Malonyl CoenzymeA Decarboxylase Regulates Lipid and Glucose Metabolism in Human Skeletal Muscle
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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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Lowering MCD activity in primary human skeletal myocytes with small interfering RNAs shifts metabolism from fatty acid to glucose oxidation and increases basal and insulin-stimulated glucose uptake.
“lowering of MCD activity in primary human skeletal myocytes using small interfering RNAs invoked a clear shift from fatty acid to glucose oxidation and a corresponding increase in both basal and insulinstimulated glucose uptake [13].”
From Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? (2010) · cites this paper as [13]
The increased glucose uptake after MCD inactivation is associated with higher cell-surface GLUT-4 but not with enhanced IRS-1 tyrosine phosphorylation, PI3-kinase activity, or Akt serine phosphorylation.
“These outcomes were associated with increased cell surface levels of the GLUT-4 glucose transporter, but surprisingly no enhancement in insulin signaling at the levels of IRS-1 tyrosine phosphorylation, PI3-kinase activity, or serine phosphorylation of Akt.”
From Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? (2010) · cites this paper as [13]
Lipid suppression of glucose utilization is mitigated by etomoxir, an inhibitor of carnitine palmitoyltransferase 1, or by knockdown of malonyl-CoA decarboxylase.
“For example, lipid suppression of glucose utilization is mitigated by etomoxir, an inhibitor of carnitine palmitoyltransferase 1, or by knockdown of malonyl-CoA decarboxylase, an enzyme that promotes mitochondrial β-oxidation by preventing malonyl-CoA–induced inhibition of CPT-I (36, 170).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [36]
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- Authors
- Bouzakri, K., Austin, R., Rune, A., Lassman, M. E., Garcia-Roves, P. M., Berger, J. P., Krook, A., Chibalin, A. V., Zhang, B. B., & Zierath, J. R.
- Affiliations
- Karolinska University Hospital (SE)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2008-06-01
- Volume
- 57
- Issue
- 6
- Pages
- 1508-1516
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2169132538
- Cited by
- 77
- References
- 47
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 2 · 2019: 2 · 2018: 2 · 2017: 2 · 2016: 4 · 2015: 6 · 2014: 6 · 2013: 5 · 2012: 8
- FWCI
- 4.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (publishedVersion, cc-by-nc-nd)
- HAL (submittedVersion)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (submittedVersion, cc-by-nc-nd)
- Funders
- University of Bath
- Vetenskapsrådet
- Centrum för idrottsforskning
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- malonyl-CoA decarboxylase, malonyl-CoA, lipid metabolism, glucose metabolism, skeletal muscle, myotubes, palmitate oxidation, palmitate uptake, glucose uptake, GLUT4, insulin signaling, IRS-1, substrate utilization
- MeSH terms
- Acetyl Coenzyme A, Biopsy, Carboxy-Lyases, Ceramides, Coenzyme A, Diglycerides, Fatty Acids, Glucose, Humans, Kinetics, Lipids, RNA, Messenger, Transfection, Muscle, Skeletal, Muscle Fibers, Skeletal, Gene Silencing, RNA, Small Interfering
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