Regulation of TBL1 transcriptional co-factor complex activity through filamin A and its implications in obesity

脂肪肝的发展代表了代谢综合征的一个标志，最近已被确定为冠心病和动脉粥样硬化表现的关键危险因素，表明肝脏代谢中的分子检查点可能在全身脂质病理学中实现更广泛的“远程控制”功能。该提议将检验肝TBL 1/TBLR 1转录辅因子复合物通过控制全身脂蛋白代谢直接影响2型糖尿病大血管终末期并发症进展的假设。使用已经建立的组织特异性TBL 1/TBLR 1缺乏的小鼠模型，我们将功能性地分析肝TBL 1/TBLR 1活性对大血管损伤发展的贡献，探讨TBL 1/TBLR 1相关转录复合物在“西式”饮食脂质暴露反应中调控脂质代谢遗传途径的分子机制，并预期在动脉粥样硬化的发病机制中建立一个新的肝血管轴，将肝脏特异性TBL 1/TBLR 1作用与血管反应性脂质代谢物形成联系起来，从而解释了肥胖相关的2型糖尿病和代谢综合征受试者中大血管损伤的增加。

The development of a fatty liver represents a hallmark of the Metabolic Syndrome and re-cently has been identified as a critical risk factor for the manifestation of coronary heart dis-ease and atherosclerosis, indicating that molecular checkpoints in liver metabolism may fulfill broader “remote control” functions in systemic lipid pathologies.Based on our own preliminary data, this proposal will test the hypothesis that the hepatic TBL1/TBLR1 transcriptional co-factor complex directly impacts the progression of macrovas-cular end-stage complications in type 2 diabetes by controlling systemic lipoprotein metabol-ism and reactive lipid metabolite generation.Using already established mouse models for tissue-specific TBL1/TBLR1 deficiency, we will functionally analyze the contribution of hepatic TBL1/TBLR1 activity to the development of macro-vascular damage, and explore the molecular mechanisms of TBL1/TBLR1- asso-ciated transcriptional complexes in the control of lipid-metabolizing genetic pathways in re-sponse to “Western style” dietary lipid exposure.We anticipate establishing a novel hepato-vascular axis in the pathogenesis of atherosclero-sis, linking liver-specific TBL1/TBLR1 action with vascular reactive lipid metabolite formation, thereby explaining the increased macro-vascular damage in subjects with obesity-related type 2 diabetes and the Metabolic Syndrome.