Carnitine acetyltransferase (CrAT) is a freely reversible mitochondrial matrix enzyme that catalyzes the exchange of short-chain acyl groups between CoA and carnitine. Unlike their acyl-CoA counterparts, acylcarnitines can traverse cellular membranes. Accordingly, the interconversion between these molecules can potentially impact cellular, and perhaps inter-tissue carbon trafficking. The primary substrate of CrAT, acetyl-CoA, holds a prominent position in intermediary metabolism as the two-carbon universal end product of fatty acid, glucose and amino acid oxidation. As its major metabolic fate, acetyl-CoA typically enters the tricarboxylic acid (TCA) cycle where it drives production of reducing equivalents that in turn fuel the electron transport chain. CrAT purportedly acts to export excess carbon fuels from the mitochondria during conditions wherein the production of short-chain acyl-CoAs exceeds TCA cycle flux. By doing so, this reaction is thought to play a key role in regenerating free CoA, modulating mitochondrial acetyl-CoA/CoA balance and relieving acetyl-CoA-mediated inhibition of pyruvate dehydrogenase (PDH), the committed step in glucose oxidation. Mounting evidence from our laboratory suggest that CrAT plays a critical role in regulating whole body substrate selection and glucose tolerance;and that CrAT inactivity might contribute to obesity- and age-related metabolic dysfunction. This NRSA application proposes to elucidate the role of this enzyme in regulating whole body and mitochondrial energy homeostasis utilizing immunoaffinity purification techniques and physiological characterizations of genetic mouse models. First, we will test the hypothesis that one of the mechanisms through which CrAT controls energy metabolism is by regulating nuclear and/or non-nuclear protein acetylation. This is an important and timely line of investigation in light of the growing number of metabolic pathways that appear to be modulated by reversible acetylation. Second, we will use an inducible gene knockout approach to determine whether total body loss of CrAT negates the antidiabetic actions of carnitine therapy. These studies are expected to shed clinically relevant insights on the role of this enzyme in combating nutrient stress and metabolic disease.
The overarching goal of this project is to elucidate mechanisms through which supplemental L- carnitine improves glucose tolerance in obese and diabetic rodents. Results from the proposed studies are likely to yield new insights regarding the therapeutic properties of L-carnitine, a conditionally essential nutrient, while also advancing our understanding of why obesity increases risk of metabolic disorders such as type 2 diabetes. These are clinically relevant topics of intense scientific interest and controversy.
|Davies, Michael N; Kjalarsdottir, Lilja; Thompson, J Will et al. (2016) The Acetyl Group Buffering Action of Carnitine Acetyltransferase Offsets Macronutrient-Induced Lysine Acetylation of Mitochondrial Proteins. Cell Rep 14:243-54|
|Seiler, Sarah E; Koves, Timothy R; Gooding, Jessica R et al. (2015) Carnitine Acetyltransferase Mitigates Metabolic Inertia and Muscle Fatigue during Exercise. Cell Metab 22:65-76|
|Laurent, GaÃ«lle; German, Natalie J; Saha, Asish K et al. (2013) SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol Cell 50:686-98|