Hepatic retinaldehyde deficiency is involved in diabetes deterioration by enhancing PCK1-and G6PC-mediated gluconeogenesis

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 liverspecific 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 acidtreated 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 a, 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.

Retinoic acid metabolic change in retina and choroid of the guinea pig with lens-induced myopia

AIM: To investigate the role of retinoic add (RA) and retinaldehyde dehydrogenase-2 (RALDH(2)) of retina and choroid in the guinea pig lens-induced myopic eyes. METHODS: Totally 45 guinea pigs, at age of three weeks, were randomly assigned into three groups: the normal control, the lens-induced group and the recovering group. Out of focus was induced by the -6.00D concave lens on the left eye, and lasted for 15 days. All animals underwent biometric measurement (corneal radius of curvature, refraction and axial length). Subsequently, RA content in the retina and RPE/choriod complex was detected by reversed-phase high-performance liquid chromatography. RALDH(2) protein in the retina and RPE/choriod complex was evaluated by the immunohistochemical staining and Western blotting. RESULTS: After wearing -6.00D lens for 15 days, axial length of the lens-induced eye extends and myopia was formed, with RA contents increasing in both the neural retina and RPE/choroid complex. Comparing with the lens-induced group, myopic degree significantly relieved, and its RA contents in both the neural retina and RPE/choroid complex decreased in the recovering group. In the normal control, RALDH(2) protein was expressed positively in the retinal nerve fiber layer (RNFL), inner plexiform layer (IPL) and lateral border of outer nuclear layer (ONL). Retinal RALDH(2) protein increased in the lens-induced group, and was also positive in the outer plexiform layer (OPL). In the recovering group, retinal RALDH(2) protein attenuated the expression in the OPL turns to negative. RALDH(2) protein was not expressed in the choroid of any group. CONCLUSION: RA of retina and chorid participates in the regulation of the lens-induced myopia in guinea pigs, which may be related with retinal RALDH(2) protein.

Metabolic balancing acts of vitamin A in type-2 diabetes and obesity

Using mice that lack retinaldehyde dehydrogenase 1 gene(Raldh1-/-mice),Kierfer et al demonstrated that retinoids(metabolites of Vitamin A) play an important role in the regulation of cellular metabolisms and energetics.The Aldh1a1-/-mice were leaner and less prone to accumulate subcutaneous and visceral fat,and to acquire insulin resistance on high fat diet.Their lower fasting glucose levels concomitant with reduced hepatic expression of glucose 6-phosphatase and phosphoenol pyruvate carboxy kinase genes indicated that Aldh1a1-/-mice were defective in gluconeogenesis.These mice also had lower plasma levels of triglycerides,very low-density lipoprotein and lowdensity lipoprotein-triacylglycerol,while their skeletal muscles elicited higher expression of carnitine palmatoyl transferase,medium chain acyl-A dehydrogenase,peroxisome proliferation activated receptor(PPARα and PPARδ.Thus,the improved lipid and lipoprotein profiles of Raldh1a1-/-mice resulted from a combination of reduced lipogenesis and enhanced fatty acid oxidation by retinoids.The mechanistic details of how retinoids integrate fasting glucose,hepatic gluconeogenesis and adaptive thermogenesis independent of body mass deserve further study.