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.

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

“…The monounsaturated fatty acid oleic acid is able to improve skeletal muscle insulin resistance partially through a PKAdependent mechanism (Coll et al 2008). Specifically, oleic acid can activate PKA/Sirt1/PGC1α pathway to stimulate fatty acid oxidation in skeletal muscle (Lim et al 2013). These data suggest that PKA is positively associated with lipid oxidation and insulin sensitivity in skeletal muscle.…”

Increased palmitate intake: higher acylcarnitine concentrations without impaired progression of β-oxidation

“…In our previous study of humans fed the HPA and HOA diets, we found, however, no evidence that the diets altered the mRNA expression of PGC-1 ␣ or known targets of PPAR ␣ or -␦ ( 9 ). However, our present fi ndings related to the MCAC/LCAC ratio, as well as our previous results ( 2 ), are partially consistent with these in vitro effects, to the extent that accumulation of MCACs may refl ect incomplete FA OX ( 48 ). Although the MCAC/LCAC ratio was increased on the HPA diet, the overall pattern of ACs, especially the relatively high C10:0 (during both diets) ( Fig.…”

“…It is not known whether these adipocytes will function like those in the subcutaneous adipose tissue, but we also acknowledge that we did not specifi cally assess PA metabolism by subcutaneous adipose tissue, although our assumption is that PA metabolism by this tissue was not included in our measurements because of the use of the deep brachial venous catheter. Fourth, in order to achieve of MCAD, as well as other targets of PPAR ␣ or -␦ ; moreover, OA increased complete oxidation of either PA or OA ( 48 ). In our previous study of humans fed the HPA and HOA diets, we found, however, no evidence that the diets altered the mRNA expression of PGC-1 ␣ or known targets of PPAR ␣ or -␦ ( 9 ).…”

Structure–activity relationship of immunomodulating pectins from elderberries

“…Oleic acid has also shown a beneficial effect on insulin sensitivity, adipocyte glucose transport and prevents T2D [62][63][64][65].…”