Hepatic PPP1R3G alleviates obesity and liver steatosis by affecting gut microbiota and bile acid metabolism

Chu Zhang a; 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

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Chu Zhang a, Gui Wang, Xin Yin, Lingshan Gou, Mengyuan Guo, Feng Suo, Tao Zhuang, Zhenya Yuan, Yanan Liu, Maosheng Gu, Ruiqin Yao. Hepatic PPP1R3G alleviates obesity and liver steatosis by affecting gut microbiota and bile acid metabolism[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2024.100976

Citation:

Chu Zhang a, Gui Wang, Xin Yin, Lingshan Gou, Mengyuan Guo, Feng Suo, Tao Zhuang, Zhenya Yuan, Yanan Liu, Maosheng Gu, Ruiqin Yao. Hepatic PPP1R3G alleviates obesity and liver steatosis by affecting gut microbiota and bile acid metabolism[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2024.100976

Citation:

Chu Zhang a, Gui Wang, Xin Yin, Lingshan Gou, Mengyuan Guo, Feng Suo, Tao Zhuang, Zhenya Yuan, Yanan Liu, Maosheng Gu, Ruiqin Yao. Hepatic PPP1R3G alleviates obesity and liver steatosis by affecting gut microbiota and bile acid metabolism[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2024.100976

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Hepatic PPP1R3G alleviates obesity and liver steatosis by affecting gut microbiota and bile acid metabolism

doi: 10.1016/j.jpha.2024.100976

1 Xuzhou Key Laboratory of Neurobiology, Department of Cell Biology and Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China;
2 Department of Genetic Medicine, Maternity and Child Health Care Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, 221009, China;
3 Department of Geriatrics, Xuzhou Second People's Hospital, 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 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
Available Online: Apr. 13, 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 highbody mass index 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 and 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 lithocholate (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 and sterol-12α-hydroxylase, and concurrently upregulated oxysterol 7-α hydroxylase and Takeda G protein-coupled receptor 5 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 microbiotaBA 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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