title: All-Trans-Retinoic Acid Enhances Mitochondrial Function in Models of Human Liver.
abstract: All-trans-retinoic acid (atRA) is the active metabolite of vitamin A. The liver is the main storage organ of vitamin A, but activation of the retinoic acid receptors (RARs) in mouse liver and in human liver cell lines has also been shown. AlthoughatRA treatment improves mitochondrial function in skeletal muscle in rodents, its role in modulating mitochondrial function in the liver is controversial, and little data are available regarding the human liver. The aim of this study was to determine whetheratRA regulates hepatic mitochondrial activity.atRA treatment increased the mRNA and protein expression of multiple components of mitochondrialβ-oxidation, tricarboxylic acid (TCA) cycle, and respiratory chain. Additionally,atRA increased mitochondrial biogenesis in human hepatocytes and in HepG2 cells with and without lipid loading based on peroxisome proliferator activated receptor gamma coactivator 1αand 1βand nuclear respiratory factor 1 mRNA and mitochondrial DNA quantification.atRA also increasedβ-oxidation and ATP production in HepG2 cells and in human hepatocytes. Knockdown studies of RARα, RARβ, and PPARδrevealed that the enhancement of mitochondrial biogenesis andβ-oxidation byatRA requires peroxisome proliferator activated receptor delta. In vivo in mice,atRA treatment increased mitochondrial biogenesis markers after an overnight fast. Inhibition ofatRA metabolism by talarozole, a cytochrome P450 (CYP) 26 specific inhibitor, increased the effects ofatRA on mitochondrial biogenesis markers in HepG2 cells and in vivo in mice. These studies show thatatRA regulates mitochondrial function and lipid metabolism and that increasingatRA concentrations in human liver via CYP26 inhibition may increase mitochondrial biogenesis and fatty acidβ-oxidation and provide therapeutic benefit in diseases associated with mitochondrial dysfunction.
authors.affiliation: Departments of Pharmaceutics (S.T., S.L.M.A., N.I.), Medicinal Chemistry (J.D.C., D.R.G.), and Diabetes Obesity Center for Excellence and the Department of Medicine, Division of Metabolism, Endocrinology and Nutrition (C.Y.H.), University of Washington, Seattle, Washington; School of Molecular Biosciences and The Center for Reproductive Biology, Washington State University, Pullman, Washington (C.A.H., J.O., T.K.); and School of Pharmacy, University of Maryland, Baltimore, Maryland (D.R.G.).
authors.forename: Sasmita
authors.initials: S
authors.lastname: Tripathy
authors.affiliation: Departments of Pharmaceutics (S.T., S.L.M.A., N.I.), Medicinal Chemistry (J.D.C., D.R.G.), and Diabetes Obesity Center for Excellence and the Department of Medicine, Division of Metabolism, Endocrinology and Nutrition (C.Y.H.), University of Washington, Seattle, Washington; School of Molecular Biosciences and The Center for Reproductive Biology, Washington State University, Pullman, Washington (C.A.H., J.O., T.K.); and School of Pharmacy, University of Maryland, Baltimore, Maryland (D.R.G.).
authors.forename: John D
authors.initials: JD
authors.lastname: Chapman
authors.affiliation: Departments of Pharmaceutics (S.T., S.L.M.A., N.I.), Medicinal Chemistry (J.D.C., D.R.G.), and Diabetes Obesity Center for Excellence and the Department of Medicine, Division of Metabolism, Endocrinology and Nutrition (C.Y.H.), University of Washington, Seattle, Washington; School of Molecular Biosciences and The Center for Reproductive Biology, Washington State University, Pullman, Washington (C.A.H., J.O., T.K.); and School of Pharmacy, University of Maryland, Baltimore, Maryland (D.R.G.).
authors.forename: Chang Y
authors.initials: CY
authors.lastname: Han
authors.affiliation: Departments of Pharmaceutics (S.T., S.L.M.A., N.I.), Medicinal Chemistry (J.D.C., D.R.G.), and Diabetes Obesity Center for Excellence and the Department of Medicine, Division of Metabolism, Endocrinology and Nutrition (C.Y.H.), University of Washington, Seattle, Washington; School of Molecular Biosciences and The Center for Reproductive Biology, Washington State University, Pullman, Washington (C.A.H., J.O., T.K.); and School of Pharmacy, University of Maryland, Baltimore, Maryland (D.R.G.).
authors.forename: Cathryn A
authors.initials: CA
authors.lastname: Hogarth
authors.affiliation: Departments of Pharmaceutics (S.T., S.L.M.A., N.I.), Medicinal Chemistry (J.D.C., D.R.G.), and Diabetes Obesity Center for Excellence and the Department of Medicine, Division of Metabolism, Endocrinology and Nutrition (C.Y.H.), University of Washington, Seattle, Washington; School of Molecular Biosciences and The Center for Reproductive Biology, Washington State University, Pullman, Washington (C.A.H., J.O., T.K.); and School of Pharmacy, University of Maryland, Baltimore, Maryland (D.R.G.).
authors.forename: Samuel L M
authors.initials: SL
authors.lastname: Arnold
authors.affiliation: Departments of Pharmaceutics (S.T., S.L.M.A., N.I.), Medicinal Chemistry (J.D.C., D.R.G.), and Diabetes Obesity Center for Excellence and the Department of Medicine, Division of Metabolism, Endocrinology and Nutrition (C.Y.H.), University of Washington, Seattle, Washington; School of Molecular Biosciences and The Center for Reproductive Biology, Washington State University, Pullman, Washington (C.A.H., J.O., T.K.); and School of Pharmacy, University of Maryland, Baltimore, Maryland (D.R.G.).
authors.forename: Jennifer
authors.initials: J
authors.lastname: Onken
authors.affiliation: Departments of Pharmaceutics (S.T., S.L.M.A., N.I.), Medicinal Chemistry (J.D.C., D.R.G.), and Diabetes Obesity Center for Excellence and the Department of Medicine, Division of Metabolism, Endocrinology and Nutrition (C.Y.H.), University of Washington, Seattle, Washington; School of Molecular Biosciences and The Center for Reproductive Biology, Washington State University, Pullman, Washington (C.A.H., J.O., T.K.); and School of Pharmacy, University of Maryland, Baltimore, Maryland (D.R.G.).
authors.forename: Travis
authors.initials: T
authors.lastname: Kent
authors.affiliation: Departments of Pharmaceutics (S.T., S.L.M.A., N.I.), Medicinal Chemistry (J.D.C., D.R.G.), and Diabetes Obesity Center for Excellence and the Department of Medicine, Division of Metabolism, Endocrinology and Nutrition (C.Y.H.), University of Washington, Seattle, Washington; School of Molecular Biosciences and The Center for Reproductive Biology, Washington State University, Pullman, Washington (C.A.H., J.O., T.K.); and School of Pharmacy, University of Maryland, Baltimore, Maryland (D.R.G.).
authors.forename: David R
authors.initials: DR
authors.lastname: Goodlett
authors.affiliation: Departments of Pharmaceutics (S.T., S.L.M.A., N.I.), Medicinal Chemistry (J.D.C., D.R.G.), and Diabetes Obesity Center for Excellence and the Department of Medicine, Division of Metabolism, Endocrinology and Nutrition (C.Y.H.), University of Washington, Seattle, Washington; School of Molecular Biosciences and The Center for Reproductive Biology, Washington State University, Pullman, Washington (C.A.H., J.O., T.K.); and School of Pharmacy, University of Maryland, Baltimore, Maryland (D.R.G.) ni2@uw.edu.
authors.forename: Nina
authors.initials: N
authors.lastname: Isoherranen
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D001678:Organelle Biogenesis; D047494:PPAR delta / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D052160:Benzothiazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D047494:PPAR delta; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014230:Triazoles; C082925:retinoic acid receptor beta; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; C406527:R 115866