Arylhydrocarbon receptor-dependent mIndy (Slc13a5) induction as possible contributor to benzo[a]pyrene-induced lipid accumulation in hepatocytes. (4th November 2015)

• Record Type: Journal Article
• Authors: Neuschäfer-Rube, Frank; Schraplau, Anne; Schewe, Bettina; Lieske, Stefanie; Krützfeldt, Julia-Mignon; Ringel, Sebastian; Henkel, Janin; Birkenfeld, Andreas L.; Püschel, Gerhard P.
• Is Part Of: Toxicology. Volume 337(2015)
• Page Start: 1
• Page End: 9
• Publication Date: 2015-11-04
• Subjects: AhR arylhydrocarbon receptor -- BaP benzo[a]pyrene -- NAFLD non-alcoholic fatty liver disease -- TCDD 2, 3, 7, 8-tetrachlorodibenzodioxin -- SDS sodiumdodecyl-sulfate -- CAR constitutive androstane receptor -- PXR pregnane X receptor -- ARNT aryl hydrocarbon receptor nuclear translocator -- SREBP sterol-responsive element binding protein -- FAS fatty acid synthase -- ACC acetyl-CoA carboxylase -- CPT-1 carnitine-palmitoyltransferase 1; SLC13A5 -- Non-alcoholic fatty liver disease -- NAFLD; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2015.08.007
• Languages: English
• ISSNs: 0300-483X

Abstract

Graphical abstract: 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). m INDY ablation protects against diet-induced steatosis whereas m INDY 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 m INDY gene might be a target of the AhR. In accordance with such a hypothesis, the AhR activator benzo[a]pyrene induced the m INDY 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 m INDY promoter that appears to be conserved in the human promoter. Elimination or mutation of this site largely abolished the activation of the m INDY promoter by benzo[a]pyrene. This study thus identified the m INDY as an AhR target gene. AhR-dependent induction of the m INDY gene might contribute to the development of hepatic steatosis.