Muscle-Specific Deletion of Carnitine Acetyltransferase Compromises Glucose Tolerance and Metabolic Flexibility

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• 作者：Deborah&#160 ; M. Muoio¹ ; ³ ; ^{muoio@duke.edu} ; Robert&#160 ; C. Noland¹ ; ³ ; Jean-Paul Kovalik¹ ; Sarah&#160 ; E. Seiler¹ ; Michael&#160 ; N. Davies¹ ; Karen&#160 ; L. DeBalsi¹ ; Olga&#160 ; R. Ilkayeva¹ ; Robert&#160 ; D. Stevens¹ ; Indu Kheterpal² ; Jingying Zhang² ; Jeffrey&#160 ; D. Covington² ; Sudip Bajpeyi² ; Eric Ravussin² ; William Kraus¹ ; Timothy&#160 ; R. Koves¹ ; Randall&#160 ; L. Mynatt² ; ³ ; ^{randall.mynatt@pbrc.edu}
• 刊名：Cell Metabolism
• 出版年：2012
• 期刊代码：46_15504131
• 类别：med
• 出版时间：2 May, 2012
• 卷：15
• 期：5
• 页码：764-777
• 文件大小：1602 K

摘要

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Summary

The concept of 鈥渕etabolic inflexibility鈥?was first introduced to describe the failure of insulin-resistant human subjects to appropriately adjust mitochondrial fuel selection in response to nutritional cues. This phenomenon has since gained increasing recognition as a core component of the metabolic syndrome, but the underlying mechanisms have remained elusive. Here, we identify an essential role for the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT), in regulating substrate switching and glucose tolerance. By converting acetyl-CoA to its membrane permeant acetylcarnitine ester, CrAT regulates mitochondrial and intracellular carbon trafficking. Studies in muscle-specific Crat knockout mice, primary human skeletal myocytes, and human subjects undergoing L-carnitine supplementation support聽a model wherein CrAT combats nutrient stress, promotes metabolic flexibility, and enhances insulin action by permitting mitochondrial efflux of excess acetyl moieties that otherwise inhibit key regulatory enzymes such as pyruvate dehydrogenase. These findings offer therapeutically relevant insights into the molecular basis of metabolic inflexibility.