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.
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DOI：
10.1016/j.isci.2023.108018
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发表时间：
2023-10-20
期刊：
影响因子：
5.8
通讯作者：
Lu, Peng
中科院分区：
文献类型：
--
作者：
Liu, Moke;Liu, Luna;Guo, Honglin;Fan, Xiude;Liu, Tianbao;Xu, Chao;He, Zhao;Song, Yongfeng;Gao, Ling;Shao, Shanshan;Zhao, Jiajun;Lu, Peng
携带HNF 1A变异体的患者可能会发生肝脏脂肪变性，但其潜在机制尚不清楚。我们建立了显性阴性HNF 1 α P291 fsinsC突变（hHNF 1Amut/-）小鼠模型，发现突变小鼠在正常饮食条件下自发发生肝脏脂肪变性。转录组分析显示，在hHNF 1Amut/-小鼠的肝脏中，Cfd和其他与先天免疫应答相关的基因显著上调。脂质代谢和补体途径的变化也被蛋白质组学证实。我们证明HNF 1 α抑制肝细胞中CFD的表达，并且P291 fsinsC突变体可以逆转这种抑制作用。此外，用特异性抑制剂或siRNA抑制CFD降低了肝细胞中的甘油三酯水平，表明CFD调节肝细胞脂质沉积。我们的研究结果表明，HNF 1 α P291 fsinsC突变体通过上调CFD表达促进肝脏脂肪变性和炎症，靶向CFD可能延缓非酒精性脂肪性肝病的进展。携带HNF 1 α P291 fsinsC突变的小鼠表现出肝脂肪变性和炎症HNF 1 α对肝细胞中的补体因子D发挥负调节作用CFD的抑制减轻肝细胞中的细胞内甘油酯积累分子生理学;分子生物学;转录组学
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. Mice harboring HNF1α P291fsinsC mutation manifest hepatic steatosis and inflammation HNF1α exerts negative regulation on Complement Factor D in hepatocytes Inhibition of CFD mitigates intracellular glyceride accumulation in hepatocytes Molecular physiology; Molecular biology; Transcriptomics
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影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
Sanyal AJ
影响因子：
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Fred, Rikard G.;Pedersen, Julie Steen;Thompson, Jonatan J.;Lee, Julie;Timshel, Pascal N.;Stender, Stefan;Rygg, Marte Opseth;Gluud, Lise Lotte;Kristiansen, Viggo Bjerregaard;Bendtsen, Flemming;Hansen, Torben;Pers, Tune H.
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Pers, Tune H.
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通讯作者：
Balabaud, Charles
影响因子：
4.5
作者：
Haddouche, Aini;Bellanne-Chantelot, Christine;Reznik, Yves
通讯作者：
Reznik, Yves