Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver.
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 (approximately 40%, 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 (approximately 35%, P < 0.001), resulting in decreased intracellular levels of malonyl-CoA (approximately 47%, 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 approximately 60%, 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.
Dobrzyn
Pawel
P
Department of Biochemistry, University of Wisconsin, Madison, WI 53706, USA.
Dobrzyn
Agnieszka
A
Miyazaki
Makoto
M
Cohen
Paul
P
Asilmaz
Esra
E
Hardie
D Grahame
DG
Friedman
Jeffrey M
JM
Ntambi
James M
JM
D055372:AMP-Activated Protein Kinases; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism*
D005227:Fatty Acids; D009097:Multienzyme Complexes; D013230:Stearoyl-CoA Desaturase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases