Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis

Xiaobo Wang, Bishuang Cai, Xiaoming Yang, Oluwatoni O. Sonubi, Ze Zheng, Rajasekhar Ramakrishnan, Hongxue Shi, Luca Valenti, Utpal B. Pajvani, Jaspreet Sandhu, Rodney E. Infante, Arun Radhakrishnan, Douglas F. Covey, Kun Liang Guan, Jochen Buck, Lonny R. Levin, Peter Tontonoz, Robert F. Schwabe, Ira Tabas

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)969-986.e7
JournalCell Metabolism
Volume31
Issue number5
DOIs
Publication statusPublished - May 5 2020

Keywords

  • ADCY10
  • cholesterol
  • Gramd1/ASTER
  • Hippo
  • liver fibrosis
  • NASH
  • RhoA
  • sAC
  • TAZ
  • WWTR1

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Wang, X., Cai, B., Yang, X., Sonubi, O. O., Zheng, Z., Ramakrishnan, R., Shi, H., Valenti, L., Pajvani, U. B., Sandhu, J., Infante, R. E., Radhakrishnan, A., Covey, D. F., Guan, K. L., Buck, J., Levin, L. R., Tontonoz, P., Schwabe, R. F., & Tabas, I. (2020). Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis. Cell Metabolism, 31(5), 969-986.e7. https://doi.org/10.1016/j.cmet.2020.03.010