Kupffer cells suppress perfluorononanoic acid-induced hepatic peroxisome proliferator-activated receptor α expression by releasing cytokines

Kupffer cells (KCs) have been demonstrated to play a role in the regulation of intra-hepatic lipid metabolism through the synthesis and secretion of biologically active products. The involvement of KCs in the disturbance of lipid metabolism that induced by perfluorononanoic acid (PFNA), a known agonist of the peroxisome proliferator-activated receptor alpha (PPAR alpha), was investigated in this study. Rats were exposed to PFNA or PFNA combined with gadolinium chloride, an inhibitor of KCs, for 14 days. PFNA exposure dose-dependently increased absolute and relative liver weights, induced triglyceride accumulation, up-regulated the expression of both SERBP-1c and PPAR alpha, and stimulated the release of TNF alpha and IL-1 beta. Inactivation of KCs markedly lowered TNF alpha and IL-1 beta level, enhanced PFNA-induced expression of PPAR alpha and its target genes, and reduced liver triglyceride levels. In vitro, PFNA-induced expression of PPAR alpha in primary cultured hepatocytes was suppressed by recombinant rat TNF alpha and IL-1 beta. However, inhibition of the NF-kappa B pathway prevented this. Transient transfection and promoter analysis further revealed that these two cytokines and NF-kappa B were coordinately involved in the suppression of PPAR alpha promoter activity. Our data demonstrate that TNF alpha and IL-1 beta released from KCs following PFNA exposure can suppress the expression of PPAR alpha via NF-kappa B pathway, which partially contribute to the evident accumulation of triglycerides in rat liver.