beta-oxidation in macrophages

Saturated fatty acids (SFA) such as palmitate activate inflammatory pathways and elicit endoplasmic reticulum (ER) stress response in macrophages, which contributes to the development of insulin resistance during metabolic syndrome. How mitochondrial fatty acid oxidation affects macrophage responses to SFA is mostly unknown. To investigate the role of endogenous fatty acid oxidation in macrophage responses to palmitate we created THP-1 monocytic cell lines with a stable knock-down of carnitine palmitoyl transferase 1a (CPT1a) and differentiated them to macrophages. Functional analyses confirmed reduced fatty acid oxidation in CPT1a-silenced cells. Compared to control virus-transduced cells, THP-1 CPT1a knock-down macrophages showed increased activation of pro-inflammatory JNK and p38 MAP kinase signaling cascades after treatment with palmitate, as well as elevated expression of pro-inflammatory cytokines. ER stress responses to palmitate were also enhanced in CPT1a-silenced cells. Pharmacologic inhibition of fatty acid oxidation with etomoxir recapitulated the phenotype of CPT1a knock-down. CPT1a knock-down macrophages also showed increased triglyceride accumulation after palmitate treatment, whereas palmitate-induced ceramide accumulation was not further increased in CPT1a-silenced cells. CPT1a inhibition also enhanced palmitate-induced pro-inflammatory and ER stress responses in primary human macrophages. Taken together, our data indicate that endogenous fatty acid oxidation attenuates inflammation and ER stress in macrophages exposed to saturated fatty acids.