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Published on: April 26, 2019
Hepatic FOXA3 overexpression prevents Western diet-induced obesity and MASH through TGR5
Raja Gopoju1, Jiayou Wang1, Xiaoli Pan1
1Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA.
Abstract:
Forkhead transcription factor 3 (FOXA3) has been shown to regulate metabolism and development. Hepatic FOXA3 is reduced in obesity and fatty liver disease. However, the role of hepatic FOXA3 in regulating obesity or steatohepatitis remains to be investigated. In this work, C57BL/6 mice were i.v. injected with AAV8-ALB-FOXA3 or the control virus. The mice were then fed a chow or Western diet for 16 weeks. The role of hepatic FOXA3 in energy metabolism and steatohepatitis was investigated. Plasma bile acid composition and the role of Takeda G protein-coupled receptor 5 (TGR5) in mediating the metabolic effects of FOXA3 were determined. Overexpression of hepatic FOXA3 reduced hepatic steatosis in chow-fed mice and attenuated Western diet-induced obesity and steatohepatitis. FOXA3 induced lipolysis and inhibited hepatic genes involved in bile acid uptake, resulting in elevated plasma bile acids. The beneficial effects of hepatic FOXA3 overexpression on Western diet-induced obesity and steatohepatitis were abolished in Tgr5-/- mice. Our data demonstrate that overexpression of hepatic FOXA3 prevents Western diet-induced obesity and steatohepatitis via activation of TGR5.
Insights
Hepatic Forkhead transcription factor 3 (FOXA3) overexpression combats obesity and fatty liver disease. This occurs by activating Takeda G protein-coupled receptor 5 (TGR5), improving metabolism and reducing liver inflammation.
Area of Science:
- Hepatology
- Metabolic disease research
- Molecular biology
Background:
- Forkhead transcription factor 3 (FOXA3) regulates metabolism but its role in obesity and non-alcoholic steatohepatitis (NASH) is unclear.
- Hepatic FOXA3 levels are decreased in obesity and fatty liver conditions.
- Investigating FOXA3's function is crucial for understanding and treating metabolic liver diseases.
Purpose of the Study:
- To investigate the role of hepatic FOXA3 in regulating obesity and steatohepatitis.
- To determine the mechanisms by which FOXA3 influences energy metabolism and liver health.
- To explore the involvement of Takeda G protein-coupled receptor 5 (TGR5) in FOXA3's metabolic effects.
Main Methods:
- Adeno-associated virus serotype 8 (AAV8) mediated in vivo overexpression of FOXA3 in C57BL/6 mice.
- Mice were fed a standard chow or a high-fat Western diet for 16 weeks.
- Analysis of liver steatosis, obesity markers, plasma bile acids, and gene expression, including studies in TGR5 knockout mice.
Main Results:
- Hepatic FOXA3 overexpression reduced liver steatosis in chow-fed mice.
- FOXA3 overexpression attenuated Western diet-induced obesity and steatohepatitis.
- FOXA3 increased lipolysis, altered bile acid uptake genes, elevated plasma bile acids, and required TGR5 for its beneficial effects.
Conclusions:
- Overexpression of hepatic FOXA3 prevents diet-induced obesity and steatohepatitis.
- The protective effects of FOXA3 are mediated through the activation of TGR5.
- Targeting FOXA3 and TGR5 pathways may offer therapeutic strategies for metabolic liver diseases.
