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

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.Background: Different fatty acids signal to control intracellular lipid dynamic metabolism.Results: In skeletal muscle cells, oleic acid induces cAMP/PKA and SIRT1 Ser-434 phosphorylation and activity, causing PGC1α deacetylation and increased fatty acid oxidation.Conclusion: Oleic acid signals to the SIRT1-PGC1α complex to increase rates of fatty acid oxidation.Significance: Pharmacological manipulation of the oleic acid signaling pathway might be a therapeutic option for conditions of lipid dysregulation. 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. Background: Different fatty acids signal to control intracellular lipid dynamic metabolism. Results: In skeletal muscle cells, oleic acid induces cAMP/PKA and SIRT1 Ser-434 phosphorylation and activity, causing PGC1α deacetylation and increased fatty acid oxidation. Conclusion: Oleic acid signals to the SIRT1-PGC1α complex to increase rates of fatty acid oxidation. Significance: Pharmacological manipulation of the oleic acid signaling pathway might be a therapeutic option for conditions of lipid dysregulation.