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.

转化生长因子-β/Smad3信号通路（TGF-beta/Smad3 signaling）在2型糖尿病（T2D）中发挥关键作用。然而，Smad3在2型糖尿病相关血脂异常与非酒精性脂肪性肝病（NAFLD）中的调控作用及分子机制仍不明确，且靶向Smad3对这类代谢异常是否具有治疗效果尚未得到探索。从机制层面来看，本研究揭示Smad3可通过靶向过氧化物酶体增殖物激活受体δ（PPAR Delta），在db/db小鼠中诱导血脂异常与非酒精性脂肪性肝病；而通过基因敲除或药物抑制Smad3可逆转该病理过程。综上，Smad3通过下调PPAR Delta在糖尿病性血脂异常与非酒精性脂肪性肝病中发挥致病作用，靶向Smad3或可成为治疗2型糖尿病相关代谢紊乱的全新治疗策略。