Objectives— During inflammation, the serum amyloid A (SAA) content of HDL increases, whereas apolipoprotein A-I (apoA-I) and paraoxonase-1 (PON-1) decrease. It remains unclear whether SAA physically displaces apoA-I or if these changes derive from coordinated but inverse transcriptional regulation of the HDL apolipoprotein genes. Because cytokines stimulate the hepatic expression of inflammatory markers, we investigated their role in regulating SAA, apoA-I, and PON-1 expression.

Methods and Results— A cytokine mixture (tumor necrosis factor [TNF]-α, interleukin [IL]-1β, and IL-6) simultaneously induced SAA and repressed apoA-I and PON-1 expression levels. These effects were partially inhibited in cells pretreated with either nuclear factor κB (NF-κB) inhibitors (pyrrolidine dithiocarbamate, SN50, and overexpression of super-repressor inhibitor κB) or after exposure to the peroxisome proliferator-activated receptor-α (PPARα) ligands (WY-14643 and fenofibrate). Consistent with these findings, the basal level of SAA was increased, whereas apoA-I and PON-1 decreased in primary hepatocytes from PPARα-deficient mice as compared with wild-type mice. Moreover, neither WY-14643 nor fenofibrate had any effect on SAA, apoA-I, or PON-1 expression in the absence of PPARα.

Conclusion— These results suggest that cytokines increase the expression of SAA through NF-κB transactivation, while simultaneously decreasing the expression of apoA-I and PON-1 by inhibiting PPARα activation. Inflammation may convert HDL de novo into a more proatherogenic form by coordinate but inverse transcriptional regulation in the liver, rather than by physical displacement of apoA-I by SAA.