Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 101, Issue 17, Pages 6409-6414Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0401627101
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Funding
- NIDDK NIH HHS [R01-DK62388, R01 DK062388, R01 DK041096, R01-DK41096] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007739] Funding Source: Medline
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Stearoyl-CoA desaturase (SCD) catalyzes the rate-limiting step in the biosynthesis of monounsaturated fatty acids. Mice with a targeted disruption of the SCD1 isoform have reduced body adiposity, increased energy expenditure, and up-regulated expression of several genes encoding enzymes of fatty acid beta-oxidation in liver. The mechanisms by which SCD deficiency leads to these metabolic changes are presently unknown. Here we show that the phosphorylation and activity of AMP-activated protein kinase (AMPK), a metabolic sensor that regulates lipid metabolism during increased energy expenditure is significantly increased (approximate to40%, P < 0.01) in liver of SCD1 knockout mice (SCD1 -/-). In parallel with the activation of AMPK, the phosphorylation of acetyl-CoA carboxylase at Ser-79 was increased and enzymatic activity was decreased (approximate to35%, P < 0.001), resulting in decreased intracellular levels of malonyl-CoA (approximate to47%, P < 0.001). An SCD1 mutation also increased AMPK phosphorylation and activity and increased acetyl-CoA carboxylase phosphorylation in leptin-deficient ob/ob mice. Lower malonyl-CoA concentrations are known to derepress carnitine palmitoyltransferase 1 (CPT1). In SCD1-/- mice, CPT1 and CPT2 activities were significantly increased (in both cases approximate to60%, P < 0.001) thereby stimulating the oxidation of mitochondrial palmitoyl-CoA. Our results identify AMPK as a mediator of increased fatty acid oxidation in liver of SCD1-deficient mice.
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