Malonyl CoenzymeA decarboxylase regulates lipid and glucose metabolism in human skeletal muscle.

Abstract:

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.

journal_name

Diabetes

journal_title

Diabetes

authors

Bouzakri K,Austin R,Rune A,Lassman ME,Garcia-Roves PM,Berger JP,Krook A,Chibalin AV,Zhang BB,Zierath JR

doi

10.2337/db07-0583

subject

Has Abstract

pub_date

2008-06-01 00:00:00

pages

1508-16

issue

6

eissn

0012-1797

issn

1939-327X

pii

db07-0583

journal_volume

57

pub_type

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