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

Patients with HNF1A variants may develop liver steatosis, while the underlying mechanism is still unclear. Here, we established a mouse model carrying the dominant-negative HNF1α P291fsinsC mutation (hHNF1A^mut/-) and found that the mutant mice developed liver steatosis spontaneously under the normal chow diet. Transcriptome analysis showed significant upregulation of Cfd and other genes related to innate immune response in the liver of hHNF1A^mut/- mice. The changes in lipid metabolism and complement pathways were also confirmed by proteomics. We demonstrated that HNF1α inhibited CFD expression in hepatocytes, and the P291fsinsC mutant could reverse this inhibitory effect. Furthermore, the suppression of CFD with specific inhibitor or siRNAs reduced triglyceride levels in hepatocytes, suggesting that CFD regulated hepatocyte lipid deposition. Our results demonstrate that the HNF1α P291fsinsC mutant promotes hepatic steatosis and inflammation by upregulating CFD expression, and targeting CFD may delay the progression of nonalcoholic fatty liver disease.