Hepatocyte nuclear factor 1α controls the expression of terminal complement genes

The terminal components of the complement system contribute to host defense by forming the multiprotein membrane attack complex (MAC) which is responsible for cell lysis and several noncytotoxic effects. Most of the complement proteins are synthesized in the liver, but the mechanisms controlling their tissue-specific expression have not been elucidated. In this study we show that mice lacking the hepatic transcription factor hepatocyte nuclear factor la (HNF1 alpha) fail to transcribe C5 and C8A complement genes. In addition, mRNAs encoding for several other terminal complement components or subunits are expressed at lower levels, including C8 beta, C8 gamma, and C9. We next used a reconstitution assay involving human sera with selective complement deficiencies to assess mouse complement activity. Sera from HNF1 alpha -deficient mice showed negligible hemolytic activity of both C5 and C8 alpha-gamma subunits. The activity of C8 beta was severely affected despite only a 50% reduction in C8 beta mRNA levels in the liver. This is reminiscent of C8 alpha-gamma -deficient patients who accumulate extremely low levels of the C8 beta subunit. Our results demonstrate that HNF1 alpha plays a key role in the expression of C5 and CSA genes, two terminal complement component genes that are essential for the assembly of MAC as a result of complement activation.