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

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.

• Authors: Yanyong Xu, Shuwei Hu, Kavita Jadhav, Yingdong Zhu, Xiaoli Pan, Fathima Cassim Bawa, Liya Yin, Yanqiao Zhang
• Journal: Diabetes (Diabetes) Vol. 70 Issue 11 Pg. 2506-2517 (11 2021) ISSN: 1939-327X [Electronic] United States
• PMID: 34475098 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2021 by the American Diabetes Association.

Chemical References

• ATF3 protein, human
• Activating Transcription Factor 3
• Atf3 protein, mouse
• HNF4A protein, human
• Hepatocyte Nuclear Factor 4
• Hnf4a protein, mouse
• MicroRNAs
• RNA, Messenger

Topics

• Activating Transcription Factor 3 (genetics, metabolism)
• Animals
• Diet, Western
• Gene Expression Regulation (physiology)
• Hepatic Stellate Cells
• Hepatocyte Nuclear Factor 4 (genetics, metabolism)
• Hepatocytes (metabolism)
• Humans
• Kupffer Cells (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, Knockout
• MicroRNAs (genetics, metabolism)
• Non-alcoholic Fatty Liver Disease (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)