دورية أكاديمية
Rho-associated protein kinase 1 inhibition in hepatocytes attenuates nonalcoholic steatohepatitis.
| العنوان: | Rho-associated protein kinase 1 inhibition in hepatocytes attenuates nonalcoholic steatohepatitis. |
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| المؤلفون: | Dohnalkova E; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.; Department of Biological and Medical Sciences, Charles University, Hradec Kralove, Czech Republic., Bayer RL; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Guo Q; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Bamidele AO; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Kim Lee HS; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Valenzuela-Pérez L; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Krishnan A; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Pavelko KD; Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA., Guisot NES; Redx Pharma Plc, Alderley Park, Macclesfield, UK., Bunyard P; Redx Pharma Plc, Alderley Park, Macclesfield, UK., Kim YB; Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA., Ibrahim SH; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.; Division of Pediatric Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Gores GJ; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Hirsova P; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA. |
| المصدر: | Hepatology communications [Hepatol Commun] 2023 Jun 02; Vol. 7 (6). Date of Electronic Publication: 2023 Jun 02 (Print Publication: 2023). |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wolters Kluwer Health, Inc Country of Publication: United States NLM ID: 101695860 Publication Model: eCollection Cited Medium: Internet ISSN: 2471-254X (Electronic) Linking ISSN: 2471254X NLM ISO Abbreviation: Hepatol Commun Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2023- : [Philadelphia] : Wolters Kluwer Health, Inc. Original Publication: [Hoboken, NJ] : Wiley Periodicals, Inc. on behalf of the American Association for the Study of Liver Diseases, [2017]- |
| مواضيع طبية MeSH: | Non-alcoholic Fatty Liver Disease*/drug therapy , Non-alcoholic Fatty Liver Disease*/enzymology , rho-Associated Kinases*/antagonists & inhibitors , rho-Associated Kinases*/genetics, Animals ; Humans ; Mice ; Diet, High-Fat/adverse effects ; Fibrosis ; Hepatocytes/metabolism ; Inflammation/drug therapy ; Mice, Knockout |
| مستخلص: | Background: NASH is the progressive form of NAFLD characterized by lipotoxicity, hepatocyte injury, tissue inflammation, and fibrosis. Previously, Rho-associated protein kinase (ROCK) 1 has been implicated in lipotoxic signaling in hepatocytes in vitro and high-fat diet-induced lipogenesis in vivo. However, whether ROCK1 plays a role in liver inflammation and fibrosis during NASH is unclear. Here, we hypothesized that pathogenic activation of ROCK1 promotes murine NASH pathogenesis. Methods and Results: Patients with NASH had increased hepatic ROCK1 expression compared with patients with fatty liver. Similarly, hepatic ROCK1 levels and activity were increased in mice with NASH induced by a western-like diet that is high in fat, fructose, and cholesterol (FFC). Hepatocyte-specific ROCK1 knockout mice on the FFC diet displayed a decrease in liver steatosis, hepatic cell death, liver inflammation, and fibrosis compared with littermate FFC-fed controls. Mechanistically, these effects were associated with a significant attenuation of myeloid cell recruitment. Interestingly, myeloid cell-specific ROCK1 deletion did not affect NASH development in FFC-fed mice. To explore the therapeutic opportunities, mice with established NASH received ROCKi, a novel small molecule kinase inhibitor of ROCK1/2, which preferentially accumulates in liver tissue. ROCK inhibitor treatment ameliorated insulin resistance and decreased liver injury, inflammation, and fibrosis. Conclusions: Genetic or pharmacologic inhibition of ROCK1 activity attenuates murine NASH, suggesting that ROCK1 may be a therapeutic target for treating human NASH. (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.) |
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| معلومات مُعتمدة: | K01 DK124358 United States DK NIDDK NIH HHS; R01 DK122948 United States DK NIDDK NIH HHS; R01 DK130884 United States DK NIDDK NIH HHS; R01 DK129946 United States DK NIDDK NIH HHS; P30 DK084567 United States DK NIDDK NIH HHS; R01 DK124182 United States DK NIDDK NIH HHS |
| المشرفين على المادة: | EC 2.7.11.1 (rho-Associated Kinases) EC 2.7.11.1 (ROCK1 protein, human) |
| تواريخ الأحداث: | Date Created: 20230602 Date Completed: 20230616 Latest Revision: 20230706 |
| رمز التحديث: | 20230706 |
| مُعرف محوري في PubMed: | PMC10241501 |
| DOI: | 10.1097/HC9.0000000000000171 |
| PMID: | 37267252 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2471-254X |
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| DOI: | 10.1097/HC9.0000000000000171 |