title: Arylhydrocarbon receptor-dependent mIndy (Slc13a5) induction as possible contributor to benzo[a]pyrene-induced lipid accumulation in hepatocytes.
abstract: Non-alcoholic fatty liver disease is a growing problem in industrialized and developing countries. Hepatic lipid accumulation is the result of an imbalance between fatty acid uptake, fatty acid de novo synthesis, β-oxidation and secretion of triglyceride-rich lipoproteins from the hepatocyte. A central regulator of hepatic lipid metabolism is cytosolic citrate that can either be derived from the mitochondrium or be taken up from the blood via the plasma membrane sodium citrate transporter NaCT, the product of the mammalian INDY gene (SLC13A5). mINDY ablation protects against diet-induced steatosis whereas mINDY expression is increased in patients with hepatic steatosis. Diet-induced hepatic steatosis is also enhanced by activation of the arylhyrocarbon receptor (AhR) both in humans and animal models. Therefore, the hypothesis was tested whether the mINDY gene might be a target of the AhR. In accordance with such a hypothesis, the AhR activator benzo[a]pyrene induced the mINDY expression in primary cultures of rat hepatocytes in an AhR-dependent manner. This induction resulted in an increased citrate uptake and citrate incorporation into lipids which probably was further enhanced by the benzo[a]pyrene-dependent induction of key enzymes of fatty acid synthesis. A potential AhR binding site was identified in the mINDY promoter that appears to be conserved in the human promoter. Elimination or mutation of this site largely abolished the activation of the mINDY promoter by benzo[a]pyrene. This study thus identified the mINDY as an AhR target gene. AhR-dependent induction of the mINDY gene might contribute to the development of hepatic steatosis.
authors: University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany.
authors: Frank
authors: F
authors: Neuschäfer-Rube
authors: University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany.
authors: Anne
authors: A
authors: Schraplau
authors: University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany.
authors: Bettina
authors: B
authors: Schewe
authors: University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany; Section of Metabolic Vascular Medicine and Paul Langerhans Institute Dresden (PLID), Medical Clinic III, University Clinic Dresden, TU Dresden, 01307, Germany.
authors: Stefanie
authors: S
authors: Lieske
authors: University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany.
authors: Julia-Mignon
authors: JM
authors: Krützfeldt
authors: University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany.
authors: Sebastian
authors: S
authors: Ringel
authors: University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany.
authors: Janin
authors: J
authors: Henkel
authors: Section of Metabolic Vascular Medicine and Paul Langerhans Institute Dresden (PLID), Medical Clinic III, University Clinic Dresden, TU Dresden, 01307, Germany; Division of Diabetes & Nutritional Sciences, Faculty of Life Sciences & Medicine, King's College London, London SE1 8WA, UK.
authors: Andreas L
authors: AL
authors: Birkenfeld
authors: University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany. Electronic address: gpuesche@uni-potsdam.de.
authors: Gerhard P
authors: GP
authors: Püschel
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000096:biosynthesis / Q000235:genetics; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D047369:Chromatin Immunoprecipitation; D002951:Citrates / Q000378:metabolism; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000473:pathology; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D027981:Symporters / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: C497398:ARNT protein, rat; D002273:Carcinogens; D002951:Citrates; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C469354:Slc13a5 protein, rat; D027981:Symporters; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001564:Benzo(a)pyrene
keywords: NAFLD; Non-alcoholic fatty liver disease; SLC13A5