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MALONYL COENZYME A DECARBOXYLASE REGULATES LIPID AND GLUCOSE METABOLISM IN HUMAN SKELETAL MUSCLE

From the Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden¹
Merck Research Laboratories, Rahway, NJ, USA² and
the Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden³

Objective: Malonyl-CoA decarboxylase (MCD) is a key enzyme responsible for malonyl-CoA turnover and functions in the control of the balance between lipid and glucose metabolism. We utilized RNA interference (siRNA) based gene silencing to determine the direct role of MCD on metabolic responses in primary human skeletal muscle.

Research Design And Methods: We used siRNA to silence MCD gene expression in cultured human myotubes from healthy volunteers (7 male and 7 female) with no known metabolic disorders. Thereafter, we determined lipid and glucose metabolism and signal transduction under basal and insulin-stimulated conditions.

Results: RNA interference-based silencing of MCD expression (75% reduction) increased malonyl-CoA levels 2-fold and shifts substrate utilization from lipid to glucose oxidation. RNA interference-based depletion of MCD reduced basal palmitate oxidation. In parallel with this reduction, palmitate uptake was decreased under basal (40%) and insulin-stimulated (49%) conditions, compared to myotubes transfected with a scrambled sequence. MCD silencing increased basal and insulin-mediated glucose oxidation 1.4- and 2.6-fold, respectively, compared to myotubes transfected with a scrambled sequence. In addition, glucose transport and cell-surface GLUT4 content was increased. In contrast, insulin action on IRS-1 tyrosine phosphorylation, tyrosine-associated PI 3-kinase activity, Akt and GSK phosphorylation was unaltered between myotubes transfected with siRNA against MCD versus a scrambled sequence.

Conclusion: These results provide evidence that MCD silencing suppresses lipid uptake and enhances glucose uptake in primary human myotubes. In conclusion MCD expression plays a key reciprocal role in the balance between lipid and glucose metabolism.

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