Expression of genes regulating malonyl-CoA in human skeletal muscle.

Abstract

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.

• Authors: Celia Pender, Anna R Trentadue, Walter J Pories, G Lynis Dohm, Joseph A Houmard, Jack F Youngren
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 99 Issue 3 Pg. 860-7 (Oct 15 2006) ISSN: 0730-2312 [Print] United States
• PMID: 16721829 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: 2006 Wiley-Liss, Inc.

Chemical References

• Isoenzymes
• Sterol Regulatory Element Binding Protein 1
• Malonyl Coenzyme A
• Carnitine O-Palmitoyltransferase
• Fatty Acid Synthases
• Carboxy-Lyases
• malonyl-CoA decarboxylase
• Pyruvate Carboxylase
• ACACB protein, human
• Acetyl-CoA Carboxylase

Topics

• Acetyl-CoA Carboxylase (genetics, metabolism)
• Adult
• Animals
• Biopsy
• Carboxy-Lyases (genetics, metabolism)
• Carnitine O-Palmitoyltransferase (genetics, metabolism)
• Fatty Acid Synthases (genetics, metabolism)
• Gene Expression Regulation, Enzymologic
• Humans
• Isoenzymes (genetics, metabolism)
• Malonyl Coenzyme A (genetics, metabolism)
• Muscle, Skeletal (enzymology, physiology)
• Obesity (metabolism)
• Pyruvate Carboxylase (genetics, metabolism)
• Sterol Regulatory Element Binding Protein 1 (genetics, metabolism)