# YAP signaling in the pathogenesis of NAFLD in people living with HIV

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $780,234

## Abstract

Project Summary/Abstract
Since the introduction of effective combination antiretroviral therapy (cART), HIV infection has been converted
from a fatal disease into a chronic condition. Liver disease has emerged as the second leading cause of non-
AIDS related death in persons living with HIV (PLWH). Nonalcoholic fatty liver disease (NAFLD) is the leading
form of chronic liver disease in the U.S., afflicting approximately 30% of adults. PLWH have a high prevalence
of NAFLD with rates as high as 53%, associated with not only higher frequency of the inflammatory non-alcoholic
steatohepatitis (NASH) but also accelerated liver fibrosis progression. Moreover, in NAFLD/HIV, there is a
disproportionate burden of progressive NASH and fibrosis compared with HIV(-) NAFLD. While recent studies
have replicated the accelerated fibrosis progression seen in PLWH/NAFLD, the precise mechanisms remain
poorly defined. We and others have led the field in demonstrating that HIV itself induces a profibrogenic program
in the liver via several pathways. The Hippo signaling pathway controls cell proliferation and fibrogenesis through
YAP transcriptional co-activators that regulate more than 400 genes through binding to TEAD, SMAD1/2/3 and
other sites. Our recent work has shown increases in YAP-related gene expression among NAFLD patients with
fibrosis and in mouse NASH models. We also observed a significant reduction in fibrosis-related parameters in
hepatocyte-specific YAP knockout mice fed a NASH diet. We have also shown that HIV induces YAP activation
in hepatocytes and macrophages via the LPA/PI3K and AKT pathways. Therefore, HIV and NAFLD likely
cooperate at the level of YAP activation to contribute to fibrogenesis and liver damage. Hepatic and monocyte-
derived macrophages, dysregulated by HIV infection and polarized during liver injury, are likely to contribute to
NAFLD and HIV-related liver disease. Studies have observed increased macrophage content in the livers of
PLWH and others have linked YAP activation to macrophage infiltration. However, comprehensive studies of the
in vitro and in vivo effects of YAP activation among the key cell types (hepatocytes, macrophages, and HSCs)
that drive fibrogenesis in PLWH are lacking. We hypothesize that HIV and NAFLD exert independent and additive
effects on YAP activation in both macrophage and hepatocyte populations that in turn accelerate hepatic fibrosis
progression through their action on HSCs. In this proposal, using novel coculture assays, ex vivo liver tissue,
and a humanized mouse model and combining the efforts of liver pathogenesis and HIV virology/pathogenesis
experts, we will: (1) define the contribution of YAP signaling to macrophage polarization, hepatocyte and hepatic
stellate cell (HSC) activation in HIV/NAFLD.; (2) assess the effect of cART regimens on macrophage, hepatocyte
and HSC phenotypes and YAP activation in models of HIV/NAFLD.; and (3) determine the effects of YAP
inhibition on fibrogenesis in HIV/...

## Key facts

- **NIH application ID:** 10931742
- **Project number:** 5R01DK138474-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** RAYMOND T CHUNG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $780,234
- **Award type:** 5
- **Project period:** 2023-09-26 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931742

## Citation

> US National Institutes of Health, RePORTER application 10931742, YAP signaling in the pathogenesis of NAFLD in people living with HIV (5R01DK138474-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10931742. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*