Hepatic nuclear factor 1-alpha: inflammation, genetics, and atherosclerosis

Increased plasma levels of C-reactive protein (CRP), a hepatic acute phase reactant, predict risk for coronary heart disease. There has been interest in identifying genetic determinants of CRP as a means of better understanding its regulation and its relation to coronary heart disease. We here review recent findings that have linked plasma CRP levels to single nucleotide polymorphisms in hepatic nuclear factor (HNF) 1-alpha, a transcription factor with a wide range of functions, including many involved in cholesterol, bile acid, and lipoprotein metabolism. Two genome-wide association studies have identified single nucleotide polymorphisms in several genes that are strongly related to plasma CRP levels, including several on chromosome 12 in the vicinity of the HNF1A gene. The CRP gene promoter has two HNF1-alpha-binding sites. Recently, it has been demonstrated that HNF1-alpha is required for cytokine-driven CRP expression and that this involves formation of a complex with STAT3 and c-Fos. Based on the recent genetic findings as well as delineation of the role of HNF1-alpha in regulating the expression of the CRP gene, it appears that this transcription factor may play a key role in linking metabolic and inflammatory pathways underlying the pathogenesis of coronary heart disease.