Journal of Pharmaceutical Analysis (Aug 2024)

Hepatic protein phosphatase 1 regulatory subunit 3G alleviates obesity and liver steatosis by regulating the gut microbiota and bile acid metabolism

  • Chu Zhang,
  • Gui Wang,
  • Xin Yin,
  • Lingshan Gou,
  • Mengyuan Guo,
  • Feng Suo,
  • Tao Zhuang,
  • Zhenya Yuan,
  • Yanan Liu,
  • Maosheng Gu,
  • Ruiqin Yao

Journal volume & issue
Vol. 14, no. 8
p. 100976

Abstract

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Intestinal dysbiosis and disrupted bile acid (BA) homeostasis are associated with obesity, but the precise mechanisms remain insufficiently explored. Hepatic protein phosphatase 1 regulatory subunit 3G (PPP1R3G) plays a pivotal role in regulating glycolipid metabolism; nevertheless, its obesity-combatting potency remains unclear. In this study, a substantial reduction was observed in serum PPP1R3G levels in high-body mass index (BMI) and high-fat diet (HFD)-exposed mice, establishing a positive correlation between PPP1R3G and non-12α-hydroxylated (non-12-OH) BA content. Additionally, hepatocyte-specific overexpression of Ppp1r3g (PPP1R3G HOE) mitigated HFD-induced obesity as evidenced by reduced weight, fat mass, and an improved serum lipid profile; hepatic steatosis alleviation was confirmed by normalized liver enzymes and histology. PPP1R3G HOE considerably impacted systemic BA homeostasis, which notably increased the non-12-OH BAs ratio, particularly lithocholic acid (LCA). 16S ribosomal DNA (16S rDNA) sequencing assay indicated that PPP1R3G HOE reversed HFD-induced gut dysbiosis by reducing the Firmicutes/Bacteroidetes ratio and Lactobacillus population, and elevating the relative abundance of Blautia, which exhibited a positive correlation with serum LCA levels. A fecal microbiome transplantation test confirmed that the anti-obesity effect of hepatic PPP1R3G was gut microbiota-dependent. Mechanistically, PPP1R3G HOE markedly suppressed hepatic cholesterol 7α-hydroxylase (CYP7A1) and sterol-12α-hydroxylase (CYP8B1), and concurrently upregulated oxysterol 7-α hydroxylase and Takeda G protein-coupled BA receptor 5 (TGR5) expression under HFD conditions. Furthermore, LCA administration significantly mitigated the HFD-induced obesity phenotype and elevated non-12-OH BA levels. These findings emphasize the significance of hepatic PPP1R3G in ameliorating diet-induced adiposity and hepatic steatosis through the gut microbiota-BA axis, which may serve as potential therapeutic targets for obesity-related disorders.

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