Expression of genes regulating Malonyl-CoA in human skeletal muscle

• Published in: Journal of cellular biochemistry Vol. 99; no. 3; pp. 860 - 867
• Main Authors: Pender, Celia, Trentadue, Anna R., Pories, Walter J., Dohm, G. Lynis, Houmard, Joseph A., Youngren, Jack F.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.10.2006
• Subjects: acetyl-CoA carboxylase; Acetyl-CoA Carboxylase - genetics; Acetyl-CoA Carboxylase - metabolism; Adult; Animals; Biopsy; Carboxy-Lyases - genetics; Carboxy-Lyases - metabolism; Carnitine O-Palmitoyltransferase - genetics; Carnitine O-Palmitoyltransferase - metabolism; fatty acid synthase; Fatty Acid Synthases - genetics; Fatty Acid Synthases - metabolism; Gene Expression Regulation, Enzymologic; Humans; Isoenzymes - genetics; Isoenzymes - metabolism; lipogenesis; Malonyl Coenzyme A - genetics; Malonyl Coenzyme A - metabolism; Muscle, Skeletal - enzymology; Muscle, Skeletal - physiology; obesity; Obesity - metabolism; pyruvate carboxylase; Pyruvate Carboxylase - genetics; Pyruvate Carboxylase - metabolism; sterol regulatory element binding protein 1; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.20944

In humans and animal models, increased intramuscular lipid (IML) stores have been implicated in insulin resistance. Malonyl‐CoA plays a critical role in cellular lipid metabolism both by serving as a precursor in the synthesis of lipids and by inhibiting lipid oxidation. In muscle, Malonyl‐CoA acts primarily as a negative allosteric regulator of carnitine palmitoyl transferase‐1 (CPT1) activity, thereby blocking the transport of long chain fatty acyl CoAs into the mitochondria for oxidation. In muscle, increased malonyl‐CoA, decreased muscle CPT1 activity, and increased IML have all been reported in obesity. In order to determine whether malonyl‐CoA synthesis might be under transcriptional as well as biochemical regulation, we measured mRNA content of several key genes that contribute to the cellular metabolism of malonyl‐CoA in muscle biopsies from lean to morbidly obese subjects. Employing quantitative real‐time PCR, we determined that expression of mitochondrial acetyl‐CoA carboxylase 2 (ACC2) was increased by 50% with obesity (P < 0.05). In both lean and obese subjects, expression of mitochondrial ACC2 was 20‐fold greater than that of cytoplasmic ACC1, consistent with their hypothesized roles in synthesizing malonyl‐CoA from acetyl‐CoA for CPT1 regulation and lipogenesis, respectively. In addition, in both lean and obese subjects, expression of malonyl‐CoA decarboxylase was approximately 40‐fold greater than fatty acid synthase, consistent with degradation, rather than lipogenesis, being the primary fate of malonyl‐CoA in human muscle. No other genes showed signs of increased mRNA content with obesity, suggesting that there may be selective transcriptional regulation of malonyl‐CoA metabolism in human obesity. J. Cell. Biochem. 99: 860–867, 2006. © 2006 Wiley‐Liss, Inc.