Reciprocal and coordinate regulation of serum amyloid A versus apolipoprotein A-I and paraoxonase-1 by inflammation in murine hepatocytes.
OBJECTIVE
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.


RESULTS
A cytokine mixture (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, 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 kappaB (NF-kappaB) inhibitors (pyrrolidine dithiocarbamate, SN50, and overexpression of super-repressor inhibitor kappaB) or after exposure to the peroxisome proliferator-activated receptor-alpha (PPARalpha) 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 PPARalpha-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 PPARalpha.


CONCLUSIONS
These results suggest that cytokines increase the expression of SAA through NF-kappaB transactivation, while simultaneously decreasing the expression of apoA-I and PON-1 by inhibiting PPARalpha 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.
Han
Chang Yeop
CY
Department of Medicine, University of Washington, Seattle, WA 98195-6426, USA.
Chiba
Tsuyoshi
T
Campbell
Jean S
JS
Fausto
Nelson
N
Chaisson
Michelle
M
Orasanu
Gabriela
G
Plutzky
Jorge
J
Chait
Alan
A
D000818:Animals; D016632:Apolipoprotein A-I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D043303:Aryldialkylphosphatase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D047493:PPAR alpha / Q000819:agonists / Q000037:antagonists & inhibitors; D010455:Peptides / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000378:metabolism*; D013859:Thiocarbamates / Q000494:pharmacology
D016632:Apolipoprotein A-I; D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; D047493:PPAR alpha; D010455:Peptides; D012333:RNA, Messenger; C118258:SN50 peptide; D000685:Serum Amyloid A Protein; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D011392:Proline; D043303:Aryldialkylphosphatase