Abstract
Calorie restriction (CR), an age delaying diet, affects fat oxidation through poorly understood mechanisms. We investigated the effect of CR on fat metabolism gene expression and intermediate metabolites of fatty acid oxidation in the liver. We found that CR changed the liver acylcarnitine profile: acetylcarnitine, short‐chain acylcarnitines, and long‐chain 3‐hydroxy‐acylcarnitines increased, and several long‐chain acylcarnitines decreased. Acetyl‐CoA and short‐chain acyl‐CoAs were also increased in CR. CR did not affect the expression of CPT1 and upregulated the expression of long‐chain and very‐long‐chain Acyl‐CoA dehydrogenases (LCAD and VLCAD, respectively). The expression of downstream enzymes such as mitochondrial trifunctional protein and enzymes in medium‐ and short‐chain acyl‐CoAs oxidation was not affected in CR. CR shifted the balance of fatty acid oxidation enzymes and fatty acid metabolites in the liver. Acetyl‐CoA generated through beta‐oxidation can be used for ketogenesis or energy production. In agreement, blood ketone bodies increased under CR in a time of the day‐dependent manner. Carnitine acetyltransferase (CrAT) is a bidirectional enzyme that interconverts short‐chain acyl‐CoAs and their corresponding acylcarnitines. CrAT expression was induced in CR liver supporting the increased acetylcarnitine and short‐chain acylcarnitine production. Acetylcarnitine can freely travel between cellular sub‐compartments. Supporting this CR increased protein acetylation in the mitochondria, cytoplasm, and nucleus. We hypothesize that changes in acyl‐CoA and acylcarnitine levels help to control energy metabolism and contribute to metabolic flexibility under CR.
Highlights
Calorie restriction (CR) increased expression of several fat catabolism enzymes the clock, in contrast with that, CR animals change substrate prefsuch as carnitine palmitoyl transferase 2 (CPT2), VLCAD, and LCAD, erence through the day: First few hours after the meal, they oxidize while CPTI and many downstream enzymes such as mitochondrial carbohydrates; they gradually switch to fatty acid oxidation trifunctional protein (MTP), medium-chain acyl-CoA dehydrogenase until the meal (Bruss et al, 2010)
(d) Daily rhythms of free carnitine. (e) Phase distribution of rhythmic acylcarnitines, AL and CR. (f) Daily rhythms in the expression of circadian clock genes Bmal1, Per2, and Per1. (g) Daily rhythms in ribosomal protein S6 phosphorylation and (h) representative Western blot and quantification. *—statistically significant difference, p < 0.05, by t test. #—statistically significant effect of diet, p < 0.05, two-way ANOVA
Profiles of absolute values for several acylcarnitines are shown in whole body fat oxidation under CR (Bruss et al, 2010)
Summary
Volha; Pearce, Ryan; Poe, Allan; Velingkaar, Nikkhil; Astafev, Artem; Ebeigbe, Oghogho P.; Makwana, Kuldeep; Sandlers, Yana; and Kondratov, Roman V., "CR Reprograms Acetyl-CoA Metabolism and Induces Long-Chain Acyl-CoA Dehydrogenase and CrAT Expression" (2020). This Article is brought to you for free and open access by the Chemistry Department at EngagedScholarship@CSU. This article is available at EngagedScholarship@CSU: https://engagedscholarship.csuohio.edu/scichem_facpub/547
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