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• W4380489119 endingPage "155630" @default.
• W4380489119 startingPage "155630" @default.
• W4380489119 abstract "Objective Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond the activation of hepatic stellate cells remains unexplored. We investigated the succinate/SUCNR1 axis in the context of NAFLD specifically in hepatocytes. Methods We studied the phenotype of wild-type and Sucnr1−/− mice fed a choline-deficient high-fat diet to induce non-alcoholic steatohepatitis (NASH), and explored the function of SUCNR1 in murine primary hepatocytes and human HepG2 cells treated with palmitic acid. Lastly, plasma succinate and hepatic SUCNR1 expression were analyzed in four independent cohorts of patients in different NAFLD stages. Results Sucnr1 was upregulated in murine liver and primary hepatocytes in response to diet-induced NASH. Sucnr1 deficiency provoked both beneficial (reduced fibrosis and endoplasmic reticulum stress) and detrimental (exacerbated steatosis and inflammation and reduced glycogen content) effects in the liver, and disrupted glucose homeostasis. Studies in vitro revealed that hepatocyte injury increased Sucnr1 expression, which when activated improved lipid and glycogen homeostasis in damaged hepatocytes. In humans, SUCNR1 expression was a good determinant of NAFLD progression to advanced stages. In a population at risk of NAFLD, circulating succinate was elevated in patients with a fatty liver index (FLI) ≥60. Indeed, succinate had good predictive value for steatosis diagnosed by FLI, and improved the prediction of moderate/severe steatosis through biopsy when added to an FLI algorithm. Conclusions We identify hepatocytes as target cells of extracellular succinate during NAFLD progression and uncover a hitherto unknown function for SUCNR1 as a regulator of hepatocyte glucose and lipid metabolism. Our clinical data highlight the potential of succinate and hepatic SUCNR1 expression as markers to diagnose fatty liver and NASH, respectively." @default.
• W4380489119 created "2023-06-14" @default.
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• W4380489119 date "2023-08-01" @default.
• W4380489119 modified "2023-10-08" @default.
• W4380489119 title "Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD" @default.
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• W4380489119 doi "https://doi.org/10.1016/j.metabol.2023.155630" @default.
• W4380489119 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37315889" @default.
• W4380489119 hasPublicationYear "2023" @default.
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