TTC39B in obesity and atherosclerosis

人类四肽重复结构域蛋白39B基因(TTC39B/T39)的SNPs 导致肝脏表达减少的因素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)- 喂饲Ldlr-/-T39-/-小鼠的脂肪肝减少，高密度脂蛋白升高，低密度脂蛋白降低， 动脉硬化。T39缺乏抑制了固醇调节元件结合蛋白的加工 1(SREBP-1)转变为核活性形式，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 表现为LXR增加，调节PUFA合成的基因表达增加，以及 炎症反应减少，提示巨噬细胞在动脉粥样硬化减轻中的作用 在全身T39缺乏的小鼠中。有趣的是，对WTD喂养的Ldlr-/-小鼠的治疗 T39反义寡核苷酸(ASO)降低肝脏和脂肪组织的表达 可以减少肥胖。而棕色脂肪组织储存库和食物摄入量 T39ASO处理后，WAT中Ucp1的表达显著增加。 提示形成了米色脂肪细胞(米色)。我们将研究T39在其中的作用 调节巨噬细胞LXR和脂肪组织PPARγ对肥胖、胰岛素的影响 抵抗和动脉粥样硬化(图1)，链接到项目1中的LXR研究，以及项目1中的PPARγ研究 AIM 1将评估髓系T39缺陷对巨噬细胞炎症的影响， 胰岛素抵抗和动脉粥样硬化。我们将探索T39缺乏症的假设 减少巨噬细胞中LXR的泛素化并促进其稳定，从而增强 LXR介导的炎症基因的抑制，主要是通过增加 含有长链多不饱和脂肪酸的磷脂。有了塔巴斯博士，我们将确定巨噬细胞T39 缺乏促进炎症消退。确定髓系T39缺乏是否具有抗炎作用 致动脉粥样硬化，我们将在Ldlr-/-背景下培育LysM-CreT39f/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的影响。我们会 饲养AdipoQ-CreT39f/f小鼠，以消耗水中的T39，并评估肥胖、褐变和， 在LDLR-/-背景下，血浆脂蛋白与动脉粥样硬化。与阿奇利和强博士在一起， 我们将研究T39缺乏对基质中米色脂肪细胞形成的影响。 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Pparg1等基因启动子中E2F结合位点的结合 米色基因，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.