Dataset Information

Pterostilbene Alleviates Cholestasis by Promoting SIRT1 Activity in Hepatocytes and Macrophages.

ABSTRACT: Background and purpose: FXR is a promising target for the treatment of human cholestatic liver disease (CLD). SIRT1 is a deacetylase which promotes FXR activity through deacetylating FXR. Pterostilbene (PTE) is an activator of SIRT1. However, the role of PTE in cholestasis has so far not been investigated. We examined whether PTE treatment alleviate liver injury in DDC or ANIT-induced experimental cholestasis, and explored the underlying mechanisms. Experimental approach: Mice with DDC- or ANIT-induced cholestasis were treated with different dose of PTE. Primary hepatocytes and bone marrow derived macrophages were used in vitro to assess the molecular mechanism by which PTE may improve CLD. Identical doses of UDCA or PTE were administered to DDC- or ANIT-induced cholestasis mice. Key results: PTE intervention attenuated DDC or ANIT-induced cholestasis. PTE inhibited macrophage infiltration and activation in mouse liver through the SIRT1-p53 signaling pathway, and it improved hepatic bile metabolism through the SIRT1-FXR signaling pathway. Compare with UDCA, the same doses of PTE was more effective in improving cholestatic liver injury caused by DDC or ANIT. Conclusion and implications: SIRT1 activation in macrophages may be an effective CLD treatment avenue. Using CLD models, we thus identified PTE as a novel clinical candidate compound for the treatment of CLD.

SUBMITTER: Ma C

PROVIDER: S-EPMC8656168 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Pterostilbene Alleviates Cholestasis by Promoting SIRT1 Activity in Hepatocytes and Macrophages.

Ma Chuanrui C Xiang Jiaqing J Huang Guixiao G Zhao Yaxi Y Wang Xinyu X Wu Han H Jiang Kewei K Liang Zhen Z Kang Lin L Yang Guangyan G Yang Shu S

Frontiers in pharmacology 20211125

<b>Background and purpose:</b> FXR is a promising target for the treatment of human cholestatic liver disease (CLD). SIRT1 is a deacetylase which promotes FXR activity through deacetylating FXR. Pterostilbene (PTE) is an activator of SIRT1. However, the role of PTE in cholestasis has so far not been investigated. We examined whether PTE treatment alleviate liver injury in DDC or ANIT-induced experimental cholestasis, and explored the underlying mechanisms. <b>Experimental approach:</b> Mice with ...[more]

PMID: 34899349

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Project description:BackgroundBerberine effectively alleviates non-alcoholic fatty liver disease (NAFLD). Nevertheless, the mechanism is incompletely comprehended. It has been reported that SIRT1 mediates lipid metabolism in liver and berberine promotes the expression of SIRT1 in hepatocytes. We hypothesized that SIRT1 mediated the effect of berberine on NAFLD.MethodsThe effects of berberine on NAFLD were evaluated in C57BL/6J mice fed a high-fat diet (HFD) and in mouse primary hepatocytes and cell lines exposed to palmitate. The change of fatty acid oxidation (FAO) and the activity of CPT1A were observed in HepG2 cells. Quantitative real-time polymerase chain reaction and Western blot were employed to observe the expression of SIRT1 and lipid metabolism-related molecules. The interaction between SIRT1 and CPT1A was investigated by using co-immunoprecipitation assay in HEK293T cells.ResultsBerberine treatment attenuated hepatic steatosis, reduced triglyceride (190.1 ± 11.2 μmol/g liver vs 113.6 ± 7.6 μmol/g liver, P < 0.001) and cholesterol (11.3 ± 2.5 μmol/g liver vs 6.3 ± 0.4 μmol/g liver, P < 0.001) concentration in the liver, and improved lipid and glucose metabolism disorders compared with the HFD group. The expression of SIRT1 was reduced in the liver of NAFLD patients and mouse models. Berberine increased the expression of SIRT1 and promoted the protein level of CPT1A and its activity in HepG2 cells. SIRT1 overexpression mimicked the effect of berberine on reducing triglyceride levels in HepG2 cells, whereas SIRT1 knock-down attenuated the effect of berberine. Mechanistically, berberine increased the expression of SIRT1. SIRT1 deacetylated CPT1A at the Lys675 site, which suppressed its ubiquitin-dependent degradation, thereby promoting FAO and alleviating non-alcoholic liver steatosis.ConclusionsBerberine promoted SIRT1 deacetylation of CPT1A at the Lys675 site, which reduced the ubiquitin-dependent degradation of CPT1A and ameliorated non-alcoholic liver steatosis.

Dataset Information

Pterostilbene Alleviates Cholestasis by Promoting SIRT1 Activity in Hepatocytes and Macrophages.

Publications

Pterostilbene Alleviates Cholestasis by Promoting SIRT1 Activity in Hepatocytes and Macrophages.

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