Smad3 mediates diabetic dyslipidemia and fatty liver in db/db mice by targeting PPAR Delta

TGF-beta/Smad3 signaling plays a critical role in type 2 diabetes(T2D). However, the regulatory role and mechanisms of Smad3 in dyslipidemia and non-alcoholic fatty liver disease(NAFLD) in type 2 diabetes remain unclear and whether targeting Smad3 has a therapeutic effect on these metabolic abnormalities remains unexplored. Mechanistically, we uncovered that Smad3 targeted PPAR Delta to induce dyslipidemia and NAFLD in db/db mice, which was reversed by genetically deleting and pharmacologically inhibiting Smad3. In conclusion, Smad3 is pathogenic in diabetic dyslipidemia and NAFLD by downregulating PPAR Delta. Targeting Smad3 may be a novel therapy for these metabolic disorders in T2D.