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

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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.