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.
