title: Insulin regulates retinol dehydrogenase expression and all-trans-retinoic acid biosynthesis through FoxO1.
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.
authors: From the Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, University of California, Berkeley, California 94720.
authors: Kristin M
authors: KM
authors: Obrochta
authors: From the Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, University of California, Berkeley, California 94720.
authors: Charles R
authors: CR
authors: Krois
authors: From the Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, University of California, Berkeley, California 94720.
authors: Benito
authors: B
authors: Campos
authors: From the Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, University of California, Berkeley, California 94720 jna@berkeley.edu.
authors: Joseph L
authors: JL
authors: Napoli
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D053898:Biosynthetic Pathways; D004435:Eating; D004734:Energy Metabolism; D005215:Fasting / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D014212:Tretinoin / Q000378:metabolism*
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D012333:RNA, Messenger; D014212:Tretinoin; D000429:Alcohol Oxidoreductases; C113992:trans-retinol dehydrogenase; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt PKB; Dehydrogenase; Energy Metabolism; FOXO; Gene Regulation; Gluconeogenesis; Insulin; Retinoic Acid; Vitamin A
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