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.

非酒精性脂肪肝病 (NAFLD) 已成为非酒精性脂肪性肝炎 (NASH) 等更严重肝病的先兆，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危险因素外，NAFLD 与 CVD 的关联可能是由致动脉粥样硬化性血脂异常（VLDL 增加、小密度 LDL 增加和 HDL 减少）驱动的，这在一定程度上反映了肝脏从头脂肪生成增加。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。人类全基因组关联研究首先表明，T39 编码基因的多态性与 T39 表达减少和 HDL 增加相关。我们发现 T39 促进 LXR 的泛素化和周转，并调节细胞核、活性 SREBP1 (nSREBP1) 和肝脂肪生成基因表达的水平。饲料喂养的 T39-/- 小鼠在肠细胞中表现出 HDL 增加和 Abca1 表达增加，反映了 LXR 水平增加。西方饮食 (WD) 喂养的 T39-/-Ldlr-/- 小鼠脂肪生成基因表达减少，免受 NAFLD 影响并减少动脉粥样硬化。因此，T39 的缺乏会激活有益的基因表达，促进胆固醇去除并抑制脂肪生成。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 在调节增殖细胞和高胰岛素肝细胞中 nSREBP1 和 LXR 水平中的作用有关。该提案的目的是阐明 T39 在调节肝脂肪生成、脂蛋白和动脉粥样硬化中的作用。我们将评估一个新的假设，即 T39 与 RB 的相互作用将脂肪生成基因和 LXR 与肝细胞和肠上皮细胞中的细胞周期基因联系起来。这可能为 T39 的治疗性抑制铺平道路，可能有益于 NAFLD 和动脉粥样硬化。