Hepatocyte nuclear factor 4α is a critical factor for the production of complement components in the liver

The complement system plays an important role in biological defense as an effector to eliminate microorganisms that invade an organism and it is composed of more than 50 proteins, most of which are produced in the liver. Of these proteins, the mRNA expression of C3 and Cfb is known to be positively regulated by the nuclear receptor HNF4α. To investigate whether HNF4α regulates the complement system, we analyzed the hepatic expression of genes involved in the complement activation pathway and membrane attack complex (MAC) formation within the complement system using liver-specific Hnf4a-null mice (Hnf4a^ΔHep mice) and tamoxifen-induced liver-specific Hnf4a-null mice (Hnf4a^{f/f;AlbERT2cre} mice). We found that hepatic expression of many complement genes including C8a, C8b, C8g, and C9 that are involved in formation of the MAC was markedly decreased in Hnf4a^ΔHep mice and Hnf4a^{f/f;AlbERT2cre} mice. Furthermore, expression of C8A, C8B, and C8G was also decreased in human hepatoma cell lines in which the expression of HNF4α was suppressed, and expression of C8G and C9 was induced in a human immortalized hepatocyte cell line with forced expression of HNF4α. Transactivation of C8g and C9 was dependent on HNF4α expression of HNF4α binding sites, indicating that C8g and C9 are novel target genes of HNF4α. The results suggest that hepatic HNF4α plays an important role in regulation of the complement system, mainly MAC formation.