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Salidroside-Mitigated Inflammatory Injury of Hepatocytes with Non-Alcoholic Fatty Liver Disease via Inhibition TRPM2 Ion Channel Activation.

ABSTRACT: Purpose:Oxidative stress plays an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). TRPM2 ion channel functions as a molecular sensor for oxidative stress. The aim of this study was to examine the protective effects of Salidroside, a powerful antioxidative plant, on TRPM2 in an established in vitro model of NAFLD. Methods:NAFLD model was established by palmitic acid (PA) in hepatic L02 cell lines and was added to the media at a final concentration of 400 ?M. Cells were used as normal group, PA group and PA receiving varied concentrations of Salidroside (75?g/mL, 150?g/mL, 300?g/mL). After treating 24 hrs, MTT assay was used to detect cell viability, and ALT level was measured using an appropriate kit assay. Intracellular lipid accumulation was observed by Oil red O staining. Cytosolic Ca2+ concentrations were evaluated by flow cytometer with Fluo-3/AM. Quantitative RT-PCR was used to measure the mRNA expression of TRPM2, IL-1? and IL-6, and the protein expressions of TRPM2, p-CaMKII and autophagy (LC3B, p62) were determined using Western blot. Results:Treatment with Salidroside effectively restored liver injury and alleviated lipid droplet deposition in a dose-dependent manner, which was associated with inhibition of TRPM2/Ca2+/CaMKII pathway. Additionally, autophagic clearance was enhanced by intervention with Salidroside in a dose-dependent manner. Further investigation indicated that Salidroside down-regulated the mRNA expression of IL-1? and IL-6-pro-inflammatory cytokines. Conclusion:These results suggest that Salidroside could alleviate inflammatory injury and steatosis via autophagy activation mediated by downregulation of the TRPM2/Ca2+/CaMKII pathway. Targeting the TRPM2 ion channel is a novel treatment strategy for oxidative stress-induced liver in NAFLD.

SUBMITTER: Feng Q

PROVIDER: S-EPMC6938192 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Salidroside-Mitigated Inflammatory Injury of Hepatocytes with Non-Alcoholic Fatty Liver Disease via Inhibition TRPM2 Ion Channel Activation.

Feng Qi Q Liu Chen C Gao Wei W Geng Xiao-Ling XL Dai Ning N

Diabetes, metabolic syndrome and obesity : targets and therapy 20191227

<h4>Purpose</h4>Oxidative stress plays an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). TRPM2 ion channel functions as a molecular sensor for oxidative stress. The aim of this study was to examine the protective effects of Salidroside, a powerful antioxidative plant, on TRPM2 in an established in vitro model of NAFLD.<h4>Methods</h4>NAFLD model was established by palmitic acid (PA) in hepatic L02 cell lines and was added to the media at a final concentration of ...[more]

PMID: 31920355

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Project description:Sirtuin (SIRT1) is a nicotinamide adenine dinucleotide-dependent protein deacetylase that regulates hepatic lipid metabolism by modifying histones and transcription factors. Ethanol exposure disrupts SIRT1 activity and contributes to alcoholic liver disease in rodents, but the exact pathogenic mechanism is not clear. We compared mice with liver-specific deletion of Sirt1 (Sirt1LKO) mice with their LOX littermates (controls).We induced alcoholic liver injury in male Sirt1LKO and control mice, placing them on Lieber-DeCarli ethanol-containing diets for 10 days and then administering a single dose of ethanol (5 g/kg body weight) via gavage. Liver and serum samples were collected. We also measured messenger RNA levels of SIRT1, SFRS10, and lipin-1? and lipin-1? in liver samples from patients with alcoholic hepatitis and individuals without alcoholic hepatitis (controls).On the ethanol-containing diet, livers of Sirt1LKO mice accumulated larger amounts of hepatic lipid and expressed higher levels of inflammatory cytokines than control mice; serum of Sirt1LKO mice had increased levels of alanine aminotransferase and aspartate aminotransferase. Hepatic deletion of SIRT1 exacerbated ethanol-mediated defects in lipid metabolism, mainly by altering the function of lipin-1, a transcriptional regulator of lipid metabolism. In cultured mouse AML-12 hepatocytes, transgenic expression of SIRT1 prevented fat accumulation in response to ethanol exposure, largely by reversing the aberrations in lipin-1 signaling induced by ethanol. Liver samples from patients with alcoholic hepatitis had reduced levels of SIRT1 and a higher ratio of Lpin1?/? messenger RNAs than controls.In mice, hepatic deletion of Sirt1 promotes steatosis, inflammation, and fibrosis in response to ethanol challenge. Ethanol-mediated impairment of hepatic SIRT1 signaling via lipin-1 contributes to development of alcoholic steatosis and inflammation. Reagents designed to increase SIRT1 regulation of lipin-1 can be developed to treat patients with alcoholic fatty liver disease.

Dataset Information

Salidroside-Mitigated Inflammatory Injury of Hepatocytes with Non-Alcoholic Fatty Liver Disease via Inhibition TRPM2 Ion Channel Activation.

Publications

Salidroside-Mitigated Inflammatory Injury of Hepatocytes with Non-Alcoholic Fatty Liver Disease via Inhibition TRPM2 Ion Channel Activation.

Similar Datasets

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