Regulation of cardiac and skeletal muscle malonyl-CoA decarboxylase by fatty acids

Malonyl-CoA decarboxylase (MCD) catalyzes the degradation of malonyl-CoA, a n important modulator of fatty acid oxidation. We hypothesized that increas ed fatty acid availability would increase the expression and activity of he art and skeletal muscle MCD, thereby promoting fatty acid utilization. The results show that high-fat feeding, fasting, and streptozotocin-induced dia betes all significantly increased the plasma concentration of nonesterified fatty acids, with a concomitant increase in both rat heart and skeletal mu scle MCD mRNA. Upon refeeding of fasted animals, MCD expression returned to basal levels. Fatty acids are known to activate peroxisome proliferator-ac tivated receptor-alpha (PPAR alpha). Specific PPAR alpha stimulation, throu gh Wy-14643 treatment, significantly increased the expression of MCD in hea rt and skeletal muscle. Troglitazone, a specific PPAR gamma agonist, decrea sed MCD expression. The sensitivity of MCD induction by fatty acids and Wy- 14643 was soleus. extensor digitorum longus. heart. High plasma fatty acids consistently increased MCD activity only in solei, whereas MCD activity in the heart actually decreased with high-fat feeding. Pressure overload-indu ced cardiac hypertrophy, in which PPAR alpha expression is decreased (and f atty acid oxidation is decreased), resulted in decreased MCD mRNA and activ ity, an effect that was dependent on fatty acids. The results suggest that fatty acids induce the expression of MCD in rat heart and skeletal muscle. Additional posttranscriptional mechanisms regulating MCD activity appear to exist.