Insulin Regulates Retinol Dehydrogenase Expression and all-trans-Retinoic Acid Biosynthesis through FoxO1 [Molecular Bases of Disease]

January 27th, 2015 by Obrochta, K. M., Krois, C. R., Campos, B., Napoli, J. L.

All-trans-retinoic acid (atRA), an autocoid derived from retinol (vitamin A), regulates energy balance and reduces adiposity. We show that energy status regulates atRA biosynthesis at the rate-limiting step, catalyzed by retinol dehydrogenases (Rdh). Six hr after re-feeding, Rdh1 expression decreased 80-90% in liver and brown adipose tissue and Rdh10 expression decreased 45-63% in liver, pancreas and kidney, all relative to mice fasted 16 hr. atRA in liver decreased 44% 3 hr after reduced Rdh expression. Oral gavage with glucose or injection with insulin decreased Rdh1 and Rdh10 mRNA 50% or greater in mouse liver. Removing serum from the medium of the human hepatoma cell line HepG2 increased Rdh10 and Rdh16 (human Rdh1 ortholog) mRNA expression 2-3 fold by 4 hr, by increasing transcription and stabilizing mRNA. Insulin decreased Rdh10 and Rdh16 mRNA in HepG2 cells incubated in serum-free medium, through inhibiting transcription and destabilizing mRNA. Insulin action required PI3K and Akt, which suppressed FoxO1. Serum removal increased atRA biosynthesis 4-fold from retinol in HepG2 cells, whereas dominant negative FoxO1 prevented the increase. Thus, energy status via insulin and FoxO1 regulate Rdh expression and atRA biosynthesis. These results reveal mechanisms for regulating atRA biosynthesis and the opposing effects of atRA and insulin on gluconeogenesis, and also suggest an interaction between atRA and insulin signaling-related diseases, such as type II diabetes and cancer.