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Thioredoxin-interacting protein mediates hepatic lipogenesis and inflammation via PRMT1 and PGC-1α regulation in vitro and in vivo

      Background & Aims

      Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and type 2 diabetes. Thioredoxin-interacting protein (TXNIP) regulates the cellular redox state and metabolism and has been linked to many diseases, including diabetes. Therefore, we examined the role of TXNIP in hepatic steatosis in vitro and in vivo.

      Methods

      Lipogenic and inflammatory proteins produced by hepatocytes treated with palmitic acid (PA) or transfected with TXNIP or Txnip siRNA were measured by Western blotting. Lipid accumulation was assessed using Oil Red O staining. Protein interactions were assessed by immunoprecipitation and proximity ligation assay. Hepatic protein levels were measured by Western blotting from wild type or Txnip−/− mice fed a high-fat diet (HFD) or chow diet. Livers from NAFLD patients were compared with normal liver by immunohistochemistry.

      Results

      PA increased TXNIP, and inflammatory and lipogenic proteins in both AML12 and H4IIE cells. It also increased the peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α), which mediated the expression of lipogenic markers and lipid accumulation. In addition, PA increased protein arginine methyltransferase-1 (PRMT1) and PRMT1 siRNA abolished the increase in lipogenic markers with PGC-1α. Furthermore, TXNIP interacted with PRMT1 in PA-treated hepatocytes. In vivo, levels of lipogenic proteins, inflammatory molecules, PGC-1α, and PRMT1 were increased in the livers of HFD mice compared with those fed a chow diet, and were ameliorated in HFD Txnip−/− mice. Moreover, TXNIP, PRMT1, and PGC-1α were elevated in the livers of human NAFLD patients.

      Conclusions

      TXNIP mediates hepatic lipogenesis via PRMT1 and PGC-1α regulation and inflammation in vitro and in vivo, implying that targeting TXNIP and PRMT1 is a potential therapeutic approach for treatment of NAFLD.

      Abbreviations:

      NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis), TXNIP (thioredoxin-interacting protein), PA (palmitic acid), SA (stearic acid), ACC (acetyl-CoA carboxylase), FAS (fatty acid synthase), SCD1 (stearoyl-CoA desaturase-1), LPL (lipoprotein lipase), NFκB (nuclear factor κB), COX-2 (cyclooxygenase-2), IL-6 (interleukin-6), ACOX1 (Acyl-CoA oxidase-1), CPT1 (carnitine palmitoyltransferase-I), HADHA (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase alpha subunit), PGC-1α (peroxisome proliferator-activated receptor gamma co-activator-1α), PRMT (protein arginine methyltransferase), ADMA (asymmetric dimethylarginine), Adox (adenosine-2′,3′-dialdehyde), L-FABP (liver type-fatty acid binding protein)

      Keywords

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