Insulin Regulates Retinol Dehydrogenase Expression and All-trans-retinoic Acid Biosynthesis through FoxO1

Kristin M. Obrochta; Charles R. Krois; Benito Campos; Joseph L. Napoli

doi:10.1074/jbc.M114.609313

Insulin Regulates Retinol Dehydrogenase Expression and All-trans-retinoic Acid Biosynthesis through FoxO1*

From the Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, University of California, Berkeley, California 94720

↵2 To whom correspondence should be addressed. Tel.: 510-642-5202; Fax: 510-642-0535; E-mail: jna{at}berkeley.edu.

↵1 Present address: Dept. of Neurosurgery, University of Heidelberg, Heidelberg, Germany.

Background: Retinoic acid regulates energy balance and induces phosphoenolpyruvate carboxykinase gene expression.

Results: Refeeding, glucose, and insulin decrease retinoic acid in vivo. Insulin suppresses retinol dehydrogenase gene expression through suppressing FoxO1.

Conclusion: Insulin inhibits retinoic acid biosynthesis through inhibition of FoxO1-induced Rdh10 gene expression.

Significance: Insulin and retinoic acid exert counter balancing effects in regulating energy status.

Abstract

All-trans-retinoic acid (atRA), an autacoid 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 h after re-feeding, Rdh1 expression decreased 80–90% in liver and brown adipose tissue and Rdh10 expression was decreased 45–63% in liver, pancreas, and kidney, all relative to mice fasted 16 h. atRA in the liver was decreased 44% 3 h 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 h, by increasing transcription and stabilizing mRNA. Insulin decreased Rdh10 and Rdh16 mRNA in HepG2 cells incubated in serum-free medium by inhibiting transcription and destabilizing mRNA. Insulin action required PI3K and Akt, which suppress 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.