Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis
Open accessAbstract
Nonalcoholic steatohepatitis (NASH) is a leading cause of liver disease worldwide. However, the molecular basis of how benign steatosis progresses to NASH is incompletely understood, which has limited the identification of therapeutic targets. Here we show that the transcription regulator TAZ (WWTR1) is markedly higher in hepatocytes in human and murine NASH liver than in normal or steatotic liver. Most importantly, silencing of hepatocyte TAZ in murine models of NASH prevented or reversed hepatic inflammation, hepatocyte death, and fibrosis, but not steatosis. Moreover, hepatocyte-targeted expression of TAZ in a model of steatosis promoted NASH features, including fibrosis. In vitro and in vivo mechanistic studies revealed that a key mechanism linking hepatocyte TAZ to NASH fibrosis is TAZ/TEA domain (TEAD)-mediated induction of Indian hedgehog (Ihh), a secretory factor that activates fibrogenic genes in hepatic stellate cells. In summary, TAZ represents a previously unrecognized factor that contributes to the critical process of steatosis-to-NASH progression.
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TAZ protein has been upregulated in human MASLD and controlled the secretion of IHH.
“TAZ protein has been upregulated in human MASLD and controlled the secretion of IHH [63]; Ihh gene was differentially regulated in the transcriptome analysis.”
From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [63]
The Results section ('TAZ Levels are Increased in the Livers of Humans and Mice with NASH'; page unavailable) reports higher TAZ protein in human NASH liver, but similar staining in normal and steatotic livers. The Results section on Indian hedgehog (page unavailable) shows that TAZ silencing reduced Ihh in mouse hepatocyte culture medium. Thus the source supports TAZ upregulation in the NASH subset and TAZ-dependent Ihh secretion in a mouse cell model, not the broader claim of upregulation across human MASLD or direct evidence of secretion control in humans. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe FPC NASH diet induces moderate liver fibrosis as well as insulin resistance.
“Mice fed the fructose, palmitate and cholesterol-rich (FPC) NASH diet for 16 weeks, which induces moderate liver fibrosis as well as insulin resistance 30 , had increased frequencies and overall number of liver Treg cells as compared to animals fed normal chow (Fig. 1B-1C).”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [30]
The Results report increased liver fibrosis, fasting glucose, and plasma insulin in FPC-fed mice after 16 weeks compared with chow-fed mice; the Discussion describes the model as developing fibrosis alongside insulin resistance. The paper does not characterize the fibrosis at 16 weeks as moderate, so that degree is not established by our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredLiver Treg cells were not enriched at an earlier timepoint (8 weeks) on the FPC diet when liver steatosis is evident but NASH has yet to develop.
“Additionally, liver Treg cells were not enriched at an earlier timepoint (8 weeks) on the FPC diet when liver steatosis is evident but NASH has yet to develop 30 (Fig. S1D-S1G).”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [30]
At 8 weeks on FPC diet, liver steatosis is evident but prior to development of NASH.
“when liver steatosis is evident but prior to the development of NASH 30”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [30]
Cholesterol and other mediators contribute to changes in transcriptional programmes in steatotic hepatocytes, leading to upregulation of developmental pathways such as Notch and TAZ, which can directly activate pro-fibrotic cell-cell communication between hepatocytes and neighbouring cells.
“In parallel, cholesterol and other mediators contribute to changes in the transcriptional programmes in steatotic hepatocytes, leading to an upregulation of developmental pathways that are often seen in bipotential progenitor cells or ductular cells, such as Notch and TAZ, which can directly activate pro-fibrotic cell-cell communication between hepatocytes and neighbouring cells.[28], [29], [30]”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [30]
Hedgehog pathway activation is triggered by injured, ballooned and/or TAZ-expressing hepatocytes in NASH via the release of sonic hedgehog or Indian hedgehog.
“Hedgehog pathway activation is triggered by injured, ballooned and/or TAZ-expressing hepatocytes in NASH via the release of sonic hedgehog or Indian hedgehog.30,38”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [30]
Activation of Notch in steatotic hepatocytes contributes to the secretion of osteopontin, which in turn contributes to HSC activation.
“Likewise, activation of Notch in steatotic hepatocytes contributes to the secretion of osteopontin, which in turn contributes to HSC activation.30”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [30]
TAZ is specifically expressed in NASH hepatocytes and directly or indirectly activates HSCs.
“Other signalling pathways that directly or indirectly activate HSCs include: TAZ, which is specifically expressed in NASH hepatocytes;128”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [128]
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 [112]
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 [112]
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- Authors
- Wang, X., Zheng, Z., Caviglia, J. M., Corey, K. E., Herfel, T. M., Cai, B., Masia, R., Chung, R. T., Lefkowitch, J. H., Schwabe, R. F., & Tabas, I.
- Affiliations
- Columbia University Irving Medical Center (US)
- Columbia University (US)
- Harvard University (US)
- Envigo (United States) (US)
- Corresponding author
- Wang, Xiaobo
- Tabas, Ira
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 24
- Issue
- 6
- Pages
- 848-862
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5226184
- OpenAlex
- W2541359632
- Cited by
- 413
- References
- 60
- Citations by year
- 2026: 28 · 2025: 44 · 2024: 62 · 2023: 48 · 2022: 66 · 2021: 55 · 2020: 47 · 2019: 29 · 2018: 24 · 2017: 5 · 2016: 2
- FWCI
- 18.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (HL087123, HL075662, DK078772, DK99422, R03DK101863)
- AASLD Foundation
- American Heart Association (UL1 TR000040)
- 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, hepatocytes, liver fibrosis, liver inflammation, Indian hedgehog, TEAD transcription factors, hepatic stellate cells, hepatocyte death, transcriptional regulation
- MeSH terms
- Transcriptional Coactivator with PDZ-Binding Motif Proteins, Animals, Base Sequence, Diet, Disease Models, Animal, Humans, Inflammation, Liver, Liver Cirrhosis, Male, Mice, Inbred C57BL, Transcription Factors, Trans-Activators, Cell Death, Disease Progression, Gene Silencing, Hepatocytes, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Hedgehog Proteins, Hepatic Stellate Cells, Non-alcoholic Fatty Liver Disease
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