Oleic Acid Stimulates Complete Oxidation of Fatty Acids Through Protein Kinase A-dependent Activation of SIRT1-PGC1α Complex

J Biol Chem. 2013 Mar 8;288(10):7117-26. doi: 10.1074/jbc.M112.415729. Epub 2013 Jan 17.

Abstract

Fatty acids are essential components of the dynamic lipid metabolism in cells. Fatty acids can also signal to intracellular pathways to trigger a broad range of cellular responses. Oleic acid is an abundant monounsaturated omega-9 fatty acid that impinges on different biological processes, but the mechanisms of action are not completely understood. Here, we report that oleic acid stimulates the cAMP/protein kinase A pathway and activates the SIRT1-PGC1α transcriptional complex to modulate rates of fatty acid oxidation. In skeletal muscle cells, oleic acid treatment increased intracellular levels of cyclic adenosine monophosphate (cAMP) that turned on protein kinase A activity. This resulted in SIRT1 phosphorylation at Ser-434 and elevation of its catalytic deacetylase activity. A direct SIRT1 substrate is the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α), which became deacetylated and hyperactive after oleic acid treatment. Importantly, oleic acid, but not other long chain fatty acids such as palmitate, increased the expression of genes linked to fatty acid oxidation pathway in a SIRT1-PGC1α-dependent mechanism. As a result, oleic acid potently accelerated rates of complete fatty acid oxidation in skeletal muscle cells. These results illustrate how a single long chain fatty acid specifically controls lipid oxidation through a signaling/transcriptional pathway. Pharmacological manipulation of this lipid signaling pathway might provide therapeutic possibilities to treat metabolic diseases associated with lipid dysregulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylation / drug effects
  • Animals
  • Blotting, Western
  • Cell Line
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Fatty Acids / metabolism*
  • Fluorescence Resonance Energy Transfer
  • Mice
  • Mice, Inbred C57BL
  • Multiprotein Complexes / metabolism
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Mutation
  • Oleic Acid / pharmacology*
  • Oxidation-Reduction / drug effects
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Phosphorylation / drug effects
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serine / genetics
  • Serine / metabolism
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors
  • Transcriptional Activation / drug effects

Substances

  • Fatty Acids
  • Multiprotein Complexes
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Trans-Activators
  • Transcription Factors
  • Oleic Acid
  • Serine
  • Cyclic AMP-Dependent Protein Kinases
  • Sirt1 protein, mouse
  • Sirtuin 1