Hepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12

JOURNAL OF HEPATOLOGY

卷:73

Article

Arab, Juan P.^1,2  Cabrera, Daniel^2,3  Sehrawat, Tejasav S.¹  Jalan-Sakrikar, Nidhi¹  Verma, Vikas K.¹  Simonetto, Douglas¹  Cao, Sheng¹  Yaqoob, Usman¹  Leon, Jonathan²  Freire, Mariela²  Vargas, Jose, I²  De Assuncao, Thiago M.¹  Kwon, Jung H.¹  Guo, Yi¹  Kostallari, Enis¹  Cai, Qing⁵  Kisseleva, Tatiana⁴  Oh, Youngman⁵  Arrese, Marco²  Huebert, Robert C.¹  Shah, Vijay H.¹ 

[1] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN 55905 USA

[2] Pontificia Univ Catolica Chile, Dept Gastroenterol, Escuela Med, Santiago, Chile

[3] Univ Bernardo OHiggins, Dept Ciencias Quim & Biol, Santiago, Chile

[4] Univ Calif San Diego, Dept Surg, San Diego, CA 92103 USA

[5] Virginia Commonwealth Univ, Dept Pathol, Med Coll, Virginia Campus, Richmond, VA USA

关键词: Alcohol;    Steatosis;    Steatohepatitis;    Neuropilin-1;    Igfbp3;    Hepatic stellate cell;    Alcoholic liver disease;    Alcoholic hepatitis;    Insulin-like growth factor-binding protein 3;    SerpinA12;    Vaspin;    Src-kinase;    Integrin;   

DOI  :  10.1016/j.jhep.2020.02.005

来源: Elsevier

【 摘 要 】

Background & Aims: Steatohepatitis drives fibrogenesis in alcohol-related liver disease. Recent studies have suggested that hepatic stellate cells (HSCs) may regulate the parenchymal cell injury and inflammation that precedes liver fibrosis, although the mechanism remains incompletely defined. Neuropilin-1 (NRP-1) and synectin are membrane proteins implicated in HSC activation. In this study, we disrupted NRP-1 and synectin as models to evaluate the role of HSC activation on the development of steatohepatitis in response to alcohol feeding in mice. Methods: Mice with HSC-selective deletion of NRP (Col(Cre)/Nrp1(loxP)) or synectin (Col(Cre)/synectin(loxP)) vs. paired Nrp1(loxP) or synectin(loxP) mice were fed a control diet or the chronic/binge alcohol feeding model. Several markers of steatosis and inflammation were evaluated. Results: Col(Cre)/Nrp1(loxP) mice showed less fibrosis, as expected, but also less inflammation and steatosis, with lower hepatic triglyceride content. Similar results were observed in the synectin model. Hepatocytes treated with supernatant of HSCs from Col(Cre)/Nrp1(loxP) mice compared to supernatant from Nrp1(loxP) mice were protected against ethanol-induced lipid droplet formation. An adipokine and inflammatory protein array from the supernatant of HSCs with NRP-1 knockdown showed a significant reduction in Igfbp3 (a major insulin-like growth factor-binding protein with multiple metabolic functions) and an increase in SerpinA12 (a serine-protease inhibitor) secretion compared to wild-type HSCs. Recombinant Igfbp3 induced lipid droplets, triglyceride accumulation, and lipogenic genes in hepatocytes in vitro, while SerpinA12 was protective against ethanol-induced steatosis. Finally, Igfbp3 was increased, and SerpinA12 was decreased in serum and liver tissue from patients with alcoholic hepatitis. Conclusion: Selective deletion of NRP-1 from HSCs attenuates alcohol-induced steatohepatitis through regulation of Igfbp3 and SerpinA12 signaling. Lay summary: Hepatic stellate cells are known for their role in fibrosis (scarring of the liver). In this study, we describe their role in the modulation of fat deposition and inflammation in the liver, which occurs secondary to alcohol damage. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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