Arylhydrocarbon Receptor-Dependent mIndy (Slc13a5) Induction as Possible Contributor to Benzo[a]pyrene-Induced Lipid Accumulation in Hepatocytes

Toxicology. 2015 Nov 4;337:1-9. doi: 10.1016/j.tox.2015.08.007. Epub 2015 Aug 21.

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.

Keywords: NAFLD; Non-alcoholic fatty liver disease; SLC13A5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aryl Hydrocarbon Receptor Nuclear Translocator / biosynthesis
  • Aryl Hydrocarbon Receptor Nuclear Translocator / genetics
  • Benzo(a)pyrene / toxicity*
  • Carcinogens / toxicity*
  • Chromatin Immunoprecipitation
  • Citrates / metabolism
  • HEK293 Cells
  • Hepatocytes / drug effects*
  • Humans
  • Lipid Metabolism / drug effects*
  • Male
  • Non-alcoholic Fatty Liver Disease / chemically induced
  • Non-alcoholic Fatty Liver Disease / pathology
  • Primary Cell Culture
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Rats
  • Rats, Wistar
  • Receptors, Aryl Hydrocarbon / physiology*
  • Symporters / biosynthesis
  • Symporters / genetics
  • Symporters / physiology*

Substances

  • ARNT protein, rat
  • Carcinogens
  • Citrates
  • RNA, Messenger
  • Receptors, Aryl Hydrocarbon
  • Slc13a5 protein, rat
  • Symporters
  • Aryl Hydrocarbon Receptor Nuclear Translocator
  • Benzo(a)pyrene