on May 18, 2006
Published online before print May 18, 2006, doi: 10.1161/01.ATV.0000227472.70734.ad
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Submitted on December 23, 2005
Accepted on May 5, 2006
Reciprocal and Coordinate Regulation of Serum Amyloid A Versus Apolipoprotein A-I and Paraoxonase-1 by Inflammation in Murine Hepatocytes
Chang Yeop Han ;
From the Departments of Medicine (C.Y.H., T.C., A.C.) and Pathology (J.S.C., N.F., M.C.), University of Washington, Seattle; and the Cardiovascular Division (G.O., J.P.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
* To whom correspondence should be addressed. E-mail: achait{at}u.washington.edu.
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]-
, interleukin [IL]-1
, 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 
B (NF-B) inhibitors (pyrrolidine dithiocarbamate, SN50, and overexpression of super-repressor IB) or after exposure to the peroxisome proliferator-activated receptor- (PPAR) 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 PPAR-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 PPAR.
Conclusion--These results suggest that cytokines increase the expression of SAA through NF-B transactivation, while simultaneously decreasing the expression of apoA-I and PON-1 by inhibiting PPAR 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.
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