TTC39B in Metabolism

描述（由申请人提供）：介导脂肪性肝炎的细胞机制，在西方世界越来越普遍，没有治疗方法，知之甚少。利用人类基因组广泛关联研究，我们最近发现TTC39B （T39）是一个影响HDL胆固醇水平的新基因，它编码一个功能未知的四肽重复结构域蛋白。我们试图通过小鼠模型了解T39的功能及其对人类疾病的潜在意义。这些研究表明，T39缺陷小鼠可以防止脂肪肝、脂肪性肝炎和动脉粥样硬化的发生。T39似乎是一种调节LXR转录后降解的支架蛋白，LXR是一种控制胆固醇外排基因和促进甘油三酯合成基因的转录因子。除了有益的脂蛋白改变和减少动脉粥样硬化外，当小鼠受到高脂肪/高胆固醇饮食的挑战时，T39缺乏还可以防止肝脂肪变性和脂肪性肝炎，这些新观察结果的潜在机制将是本提案的主要焦点。我们还将探讨T39的基本功能，如促进泛素化和降解的能力

DESCRIPTION (provided by applicant): Cellular mechanisms that mediate steatohepatitis, an increasingly prevalent condition in the Western world for which no therapies are available, are poorly understood. Using human genome wide association studies, we recently identified TTC39B (T39), which encodes a tetratricopeptide repeat-domain protein of unknown function, as a novel gene influencing HDL cholesterol levels. We have sought to understand the functions of T39 and its potential significance for human diseases using mouse models. These studies have revealed that T39 deficient mice are protected from development of fatty liver, steatohepatitis and atherosclerosis. T39 appears to be a scaffolding protein that regulates the post-transcriptional degradation of LXR, a transcription factor controlling cholesterol efflux genes and well as genes promoting triglyceride synthesis. In addition to beneficial lipoprotein changes and reduced atherosclerosis, T39 deficiency protects from hepatic steatosis and steatohepatitis when mice are challenged with high fat/high cholesterol diets, and the underlying mechanisms of these novel observations will be the main focus of this proposal. We will also explore the basic functions of T39 such as its ability to facilitate ubiquitination and degradation of LXR. Aim 1 will assess the mechanisms of reduced hepatic steatosis in T39-/- mice, Aim2 will determine tissue-specific effects of T39 in liver, spleen and hematopoietic cells; Aim 3 will explore the mechanisms of the post- transcriptional increase in LXR protein in T39-/- hepatocytes. These studies have the potential to uncover new treatments for steatohepatitis and atherosclerosis.