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Regulation of hepatic lipid homeostasis by transcriptional co-factor complexes

转录辅助因子复合物对肝脂质稳态的调节

基本信息

批准号：
82204417
负责人：
Professor Dr. Stephan Herzig
金额：
--
依托单位：
Institut für Klinische Diabetologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2008
资助国家：
德国
起止时间：
2007-12-31 至 2014-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/82204417?language=en
关键词：
Regulation hepatic lipid homeostasis transcriptional

项目摘要

In mammals, storage of fat in adipose tissue is essential for the maintenance of energy homeostasis. In contrast, aberrant accumulation of lipids in the liver (“fatty liver”) represents a hallmark of the Metabolic Syndrome and is tightly associated with malign obesity and type II diabetes. While fatty liver has been connected with numerous abnormalities of liver function, the molecular mechanisms of fatty liver development remain largely enigmatic. To this end, our recent studies have identified the WD40 transcriptional co-repressor TBL1 as a novel regulator of hepatic lipid metabolism and uncovered TBL1’s dysregulation in diabetic fatty liver mouse models. Based on our preliminary data we will therefore test to which extent TBL1 is functionally implicated in the switch between benign and malign obesity and hepatic dyslipidemia, and whether its regulatory role can be partly compensated by highly related co-repressor proteins. We expect to define a novel transcriptional control level of hepatic energy homeostasis, potentially triggering dysfunctional energy metabolism in diet-dependent, malign obesity and type II diabetes. The molecular characterization of TBL1-associated co-repressor complexes may, thereby, provide novel susceptibility genes for these severe metabolic disorders.

在哺乳动物中，脂肪组织中的脂肪储存对于维持能量稳态是必不可少的。相反，肝脏中脂质的异常积累（“脂肪肝”）代表代谢综合征的标志，并且与恶性肥胖和II型糖尿病密切相关。虽然脂肪肝与许多肝功能异常有关，但脂肪肝发展的分子机制在很大程度上仍然是个谜。为此，我们最近的研究已经确定了WD 40转录辅抑制因子TBL 1作为肝脏脂质代谢的新调节因子，并揭示了TBL 1在糖尿病脂肪肝小鼠模型中的失调。因此，基于我们的初步数据，我们将测试TBL 1在良性和恶性肥胖和肝脏血脂异常之间的转换中在功能上有多大程度的牵连，以及其调节作用是否可以通过高度相关的辅阻遏蛋白来部分补偿。我们期望定义一种新的肝脏能量稳态的转录控制水平，可能引发饮食依赖性、恶性肥胖和II型糖尿病的能量代谢功能障碍。因此，TBL 1相关的辅阻遏物复合物的分子表征可能为这些严重的代谢紊乱提供新的易感基因。