title: 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.affiliation: Department of Medicine, Diabetes and Endocrine Research, Mount Zion Medical Center, University of California, San Francisco, California 94143-1616, USA.
authors.forename: Celia
authors.initials: C
authors.lastname: Pender
authors.forename: Anna R
authors.initials: AR
authors.lastname: Trentadue
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Pories
authors.forename: G Lynis
authors.initials: GL
authors.lastname: Dohm
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Houmard
authors.forename: Jack F
authors.initials: JF
authors.lastname: Youngren
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000818:Animals; D001706:Biopsy; D002262:Carboxy-Lyases / Q000235:genetics / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008316:Malonyl Coenzyme A / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000502:physiology*; D009765:Obesity / Q000378:metabolism*; D011766:Pyruvate Carboxylase / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D051780:Sterol Regulatory Element Binding Protein 1; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D064429:Fatty Acid Synthases; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D011766:Pyruvate Carboxylase; C520105:ACACB protein, human; D000103:Acetyl-CoA Carboxylase