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Publication
Muscle-specific deletion of carnitine acetyltransferase compromises glucose
tolerance and metabolic flexibility.
Authors Muoio DM, Noland RC, Kovalik JP, Seiler SE, Davies MN, DeBalsi KL, Ilkayeva OR,
Stevens RD, Kheterpal I, Zhang J, Covington JD, Bajpeyi S, Ravussin E, Kraus W,
Koves TR, Mynatt RL
Submitted By Submitted Externally on 7/31/2017
Status Published
Journal Cell Metabolism
Year 2012
Date Published
Volume : Pages 15 : 764 - 77
PubMed Reference 22560225
Abstract 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.




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