Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis.,Cell Metabolism

当前位置： X-MOL 学术 › Cell Metab. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis.
Cell Metabolism ( IF 27.7 ) Pub Date : 2020-04-06 , DOI: 10.1016/j.cmet.2020.03.010
Xiaobo Wang ₁ , Bishuang Cai ₁ , Xiaoming Yang ₂ , Oluwatoni O Sonubi ₃ , Ze Zheng ₁ , Rajasekhar Ramakrishnan ₄ , Hongxue Shi ₁ , Luca Valenti ₅ , Utpal B Pajvani ₁ , Jaspreet Sandhu ₆ , Rodney E Infante ₇ , Arun Radhakrishnan ₇ , Douglas F Covey ₈ , Kun-Liang Guan ₉ , Jochen Buck ₃ , Lonny R Levin ₃ , Peter Tontonoz ₆ , Robert F Schwabe ₁₀ , Ira Tabas ₁₁

Affiliation

Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
Department of Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia 750004, PRC.
Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA.
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano 20122, Italy; Translational Medicine - Transfusion Medicine and Hematology, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano 20122, Italy.
Department of Pathology and Laboratory Medicine, Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90272, USA.
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Developmental Biology and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Institute of Human Nutrition, Columbia University, New York, NY 10032, USA.
Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA.

Incomplete understanding of how hepatosteatosis transitions to fibrotic non-alcoholic steatohepatitis (NASH) has limited therapeutic options. Two molecules that are elevated in hepatocytes in human NASH liver are cholesterol, whose mechanistic link to NASH remains incompletely understood, and TAZ, a transcriptional regulator that promotes fibrosis but whose mechanism of increase in NASH is unknown. We now show that increased hepatocyte cholesterol upregulates TAZ and promotes fibrotic NASH. ASTER-B/C-mediated internalization of plasma membrane cholesterol activates soluble adenylyl cyclase (sAC; ADCY10), triggering a calcium-RhoA-mediated pathway that suppresses β-TrCP/proteasome-mediated TAZ degradation. In mice fed with a cholesterol-rich NASH-inducing diet, hepatocyte-specific silencing of ASTER-B/C, sAC, or RhoA decreased TAZ and ameliorated fibrotic NASH. The cholesterol-TAZ pathway is present in primary human hepatocytes, and associations among liver cholesterol, TAZ, and RhoA in human NASH liver are consistent with the pathway. Thus, hepatocyte cholesterol contributes to fibrotic NASH by increasing TAZ, suggesting new targets for therapeutic intervention.

中文翻译：

胆固醇稳定肝细胞中的 TAZ 以促进实验性非酒精性脂肪性肝炎。

对肝脂肪变性如何转变为纤维化非酒精性脂肪性肝炎 (NASH) 的不完全了解限制了治疗选择。在人类 NASH 肝脏的肝细胞中升高的两种分子是胆固醇，其与 NASH 的机制联系仍不完全清楚，以及 TAZ，一种促进纤维化的转录调节因子，但其增加 NASH 的机制尚不清楚。我们现在表明，增加的肝细胞胆固醇上调 TAZ 并促进纤维化 NASH。ASTER-B/C 介导的质膜胆固醇内化激活可溶性腺苷酸环化酶 (sAC; ADCY10)，触发钙-RhoA 介导的通路，抑制 β-TrCP/蛋白酶体介导的 TAZ 降解。在喂食富含胆固醇的 NASH 诱导饮食的小鼠中，ASTER-B/C、sAC、或 RhoA 降低 TAZ 并改善纤维化 NASH。胆固醇-TAZ 通路存在于人原代肝细胞中，人 NASH 肝脏中的肝胆固醇、TAZ 和 RhoA 之间的关联与该通路一致。因此，肝细胞胆固醇通过增加 TAZ 促进纤维化 NASH，为治疗干预提供了新的靶点。

更新日期：2020-04-06

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11