Kandhi Rajani, Menendez Alfredo, Ramanathan Sheela, Ilangumaran Subburaj
Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.
Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.
J Clin Exp Hepatol. 2024 Jan-Feb;14(1):101280. doi: 10.1016/j.jceh.2023.09.001. Epub 2023 Sep 9.
Hepatic stellate cells (HSC) are the key mediators of fibrosis development in non-alcoholic fatty liver disease (NAFLD). Hepatic inflammation induced by high-fat diet activates HSCs, which differentiate to myofibroblasts and produce extracellular fibrillar matrix. HSC activation during hepatic fibrogenesis is modulated by cytokines and growth factors produced by stressed hepatocytes and macrophages. SOCS1 is a negative feedback regulator of certain cytokines and growth factors implicated in liver fibrosis.
The goal of this study was to understand the regulatory functions of SOCS1 in HSCs during NAFLD-induced liver fibrosis.
Mice lacking SOCS1 specifically in HSCs () and control -floxed () mice were fed choline-deficient L-amino acid-defined high-fat diet (CDA-HFD) or normal control diet for 14 weeks. Body weight gain was regularly monitored. Serum alanine aminotransferase levels and liver weight were assessed at the endpoint. Fibrosis development was evaluated by Sirius red staining and hydroxyproline content, and myofibroblast differentiation by immunohistochemistry. Expression of genes encoding pro-fibrogenic factors, cytokines, growth factors and chemokines, and the phenotype and numbers of intrahepatic leukocytes were evaluated.
mice showed increased liver/body weight ratio and displayed increased collagen deposition and myofibroblast differentiation. Induction of , , , and genes was significantly elevated in mice compared to controls fed CDA-HFD. gene induction was comparable between the two groups, however, livers displayed increased SMAD3 phosphorylation. The fibrotic livers of mice showed increased inflammatory cell infiltration, and flow cytometry analysis revealed elevated numbers of myeloid cells, granulocytes and myeloid-derived dendritic cells. livers harbored increased numbers of Ly6CCCR2+ pro-inflammatory macrophages, largely comprised of Ly6CCCR2+CX3CR1+ cells, suggesting impaired transition to anti-inflammatory macrophages.
Our findings show that SOCS1 exerts non-redundant regulatory functions in HSCs that are critical for attenuating high-fat diet-induced inflammatory response and liver fibrosis development.
肝星状细胞（HSC）是非酒精性脂肪性肝病（NAFLD）纤维化发展的关键介质。高脂饮食诱导的肝脏炎症激活HSC，其分化为肌成纤维细胞并产生细胞外纤维状基质。肝纤维化过程中HSC的激活受应激肝细胞和巨噬细胞产生的细胞因子和生长因子调节。SOCS1是与肝纤维化相关的某些细胞因子和生长因子的负反馈调节因子。
本研究的目的是了解SOCS1在NAFLD诱导的肝纤维化过程中对HSC的调节功能。
将HSC中特异性缺失SOCS1的小鼠（ ）和对照floxed小鼠（ ）喂食胆碱缺乏的L-氨基酸定义的高脂饮食（CDA-HFD）或正常对照饮食14周。定期监测体重增加。在实验终点评估血清丙氨酸转氨酶水平和肝脏重量。通过天狼星红染色和羟脯氨酸含量评估纤维化发展，通过免疫组织化学评估肌成纤维细胞分化。评估编码促纤维化因子、细胞因子、生长因子和趋化因子的基因表达，以及肝内白细胞的表型和数量。
小鼠的肝/体重比增加，胶原沉积和肌成纤维细胞分化增加。与喂食CDA-HFD的 对照相比， 小鼠中 、 、 、 和 基因的诱导显著升高。两组之间 基因的诱导相当，然而， 小鼠肝脏中SMAD3磷酸化增加。 小鼠的纤维化肝脏显示炎症细胞浸润增加，流式细胞术分析显示髓样细胞、粒细胞和髓样来源的树突状细胞数量增加。 小鼠肝脏中Ly6C+CCR2+促炎巨噬细胞数量增加，主要由Ly6C+CCR2+CX3CR1+细胞组成，提示向抗炎巨噬细胞的转变受损。
我们的研究结果表明，SOCS1在HSC中发挥非冗余的调节功能，这对于减轻高脂饮食诱导的炎症反应和肝纤维化发展至关重要。
