Function and Regulation of SLC13A5 in the Liver

SLC13A5在肝脏中的功能和调节

• 批准号: 10082455
• 负责人: Hongbing Wang
• 金额: $ 29.74万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10082455
• 关键词: 3-Dimensional; ATP Citrate (pro-S)-Lyase; Acetyl Coenzyme A; Affect; Affinity; Anabolism; Attenuated; Binding; Biological Process; Blood Circulation; Cell Cycle Progression; Cell Line; Cell Proliferation; Cell membrane; Cells; Citrates; Clinical; Coupled; Cytoplasm; Data; Development; Drug usage; Energy Metabolism; Equilibrium; FRAP1 gene; Family; Fatty Acids; Fatty Liver; Gene Expression; Gene Silencing; Genes; Genetic Transcription; Hepatic; Hepatocyte; High Fat Diet; Histone Acetylation; Homeostasis; Human; Introns; Knowledge; Lead; Lipids; Liver; Longevity; Macaca mulatta; Malignant Epithelial Cell; Malignant neoplasm of liver; Mediating; Metabolic; Metabolic Diseases; Metformin; Mitochondria; Molecular; Mus; Mutation; Nutrient; Obesity; Orthologous Gene; Outcome; Outcome Study; Oxaloacetates; Patients; Pharmaceutical Preparations; Pharmacology; Play; Primary carcinoma of the liver cells; Process; Production; Rattus; Receptor Activation; Regulation; Repression; Research; Response Elements; Risk Factors; Role; Signal Transduction; Sodium; Steroids; Stimulus; Testing; Transcriptional Regulation; Up-Regulation; Xenobiotics; base; carbohydrate metabolism; citrate carrier; constitutive androstane receptor; hepatoma cell; improved; in vivo; insulin secretion; knock-down; liver cell proliferation; mTOR Signaling Pathway; member; non-alcoholic fatty liver disease; novel; novel strategies; obese patients; pregnane X receptor; sensor; solute; transcription factor; tumor progression; uptake

Project Summary Citrate is a key energy sensor that plays a central role in carbohydrate metabolism, energy production, and histone acetylation. The intracellular level of citrate is tightly controlled through a balance of biosynthesis and transport. In the liver, the solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter, is essential for the import of citrate from the circulation to hepatocytes, a process that can be perturbed by both xenobiotic and endobiotic stimuli. Recent studies have shown that expression of SLC13A5 was increased in obese, non-alcoholic fatty liver disease (NAFLD) patients, high-fat diet (HFD)-treated rhesus monkeys, and in xenobiotic-treated human and rat hepatocytes, suggesting upregulation of SLC13A5 can be a risk factor for metabolic disorders. In contrast, deletion of SLC13A5 protects mice from HFD-induced hepatic steatosis and mutations of the SLC13A5 ortholog in D. melanogaster promote longevity. However, despite the emerging importance of SLC13A5 in energy homeostasis, the mechanism(s) by which the SLC13A5 gene is transcriptionally regulated and whether clinically used drugs disturb the expression of this transporter are not well characterized. Moreover, whether SLC13A5 affects hepatic functions beyond lipid homeostasis is largely unknown. The overall objective of this proposal is to understand the molecular mechanisms governing hepatic SLC13A5 gene expression and to delineate the role of SLC13A5 in human liver cell proliferation. To this end, we have shown that 1) prototypical activators of the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) robustly induce expression of human SLC13A5; 2) knockdown of SLC13A5 attenuates the proliferation of hepatocellular carcinoma cells; and 3) expression of SLC13A5 is inversely correlated with the activation of AMPK signaling. Building on these preliminary results, we hypothesize that CAR and PXR are key regulators of the inductive expression of SLC13A5 in the liver, and SLC13A5 functions as a nutrient regulator altering the proliferation of hepatoma cells by modulating AMPK/mTOR signaling pathways. This central hypothesis will be tested in the following specific aims: Aim 1. Define the role of CAR and PXR in xenobiotic- induced expression of SLC13A5; Aim 2. Elucidate the mechanism(s) underlying CAR- and PXR-mediated induction of SLC13A5; Aim 3. Determine the effects of SLC13A5 on hepatoma cell proliferation. The outcomes are expected to provide fundamental novel knowledge on the transcriptional regulation of SLC13A5 in the liver, and to delineate a crucial role of SLC13A5 in bridging energy metabolism with liver cancer progression.

项目摘要 柠檬酸盐是一种关键能量传感器，在碳水化合物代谢，能源生产和 组蛋白乙酰化。柠檬酸盐的细胞内水平通过生物合成和 运输。在肝脏中，溶质载体家族13成员5（SLC13A5），钠耦合柠檬酸盐转运蛋白， 对于从循环到肝细胞的进口柠檬酸盐至关重要，这两个过程都可能受到两者的干扰 异种生物和内生物刺激。最近的研究表明，SLC13A5的表达增加了 肥胖，非酒精性脂肪肝疾病（NAFLD）患者，高脂饮食（HFD）处理的恒河猴和IN 用异源生物处理的人和大鼠肝细胞，表明SLC13A5的上调可能是危险因素 代谢障碍。相反，SLC13A5的缺失保护小鼠免受HFD诱导的肝脂肪变性和 D. melanogaster中SLC13A5直系同源物的突变促进寿命。但是，尽管出现了 SLC13A5在能量稳态中的重要性，SLC13A5基因的机制 转录调节以及临床使用的药物是否干扰该转运蛋白的表达不是 特征很好。此外，SLC13A5是否影响脂质稳态以外的肝功能很大 未知。该提议的总体目的是了解有关肝的分子机制 SLC13A5基因表达并描述SLC13A5在人肝细胞增殖中的作用。为此， 我们已经表明，1）构成雄激素受体（CAR）和妊娠的原型激活剂 X受体（PXR）鲁棒诱导人Slc13a5的表达； 2）SLC13A5的敲低减弱 肝细胞癌细胞的增殖； 3）SLC13A5的表达与 AMPK信号的激活。在这些初步结果的基础上，我们假设汽车和PXR是关键 SLC13A5在肝脏中的诱导表达的调节剂，SLC13A5充当营养调节剂 通过调节AMPK/MTOR信号通路来改变肝癌细胞的增殖。这个中央 假设将在以下特定目的中进行检验：目标1。定义CAR和PXR在异种生物生物中的作用 诱导SLC13A5的表达； AIM 2。阐明了CAR和PXR介导的基础机制 SLC13A5的诱导;目标3。确定SLC13A5对肝癌细胞增殖的影响。结果 预计将提供有关SLC13A5在肝脏中的转录调节的基本新知识， 并描述了SLC13A5在与肝癌进展的桥接能量代谢中的关键作用。