Hepatic protein phosphatase 1 regulatory subunit 3G alleviates obesity and liver steatosis by regulating the gut microbiota and bile acid metabolism
10.1016/j.jpha.2024.100976
- Author:
Zhang CHU
1
;
Wang GUI
;
Yin XIN
;
Gou LINGSHAN
;
Guo MENGYUAN
;
Suo FENG
;
Zhuang TAO
;
Yuan ZHENYA
;
Liu YANAN
;
Gu MAOSHENG
;
Yao RUIQIN
Author Information
1. Xuzhou Key Laboratory of Neurobiology,Department of Cell Biology and Neurobiology,Xuzhou Medical University,Xuzhou,Jiangsu,221004,China
- Keywords:
PPP1R3G;
Obesity;
Liver steatosis;
Gut microbiota;
Bile acid metabolism
- From:
Journal of Pharmaceutical Analysis
2024;14(8):1222-1237
- CountryChina
- Language:Chinese
-
Abstract:
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 ther-apeutic targets for obesity-related disorders.
