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

doi:10.1016/j.jpha.2024.100976

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

J Pharm Anal. 2024 Aug;14(8):100976. doi: 10.1016/j.jpha.2024.100976. Epub 2024 Apr 11.

Authors

Chu Zhang¹, Gui Wang¹, Xin Yin², Lingshan Gou², Mengyuan Guo³, Feng Suo², Tao Zhuang¹, Zhenya Yuan², Yanan Liu¹, Maosheng Gu², Ruiqin Yao¹

Affiliations

¹ Xuzhou Key Laboratory of Neurobiology, Department of Cell Biology and Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
² Department of Genetic Medicine, Xuzhou Maternity and Child Health Care Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, 221009, China.
³ Department of Geriatrics, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221006, China.

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 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.

Keywords: Bile acid metabolism; Gut microbiota; Liver steatosis; Obesity; PPP1R3G.