# TAZ and YAP in Non-Alcoholic Steatohepatitis and its Complications

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $664,138

## Abstract

Non-alcoholic steatohepatitis (NASH) is the leading cause of chronic liver disease worldwide. The
pathophysiology that underlies the progression from bland steatosis to NASH, fibrosis, and hepatocellular
carcinoma (HCC) remains largely unknown, and there are currently no FDA-approved drugs to treat NASH.
The two PIs have recently published that hepatocytes (HCs) in human and mouse NASH liver have elevated
levels of the transcription factor TAZ and that silencing HC TAZ suppresses steatosis-to-NASH fibrosis
progression. We have since shown that the closely related protein YAP is also elevated in NASH and that HC
YAP, surprisingly, suppresses steatosis, NASH, and fibrosis. We have also shown that HC cholesterol
accumulation, a key feature of human NASH, increases HC TAZ/YAP by blocking their proteasomal
degradation. Finally, we found high levels of TAZ/YAP in NASH-induced HCC, and our pilot studies show that
HC-TAZ silencing prevents NASH-to-HCC progression. The objective of this proposal is to explore the
hypothesis that cholesterol-induced elevations in HC TAZ and YAP modulate the progression to NASH,
fibrosis, and HCC and that TAZ may represent a therapeutic target for all disease stages. Aim 1
explores the mechanisms and consequences of how HC YAP suppresses steatosis. We will test the
hypothesis that HC YAP (a) represses genes involved in de novo lipogenesis and triglyceride synthesis, in part
via HC YAP-mediated decrease in PPAR and (b) induces genes involved in fatty acid oxidation. We will then
test the hypothesis that blocking HC YAP promotes NASH fibrosis via its pro-steatotic actions and possibly by
increasing HC TAZ. We will also test whether forced expression of HC-YAP in early fatty liver disease can
prevent steatosis and the progression to NASH. Aim 2 investigates the mechanism of up-regulation of HC TAZ
and YAP in NASH. We propose that proteasomal degradation of TAZ/YAP mediated by the E3 ligase TrCP is
inhibited in NASH and the mechanism involves cholesterol accumulation in HCs. We hypothesize that
elevation of HC membrane cholesterol alters cell signaling to block the phosphorylation of sites on TAZ and
YAP required for TrCP recognition or directly inhibit TrCP itself. Aim 3 explores the role of the cholesterol-
TAZ/YAP pathway in NASH-induced HCC. We hypothesize that cholesterol-induced TAZ accumulation – both
via cholesterol uptake and HMG-CoA reductase-mediated pathways - promotes the development of HCC in
advanced NASH. We will first test if the progression from NASH to HCC can be prevented by genetic targeting
of HC TAZ, as suggested by pilot data, HC YAP, and HC TAZ + YAP. We will then test the hypotheses that (a)
cholesterol-induced HC-TAZ accelerates the NASH-fibrosis-HCC sequence; (b) cholesterol-induced TAZ and
YAP also drive malignant transformation in tumor-initiating HC via cell-autonomous mechanisms; and (c)
statins inhibit TAZ/YAP and NASH-induced HCC. Successful completion of these aims will provide critical new
...

## Key facts

- **NIH application ID:** 9838744
- **Project number:** 5R01DK116620-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Robert F. Schwabe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $664,138
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838744

## Citation

> US National Institutes of Health, RePORTER application 9838744, TAZ and YAP in Non-Alcoholic Steatohepatitis and its Complications (5R01DK116620-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838744. Licensed CC0.

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