Dominant-negative HNF1α mutant promotes liver steatosis and inflammation by regulating hepatic complement factor D

Heterozygous mutations of HNF1A gene are the pathogenic cause of MODY3. A few studies reported that MODY3 patients may have dyslipidemia and early onset of liver steatosis in some cases. However, there is a lack of sufficient and reliable experimental evidence on how HNF1α regulates NAFLD progression under the genetic background of MODY3. We established a novel mouse model carrying the dominant-negative human HNF1α P291fsinsC mutation (termed as hHNF1Amut/- mice). The hepatic morphological phenotypes and the changes of lipid metabolism were investigated. To reveal the molecular changes, we performed the transcriptome and proteome analysis. As the transcriptome and proteome analysis suggested, the expression of complement factor D (CFD), which was reported to promote HFD-induced hepatic steatosis and inflammation, was significantly upregulated. Comparative gene expression profiling analysis of RNA-seq data for hHNF1A-/- and hHNF1Amut/- mice liver (3 Control vs 4 KI).