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

Volume 14 Issue 8

Aug. 2024

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Chu Zhang, Gui Wang, Xin Yin, Lingshan Gou, Mengyuan Guo, Feng Suo, Tao Zhuang, Zhenya Yuan, Yanan Liu, Maosheng Gu, Ruiqin Yao. Hepatic protein phosphatase 1 regulatory subunit 3G alleviates obesity and liver steatosis by regulating the gut microbiota and bile acid metabolism[J]. Journal of Pharmaceutical Analysis, 2024, 14(8): 100976. doi: 10.1016/j.jpha.2024.100976

Citation:

Chu Zhang, Gui Wang, Xin Yin, Lingshan Gou, Mengyuan Guo, Feng Suo, Tao Zhuang, Zhenya Yuan, Yanan Liu, Maosheng Gu, Ruiqin Yao. Hepatic protein phosphatase 1 regulatory subunit 3G alleviates obesity and liver steatosis by regulating the gut microbiota and bile acid metabolism[J]. Journal of Pharmaceutical Analysis, 2024, 14(8): 100976. doi: 10.1016/j.jpha.2024.100976

Citation:

Chu Zhang, Gui Wang, Xin Yin, Lingshan Gou, Mengyuan Guo, Feng Suo, Tao Zhuang, Zhenya Yuan, Yanan Liu, Maosheng Gu, Ruiqin Yao. Hepatic protein phosphatase 1 regulatory subunit 3G alleviates obesity and liver steatosis by regulating the gut microbiota and bile acid metabolism[J]. Journal of Pharmaceutical Analysis, 2024, 14(8): 100976. doi: 10.1016/j.jpha.2024.100976

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

doi: 10.1016/j.jpha.2024.100976

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

Funds:

This work was supported by the Natural Science Foundation for Young Scientists of China (Grant No.: 82201545), the Natural Science Foundation of Jiangsu Province, China (Grant No.: BK20221221), the Practice Innovation Program of Jiangsu Province, China (Grant No.: KYCX21_2641), the Medical Science Foundation of Jiangsu Province, China (Grant No.: H2019007), the Key Medical Talents Training Project of Xuzhou, China (Grant No.: XWRCHT20220060), the Xuzhou “Pengcheng Talent” Youth Medical Reserve Talent Project, China (Grant No.: XWRCHT20220014), and the Science and Technology Projects of Xuzhou, China (Grant No.: KC21061). We acknowledge the Prof. Chanmin Liu and Prof. Xingqi Wang from Jiangsu Normal University for providing us with transgenic mice. Graphical abstract was created with BioRender.

Received Date: Nov. 12, 2023
Accepted Date: Apr. 08, 2024
Rev Recd Date: Mar. 05, 2024
Publish Date: Apr. 11, 2024

Abstract

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 therapeutic targets for obesity-related disorders.
- PPP1R3G,
- Obesity,
- Liver steatosis,
- Gut microbiota,
- Bile acid metabolism

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References(68)

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