TUDCA was identified as a potential therapeutic drug for nonalcoholic steatohepatitis complicated with hypercholesterolemia targeting ADRA2C by integrated bioinformatics and experimental verification

Abstract Nonalcoholic steatohepatitis (NASH) is a type of liver disease in which fat accumulates in the liver with inflammation. Hypercholesterolemia is a common autosomal dominant inherited metabolic disease. Previous studies have suggested a potential association between NASH and hypercholesterolemia, but the pathophysiological mechanisms were unclear. Bioinformatics analysis identified four core comorbidity genes (ADRA2C, IL27RA, LDB3, SF3A2). Molecular docking showed that TUDCA had the lowest binding affinity with ADRA2C and formed a stable hydrogen bond network. In vitro experiments demonstrated that TUDCA reverses PA/OA-induced high expression of ADRA2C. The cell thermal shift assay confirmed that TUDCA can directly bind to ADRA2C and enhance its thermal stability. Mechanistically, overexpression of ADRA2C significantly weakened the activation effect of TUDCA on the cGMP-PKG pathway and the recovery effect of downstream VASP phosphorylation. In vivo experiments showed that TUDCA dose-dependently improved liver function indicators infiltration in the two mice models, and inhibited the expression of core genes in liver tissue and restored the level of p-VASP protein. This research reveals the co-pathogenesis of NASH and hypercholesterolemia. These common hub genes and candidate drug may provide new targets for further mechanistic research as well as new therapies for patients with NASH and hypercholesterolemia.