwei Hu
Kavita Jadhav
Liya Yin
Fathima Cassim Bawa
Source :
Diabetes
Publication Year :
2021
Publisher :
American Diabetes Association, 2021.

Abstract

Activating transcription factor 3 (ATF3) has been shown to play an important role in HDL metabolism; yet, the role of hepatocytic ATF3 in the development of steatohepatitis remains elusive. Here we show that adenoassociated virus-mediated overexpression of human ATF3 in hepatocytes prevents diet-induced steatohepatitis in C57BL/6 mice and reverses steatohepatitis in db/db mice. Conversely, global or hepatocyte-specific loss of ATF3 aggravates diet-induced steatohepatitis. Mechanistically, hepatocytic ATF3 induces hepatic lipolysis and fatty acid oxidation and inhibits inflammation and apoptosis. We further show that hepatocyte nuclear factor 4α (HNF4α) is required for ATF3 to improve steatohepatitis. Thus, the current study indicates that ATF3 protects against steatohepatitis through, at least in part, hepatic HNF4α. Targeting hepatic ATF3 may be useful for treatment of steatohepatitis.

Details

ISSN :
00121797
Volume :
70
Database :
OpenAIRE
Journal :
Diabetes
Accession number :
edsair.doi.dedup.....1780b03efe272ff85a80080b8d54341b