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

作者：Muoio Deborah M^*; Noland Robert C; Kovalik Jean Paul; Seiler Sarah E; Davies Michael N; DeBalsi Karen L; Ilkayeva Olga R; Stevens Robert D; Kheterpal Indu; Zhang Jingying; Covington Jeffrey D; Bajpeyi Sudip; Ravussin Eric; Kraus William; Koves Timothy R; Mynatt Randall L

来源：Cell Metabolism, 2012, 15(5): 764-777.

DOI：10.1016/j.cmet.2012.04.005

The concept of "metabolic inflexibility" 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 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.

• 出版日期2012-5-2