Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis
Open accessAbstract
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.
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Inhibiting hedgehog signaling can attenuate HSC activation and MASH fibrosis.
“Inhibiting hedgehog signaling can attenuate HSC activation and MASH fibrosis (112, 113).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [113]
Other major sources of hedgehog ligands may be reactive-appearing ductular cells that correlate with fibrosis in MASH patients, or MASH-associated hepatocytes in which increased cholesterol activates TAZ to drive Indian hedgehog expression and secretion.
“Other major sources of hedgehog ligands may be reactive-appearing ductular cells that strongly correlate with fibrosis in patients with MASH or in MASH-associated hepatocytes where increased cholesterol intake activate TAZ to drive Indian hedgehog expression and secretion (112, 113, 163).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [113]
Increased cholesterol promotes MASH fibrosis through the TAZ/Indian hedgehog pathway.
“Increased cholesterol in turn promotes MASH fibrosis through the TAZ/Indian hedgehog pathway described above (232-234).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [234]
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Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease
Wiering, L., Subramanian, P., & Hammerich, L. (2023) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2023.02.010 · Cited by 80 · see citing works
The Origin and Fate of Liver Myofibroblasts
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The interplay between nonalcoholic fatty liver disease and atherosclerotic cardiovascular disease
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- Authors
- 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.
- Affiliations
- Columbia University Irving Medical Center (US)
- Ningxia Medical University (CN)
- Weill Cornell Medicine (US)
- University of Milan (IT)
- University of California, Los Angeles (US)
- The University of Texas Southwestern Medical Center (US)
- Washington University in St. Louis (US)
- University of California San Diego (US)
- Corresponding author
- Wang, Xiaobo
- Tabas, Ira
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 31
- Issue
- 5
- Pages
- 969-986.e7
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC7313619
- OpenAlex
- W3015115032
- Cited by
- 204
- References
- 75
- Citations by year
- 2026: 24 · 2025: 37 · 2024: 31 · 2023: 34 · 2022: 35 · 2021: 29 · 2020: 13
- FWCI
- 19.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- American Society of Hematology (19CDA34660043)
- University of Pittsburgh
- Welch Foundation (DE015964, DK103818, I-1793, HL067773, HL087123, R35CA196878, HL136618, AG061290, HD088571, HL132412, DK119767)
- University of Minnesota
- American Heart Association
- European Commission
- National Institutes of Health (DK116620, HHSN276201200017C)
- Associazione Italiana per la Ricerca sul Cancro (16888)
- National Cancer Institute (P30 CA013696)
- National Heart, Lung, and Blood Institute (T32HL007343)
- American Liver Foundation (1K99DK115778, XAB2018AW09)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- nonalcoholic steatohepatitis, cholesterol, TAZ, liver fibrosis, soluble adenylyl cyclase, RhoA, calcium signaling, β-TrCP, proteasomal degradation, hepatic steatosis
- MeSH terms
- Transcriptional Coactivator with PDZ-Binding Motif Proteins, Animals, Cells, Cultured, Cholesterol, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Hepatocytes, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, Non-alcoholic Fatty Liver Disease
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