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Download fileHepatocytic activating transcription factor 3 protects against steatohepatitis via hepatocyte nuclear factor 4
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posted on 2021-09-02, 19:44 authored by Yanyong Xu, Shuwei Hu, Kavita Jadhav, Yingdong Zhu, Xiaoli Pan, Fathima Cassim Bawa, Liya Yin, Yanqiao ZhangActivating 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 adeno-associated virus-mediated over-expression 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 4a
(HNF4a) is required for ATF3 to improve steatohepatitis.
Thus, the current study indicates that ATF3 protects against steatohepatitis through,
at least in part, hepatic HNF4a.
Targeting hepatic ATF3 may be useful for treatment of steatohepatitis.
Funding
This work was supported by NIH grants R01HL142086, R01DK118941, R01DK118805, and R01DK121548 to Y.Z.
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Keywords
ApoptosisBile AcidsFatty Acid OxidationFatty LiverFree Fatty AcidsFructoseGene ExpressionHepatic FatHepatic SteatosisHepatocyteHigh Fructose Corn SyrupHNFInflammationInflammation and Oxidative StressNon-Alcoholic Fatty Liver DiseaseNon-Esterfied Fatty AcidsSteatosisTriglyceride MetabolismCholesterol MetabolismAdeno-Associated Viral VectorsBiological Sciences not elsewhere classified