2. Academic Validation
  3. Dominant-negative HNF1α mutant promotes liver steatosis and inflammation by regulating hepatic complement factor D

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

  • iScience. 2023 Sep 22;26(10):108018. doi: 10.1016/j.isci.2023.108018.
Moke Liu 1 2 3 4 5,  Luna Liu 2 3 4 5,  Honglin Guo 2,  Xiude Fan 2 3 4 5,  Tianbao Liu 2 3 4 5,  Chao Xu 2 3 4 5,  Zhao He 2 3 4 5,  Yongfeng Song 2 3 4 5,  Ling Gao 2 3 4 5,  Shanshan Shao 2 3 4 5,  Jiajun Zhao 2 3 4 5,  Peng Lu 1 2 3 4 2
Affiliations

Affiliations

  • 1 Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan 250021, China.
  • 2 Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
  • 3 Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 250021, China.
  • 4 Shandong Institute of Endocrine and Metabolic Diseases, Jinan 250021, China.
  • 5 Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan 250021, China.
PMID: 37841581 DOI: 10.1016/j.isci.2023.108018
Abstract

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 (hHNF1Amut/-) 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 hHNF1Amut/- 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.

Keywords

Molecular biology; Molecular physiology; Transcriptomics.

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