Abstract:
Type 2 diabetes (T2D) is often accompanied with an induction of retinaldehyde dehydrogenase 1 (RALDH1 or ALDH1A1) expression and a consequent decrease in hepatic retinaldehyde (Rald) levels. However, the role of hepatic Rald deficiency in T2D progression remains unclear. In this study, we demonstrated that reversing T2D-mediated hepatic Rald deficiency by Rald or citral treatments, or liver-specific Raldh1 silencing substantially lowered fasting glycemia levels, inhibited hepatic glucogenesis, and downregulated phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6-phosphatase (G6PC) expression in diabetic db/db mice. Fasting glycemia and Pck1/G6pc mRNA expression levels were strongly negatively correlated with hepatic Rald levels, indicating the involvement of hepatic Rald depletion in T2D deterioration. A similar result that liver-specific Raldh1 silencing improved glucose metabolism was also observed in high-fat diet-fed mice. In primary human hepatocytes and oleic acid-treated HepG2 cells, Rald or Rald + RALDH1 silencing resulted in decreased glucose production and downregulated PCK1/G6PC mRNA and protein expression. Mechanistically, Rald downregulated direct repeat 1-mediated PCK1 and G6PC expression by antagonizing retinoid X receptor α, as confirmed by luciferase reporter assays and molecular docking. These results highlight the link between hepatic Rald deficiency, glucose dyshomeostasis, and the progression of T2D, whilst also suggesting RALDH1 as a potential therapeutic target for T2D.
摘要:
2型糖尿病(T2D)通常伴随着视黄醛脱氢酶1(RALDH1或ALDH1A1)表达的诱导以及随之而来的肝视黄醛(Rald)水平的降低。然而,肝Rald缺乏症在T2D进展中的作用尚不清楚.在这项研究中,我们证明了通过Rald或柠檬醛治疗逆转T2D介导的肝Rald缺乏症,或肝脏特异性Raldh1沉默显著降低空腹血糖水平,抑制肝葡萄糖生成,在糖尿病db/db小鼠中下调磷酸烯醇丙酮酸羧激酶1(PCK1)和葡萄糖-6-磷酸酶(G6PC)的表达。空腹血糖和Pck1/G6pcmRNA表达水平与肝脏Rald水平呈强烈负相关,表明肝脏Rald耗竭参与T2D恶化。在高脂肪饮食喂养的小鼠中也观察到肝脏特异性Raldh1沉默改善葡萄糖代谢的类似结果。在原代人肝细胞和油酸处理的HepG2细胞中,Rald或Rald+RALDH1沉默导致葡萄糖产生减少并下调PCK1/G6PCmRNA和蛋白表达。机械上,Rald通过拮抗类维生素AX受体α下调直接重复1介导的PCK1和G6PC表达,如荧光素酶报告基因测定和分子对接所证实。这些结果突出了肝Rald缺乏症之间的联系,葡萄糖代谢异常,以及T2D的发展,同时还建议RALDH1作为T2D的潜在治疗靶标。