TTC39B in obesity and atherosclerosis

在人类GWAS中，三肽重复结构域蛋白39 B基因（TTC 39 B/T39）中的SNP 导致肝脏表达减少的蛋白质与高密度脂蛋白胆固醇增加有关。T39，a 支架蛋白，促进LXR的泛素化和周转。西式饮食（WTD）- 喂食Ldlr-/-T39-/-小鼠显示脂肪肝减少，HDL增加，LDL减少， 动脉粥样硬化T39缺陷抑制固醇调节元件结合蛋白的加工 1（SREBP-1）转化为其核活性形式，这是由于微粒体磷脂的增加 含有多不饱和脂肪酸（PUFA）。我们发现T39-/-巨噬细胞也 显示LXR增加，增加介导PUFA合成的基因的表达，以及 减少炎症反应，表明巨噬细胞在减少动脉粥样硬化中的作用 在全身T39缺乏的小鼠中。有趣的是，WTD-喂养的Ldlr-/-小鼠的治疗中， T39反义寡核苷酸（阿索）在肝脏和脂肪组织中的表达均降低 减少肥胖。而棕色脂肪组织库和食物摄入量 T39阿索处理导致WAT中Ucp 1的表达显著增加， 表明形成米色脂肪细胞（beiging）。我们将研究T39的作用， 调节巨噬细胞中的LXR和脂肪组织中的PPARγ以及对肥胖、胰岛素的影响 抵抗和动脉粥样硬化（图1），与项目1中的LXR研究和项目1中的PPARγ研究有关。 项目3.目的1将评估髓样T39缺乏对巨噬细胞炎症的影响， 胰岛素抵抗和动脉粥样硬化。我们将探讨T39缺乏症 减少泛素化并促进巨噬细胞中LXR的稳定，从而增强 LXR介导的炎症基因抑制，主要是通过增加 含有长链PUFA的磷脂。和塔巴斯博士一起，我们将确定巨噬细胞T39 为了确定髓系T39缺乏是否是抗- 在Ldlr-/-背景下繁殖LysM-CreT 39 f/f小鼠。目标2将评估 脂肪细胞T39缺乏对肥胖、胰岛素抵抗和动脉粥样硬化影响我们将 繁殖AdipoQ-CreT 39 f/f小鼠以消耗WAT中的T39并评估肥胖， Ldlr-/-背景、血浆脂蛋白和动脉粥样硬化。与阿奇利博士和强博士一起， 我们将研究T39缺乏对从间质形成米色脂肪细胞的影响， 血管分数（SVF）。我们将评估一个特定的假设，即T39缺乏会降低 Rb家族成员与Pparg 1启动子中的E2 F结合位点的结合，以及其他 beiging基因，促进米色脂肪细胞的形成。

In human GWAS SNPs in the tetratricopeptide repeat domain protein 39B gene (TTC39B/T39) that cause reduced hepatic expression are associated with increased HDL cholesterol. T39, a scaffolding protein, promotes the ubiquitination and turnover of LXR. Western Type Diet (WTD)- fed Ldlr-/-T39-/- mice showed decreased fatty liver, increased HDL, decreased LDL and reduced atherosclerosis. T39 deficiency inhibited processing of sterol regulatory element binding protein 1 (SREBP-1) into its nuclear active form, due to an increase in microsomal phospholipids containing polyunsaturated fatty acids (PUFA). We discovered that T39-/- macrophages also show increased LXR., increased expression of genes mediating synthesis of PUFA, and reduced inflammatory responses, suggesting a role of macrophages in reduced atherosclerosis in mice with whole body T39 deficiency. Interestingly, treatment of WTD-fed Ldlr-/- mice with a T39 antisense oligonucleotide (ASO) that decreased expression in both liver and adipose tissue leads to reduced adiposity. While brown adipose tissue depots and food intake were unchanged, T39 ASO treatment led to markedly increased expression of Ucp1 in WAT, suggesting formation of beige adipocytes (beiging). We will investigate the role of T39 in regulating LXR in macrophages and PPARγ in adipose tissue and effects on adiposity, insulin resistance and atherosclerosis (Fig 1), linking to LXR studies in Proj 1, and of PPARγ studies in Proj 3. Aim 1 will assess the impact of myeloid T39 deficiency on macrophage inflammation, insulin resistance and atherosclerosis. We will explore the hypothesis that T39 deficiency reduces ubiquitination and promotes stabilization of LXR in macrophages and thus enhances LXR-mediated repression of inflammatory genes, primarily by increasing the synthesis of phospholipids containing long chain PUFA. With Dr Tabas, we will determine if macrophage T39 deficiency promotes inflammation resolution.To determine if myeloid T39 deficiency is anti- atherogenic, we will breed LysM-CreT39f/f mice in the Ldlr-/- background. Aim 2 will assess the impact of adipocyte T39 deficiency on adiposity, insulin resistance and atherosclerosis. We will breed AdipoQ-CreT39f/f mice in order to deplete T39 in WAT and assess adiposity, beiging and, on the Ldlr-/- background, plasma lipoproteins and atherosclerosis. With Drs Accili and Qiang, we will examine the impact of T39 deficiency on formation of beige adipocytes from the stromal- vascular fraction (SVF). We will assess a specific hypothesis that T39 deficiency decreases the binding of Rb family members to the E2F binding site in the promoter of Pparg1and other beiging genes, promoting formation of beige adipocytes.