title: Retinaldehyde dehydrogenase 1 coordinates hepatic gluconeogenesis and lipid metabolism.
abstract: Recent data link vitamin A and its retinoid metabolites to the regulation of adipogenesis, insulin sensitivity, and glucose homeostasis. Retinoid metabolism is tightly controlled by an enzymatic network in which retinaldehyde dehydrogenases (Aldh1-3) are the rate-limiting enzymes that convert retinaldehyde to retinoic acid. Aldh1a1-deficient mice are protected from diet-induced obesity and hence diabetes. Here we investigated whether Aldh1a1 and the retinoid axis regulate hepatic glucose and lipid metabolism independent of adiposity. The impact of Aldh1a1 and the retinoid pathway on glucose homeostasis and lipid metabolism was analyzed in hepatocytes in vitro and in chow-fed, weight-matched Aldh1a1-deficient vs. wild-type (WT) mice in vivo. Aldh1a1-deficient mice displayed significantly decreased fasting glucose concentrations compared with WT controls as a result of attenuated hepatic glucose production. Expression of key gluconeogenic enzymes as well as the activity of Forkhead box O1 was decreased in Aldh1a1-deficient vs. WT livers. In vitro, retinoid or cAMP agonist stimulation markedly induced gluconeogenesis in WT but not Aldh1a1-deficient primary hepatocytes. Aldh1a1 deficiency increased AMP-activated protein kinase α activity, decreased expression of lipogenic targets of AMP-activated protein kinase α and significantly attenuated hepatic triacylglycerol synthesis. In metabolic cage studies, lean Aldh1a1-deficient mice manifested enhanced oxygen consumption and reduced respiratory quotient vs. WT controls, consistent with increased expression of fatty acid oxidation markers in skeletal muscle. Taken together, this work establishes a role for retinoid metabolism in glucose homeostasis in vivo and for Aldh1a1 as a novel determinant of gluconeogenesis and lipid metabolism independent of adiposity.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
authors.forename: Florian W
authors.initials: FW
authors.lastname: Kiefer
authors.forename: Gabriela
authors.initials: G
authors.lastname: Orasanu
authors.forename: Shriram
authors.initials: S
authors.lastname: Nallamshetty
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Brown
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Philip
authors.initials: P
authors.lastname: Luger
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Qi
authors.forename: Charles F
authors.initials: CF
authors.lastname: Burant
authors.forename: Gregg
authors.initials: G
authors.lastname: Duester
authors.forename: Jorge
authors.initials: J
authors.lastname: Plutzky
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D002151:Calorimetry / Q000379:methods; D003433:Crosses, Genetic; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005943:Gluconeogenesis / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology; D006706:Homeostasis; D007527:Isoenzymes / Q000235:genetics* / Q000502:physiology*; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry*; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010101:Oxygen Consumption; D020033:Protein Isoforms; D050697:Retinal Dehydrogenase / Q000235:genetics* / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007527:Isoenzymes; D008055:Lipids; D020033:Protein Isoforms; D014280:Triglycerides; D000080924:Aldehyde Dehydrogenase 1 Family; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D005947:Glucose