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专题学术讲座
Mechanisms of ER stress and Metabolic Dysregulation in Obesity
发布时间:2011-11-15关键字:

Abstact

The development of metabolic syndrome in obesity and its ultimate manifestation in the forms of cardiovascular diseases and diabetes has become a major health challenge around the globe. Endoplasmic reticulum (ER) stress is present in multiple tissues of obesity, and it has been proposed as a critical mechanism of insulin resistance, diabetes and atherosclerosis. However, the cause of ER stress in obesity has not been identified in vivo. Here we undertook systematic, high-throughput approaches to explore the mechanisms of ER stress and cellular dysfunction in obesity. For the first part, I will show that the chronic upregulation of de novo lipogenesis in obesity alters both the fatty acid and lipid compositions of ER. In particular, we found that the increase in phosphatidylcholine/phosphatidylethanolamine (PC/PE) ratio in the obese ER inadvertently led to the inhibition of sarco/endoplasmic reticulum calcium ATPase (SERCA) function and ER stress. Correcting a specific obesity-induced alteration in ER lipid composition or hepatic Serca expression in vivo both reduced ER stress and improved glucose homeostasis. Hence, we established chronic upregulation of de novo lipogenesis as a critical mechanism of ER stress in the obese liver. For the second part, I will present comparative translatome analysis of the mouse liver ER that revealed a concerted program in repressing protein synthesis in obesity, and the translational downregulation contributes to mitochondrial dysfunction. Translatome analysis also identified a dramatic downregulation of a specific bile acid synthesis pathway, although most lipid metabolism pathways are upregulated. Restoration of bile acid synthesis in vivo enhanced protein synthesis, suppressed hepatic gluconeogenesis and de novo lipogenesis, improved hepatic steatosis and hyperglycemia, suggesting an important role of bile acids in balancing protein and lipid metabolism. Together, our results demonstrated that the imbalance in protein and lipid metabolism contributes to ER stress and metabolic dysfunction, and such an imbalance can be at least partially corrected by bile acids.
 
 




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