TTC39B in Metabolism

非酒精性脂肪性肝病（NAFLD）已成为更严重形式的肝病（如非酒精性脂肪性肝炎（NASH））的先驱，并且还显示出与动脉粥样硬化性心血管疾病（CVD）的强烈关联。除了共同的风险因素如肥胖和胰岛素抵抗外，NAFLD与CVD的相关性可能是由致动脉粥样硬化性血脂异常（VLDL增加，小密度LDL和HDL降低）驱动的，这部分反映了肝脏新生脂肪生成增加。我们最近发现了一种新的支架蛋白TTC 39 B（T39），它将高脂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次表明，编码T39的基因中的多态性与T39表达降低和HDL增加相关。我们发现T39促进LXR的泛素化和周转，并调节核活性SREBP 1（nSREBP 1）和肝脏脂肪生成基因表达的水平。喂食Chow的T39-/-小鼠显示出HDL增加和肠上皮细胞中Abca 1表达增加，反映了LXR水平增加。西方饮食（WD）喂养的T39-/-Ldlr-/-小鼠具有降低的脂肪生成基因表达、保护免于NAFLD和减少的动脉粥样硬化。因此，T39的缺乏激活促进胆固醇去除和抑制脂肪生成的基因表达的有益特征。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nSREBP 1和LXR水平的作用有关。本研究的目的是阐明T39在调节肝脏脂肪生成、脂蛋白和动脉粥样硬化中的作用。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。这可能为潜在有益于NAFLD和动脉粥样硬化的T39的治疗性抑制铺平道路。

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.