Neuschäfer-Rube Frank, Schraplau Anne, Schewe Bettina, Lieske Stefanie, Krützfeldt Julia-Mignon, Ringel Sebastian, Henkel Janin, Birkenfeld Andreas L, Püschel Gerhard P
University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany.
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.
Toxicology. 2015 Nov 4;337:1-9. doi: 10.1016/j.tox.2015.08.007. Epub 2015 Aug 21.
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.
非酒精性脂肪性肝病在工业化国家和发展中国家正成为一个日益严重的问题。肝脏脂质蓄积是脂肪酸摄取、脂肪酸从头合成、β-氧化以及富含甘油三酯的脂蛋白从肝细胞分泌之间失衡的结果。肝脏脂质代谢的一个核心调节因子是胞质柠檬酸，它既可以来自线粒体，也可以通过质膜柠檬酸钠转运体NaCT（哺乳动物INDY基因（SLC13A5）的产物）从血液中摄取。敲除mINDY可预防饮食诱导的脂肪变性，而在肝脂肪变性患者中mINDY表达增加。在人类和动物模型中，芳烃受体（AhR）的激活也会增强饮食诱导的肝脏脂肪变性。因此，研究人员检验了mINDY基因是否可能是AhR的一个靶点这一假设。根据这一假设，AhR激活剂苯并[a]芘以AhR依赖的方式诱导大鼠原代肝细胞培养物中mINDY的表达。这种诱导导致柠檬酸盐摄取增加以及柠檬酸盐掺入脂质，这可能因苯并[a]芘依赖的脂肪酸合成关键酶的诱导而进一步增强。在mINDY启动子中鉴定出一个潜在的AhR结合位点，该位点在人类启动子中似乎是保守的。消除或突变该位点在很大程度上消除了苯并[a]芘对mINDY启动子的激活。因此，这项研究确定mINDY是一个AhR靶基因。AhR依赖的mINDY基因诱导可能有助于肝脏脂肪变性的发展。
