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TTC39B in Metabolism

TTC39B 在新陈代谢中的作用

基本信息

批准号：
10064114
负责人：
ALAN richard TALL
金额：
$ 47.35万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-11-04 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064114
关键词：
ATAC-seq ATP binding cassette transporter 1 Algorithms Antiatherogenic Antisense Oligonucleotides Atherosclerosis Binding CDK4 gene Cardiovascular Diseases Cell Cycle Cell Line Cells Cholesterol Cholesterol Homeostasis Chromatin Cyclin-Dependent Kinase 5 Cyclin-Dependent Kinase Inhibitor Diet Disease Dyslipidemias E2F transcription factors Enterocytes Excision Fatty Liver Fatty acid glycerol esters Gene Expression Genes Genetic Polymorphism Genetic Transcription Goals Hepatic Hepatocyte High Density Lipoproteins High Fat Diet Human Human Genome Insulin Resistance Intestines Knock-out Link Lipids Lipoproteins Liver Liver diseases Low-Density Lipoproteins Metabolic Metabolism Modeling Molecular Mus Nuclear Obesity Pathway interactions Phosphoproteins Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Process Production Proliferating Protein Dephosphorylation Proteins Proteomics Regulation Retinoblastoma Protein Risk Factors Role Scaffolding Protein Sucrose Tertiary Protein Structure Therapeutic Transfection Tumor Suppressor Proteins Ubiquitination Very low density lipoprotein absorption anaphase-promoting complex atherogenesis cdc Genes genome wide association study hepatoma cell knock-down lipid biosynthesis non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel programs protein protein interaction response risk sharing sex transcriptome sequencing western diet

项目摘要

Non-alcoholic fatty liver disease (NAFLD) has emerged as the forerunner of more serious forms of liver disease such as non-alcoholic steatohepatitis (NASH) and also shows a strong association with atherosclerotic cardiovascular disease (CVD). As well as sharing risk factors such as obesity and insulin resistance, the association of NAFLD with CVD is likely driven by atherogenic dyslipidemia (increased VLDL, small dense LDL and reduced HDL) which in part reflects increased hepatic de novo lipogenesis. We have recently discovered a novel scaffolding protein called TTC39B (T39) that links high fat diet-induced metabolic responses to transcriptional programs regulating lipogenesis and cholesterol metabolism. Our studies suggest that inhibiting hepatic T39 might be a new strategy for treating NAFLD and CVD. Human genome wide association studies first showed that polymorphisms in the gene encoding T39 are associated with reduced T39 expression and increased HDL. We showed that T39 promotes the ubiquitination and turnover of LXR and regulates levels of nuclear, active SREBP1 (nSREBP1) and hepatic lipogenic gene expression. Chow-fed T39-/- mice showed increased HDL and increased Abca1 expression in enterocytes, reflecting increased LXR levels. Western Diet (WD)- fed T39-/-Ldlr-/- mice had decreased lipogenic gene expression, protection from NAFLD and reduced atherosclerosis. Thus, deficiency of T39 activates a beneficial profile of gene expression that promotes cholesterol removal and inhibits lipogenesis. Our recent studies have shown that T39 interacts with the Retinoblastoma protein (RB) promoting its proteasomal degradation. This may be linked to the role of T39 in regulating the levels of nSREBP1 and LXR in proliferating cells and in hyperinsulinemic hepatocytes. The goal of this proposal is to elucidate the role of T39 in the regulation of hepatic lipogenesis, lipoproteins and atherosclerosis. We will evaluate a novel hypothesis that the interaction of T39 with RB links lipogenic genes and LXR to cell cycle genes in hepatocytes and enterocytes. This may pave the way for therapeutic inhibition of T39 potentially benefiting NAFLD and atherosclerosis.

非酒精性脂肪性肝病（NAFLD）已成为非酒精性脂肪性肝炎（NASH）等更严重形式肝病的先驱，并且与动脉粥样硬化性心血管疾病（CVD）密切相关。除了肥胖和胰岛素抵抗等共同的危险因素外，NAFLD与CVD的关联可能是由动脉粥样硬化性血脂异常（VLDL升高、小密度LDL升高和HDL降低）驱动的，这在一定程度上反映了肝脏新生脂肪生成增加。我们最近发现了一种名为TTC39B （T39）的新型支架蛋白，它将高脂肪饮食诱导的代谢反应与调节脂肪生成和胆固醇代谢的转录程序联系起来。我们的研究表明，抑制肝脏T39可能是治疗NAFLD和CVD的新策略。人类基因组广泛关联研究首次表明，编码T39基因的多态性与T39表达减少和HDL升高有关。我们发现T39促进了LXR的泛素化和周转，并调节了核、活性SREBP1 （nSREBP1）和肝脏脂肪生成基因的表达水平。鼠饲T39-/-小鼠肠细胞中HDL和Abca1表达升高，反映LXR水平升高。西方饮食（WD）喂养的T39-/- ldlr -/-小鼠脂质基因表达降低，对NAFLD有保护作用，并减少动脉粥样硬化。因此，缺乏T39激活了促进胆固醇去除和抑制脂肪生成的有益基因表达谱。我们最近的研究表明，T39与视网膜母细胞瘤蛋白（RB）相互作用，促进其蛋白酶体降解。这可能与T39在增殖细胞和高胰岛素血症肝细胞中调节nSREBP1和LXR水平的作用有关。本研究的目的是阐明T39在肝脏脂肪生成、脂蛋白和动脉粥样硬化中的调节作用。我们将评估一种新的假设，即T39与RB的相互作用将脂肪生成基因和LXR与肝细胞和肠细胞中的细胞周期基因联系起来。这可能为治疗性抑制T39可能有益于NAFLD和动脉粥样硬化铺平道路。