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Malonyl CoenzymeA Decarboxylase Regulates Lipid and Glucose Metabolism in Human Skeletal Muscle

¹ Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
² Merck Research Laboratories, Rahway, NJ
³ Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

Corresponding author: Prof. Juleen R. Zierath, Karolinska Institutet, Department of Molecular Medicine and Surgery, Section of Integrative Physiology, von Eulers väg 4, 4th floor, S-171 77 Stockholm, Sweden. E-mail: juleen.zierath{at}ki.se

Abbreviations: ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; CoA, coenzyme A; CPT-1, carnitine palmitoyl transferase 1; DAG, diacylglycerol; DMEM, Dulbecco's modified Eagle's medium; FATP, fatty acid transport protein; GSK, glycogen synthase kinase; LCFA, long-chain fatty acid; MCD, malonyl-CoA decarboxylase; LCFA, long chain fatty acids; PBS, phosphate-buffered saline; PDK, pyruvate dehydrogenase kinase; PI, phosphatidylinositol; TBST, Tris-buffered saline plus Tween

OBJECTIVE—Malonyl coenzyme A (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 (seven male and seven 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 twofold and shifted 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 with myotubes transfected with a scrambled sequence. MCD silencing increased basal and insulin-mediated glucose oxidation 1.4- and 2.6-fold, respectively, compared with 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 phosphatidylinositol (PI) 3-kinase activity, Akt, and glycogen synthase kinase (GSK) phosphorylation was unaltered between myotubes transfected with siRNA against MCD versus a scrambled sequence.

CONCLUSIONS—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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