2. Academic Validation
  3. Inhibition of FoxO1 ameliorates hepatic steatosis and hepatitis in nonalcoholic steatohepatitis mice through regulation of gut microbiota

Inhibition of FoxO1 ameliorates hepatic steatosis and hepatitis in nonalcoholic steatohepatitis mice through regulation of gut microbiota

  • J Dig Dis. 2024 Jul;25(7):453-462. doi: 10.1111/1751-2980.13306.
Di Wen Shou 1 2,  Ying Quan 1 2,  Jie Min Cheng 1 2,  Si Qi Yang 1 2,  Jia Wei Chen 1 2,  Yong Qiang Li 1 2,  Chen Huang 1 2,  Hui Ting Chen 1 2,  Yong Jian Zhou 1 2
Affiliations

Affiliations

  • 1 Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, Guangdong Province, China.
  • 2 Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong Province, China.
PMID: 39211938 DOI: 10.1111/1751-2980.13306
Abstract

Objective: We aimed to investigate the role of forkhead box O1 (FoxO1) inhibitor AS1842856 (AS) in nonalcoholic steatohepatitis (NASH) mice and the potential mechanisms.

Methods: Mice were given methionine-choline-sufficient (MCS), or methionine- and choline-deficient (MCD) diet for 5 weeks, along with AS (60 mg/kg) or vehicle gavage treatment (0.2 mL/day). Body and liver weight, serum triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting glucose and Insulin levels were measured. Liver macrophage infiltration and ileal ZO-1 protein expression were also detected. Interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α, sterol regulatory element binding protein (SREBP)-1c, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase), α-smooth muscle actin (SMA), recombinant collagen type III α1 (Col3a1), and connective tissue growth factor (CTGF) expressions were measured. Stool samples were collected for 16S rDNA Sequencing.

Results: Compared to the MCD group, AS attenuated liver weight, reduced serum TG, ALT, and AST levels, increased HDL-C levels, mitigated hepatic steatosis, decreased macrophage infiltration, and augmented ileal ZO-1 proteins in NASH mice. It also reduced the levels of IL-6, IL-1β, and TNF-α, alongside with the Srebp-1c mRNA expression. However, no significant effects on PEPCK, G6Pase, α-SMA, Col3a1, or CTGF were observed. Furthermore, AS promoted diversity and altered gut microbiota composition in NASH mice, causing increased beneficial bacteria like Akkermansia muciniphila, Parabacteroides distasonis, and Prevotellamassilia, which were associated with metabolic functions.

Conclusion: FoxO1 inhibitor AS ameliorated hepatic steatosis, inflammation, and intestinal dysbiosis in NASH mice, making it a potentially promising treatment for NASH.

Keywords

forkhead box protein O1; gastrointestinal microbiome; hepatitis; non‐alcoholic fatty liver disease.

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