# A lipid signaling network through stearoyl Co-A desaturase regulates hepatocellular carcinogenesis through YAP/TAZ activity

> **NIH VA IK2** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2024 · —

## Abstract

Nonalcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is the fastest growing
cause of HCC and predicted to become the leading indication for liver transplantation. As liver transplantation
remains a scarce resource, chemoprevention and early treatment are imperative. NAFLD patients represent a
distinct high-risk population due to the challenges of HCC screening related to obesity, potential absence of
elevated tumor markers, and the observation that 20-30% of cases occur in the absence of cirrhosis, who are
not targeted for screening. Given that early detection is key in improved survival and receipt of curative treatment,
understanding the mechanisms leading to NAFLD-related HCC have important clinical consequences. Although
lipophilic statins have been associated with decreased HCC incidence, their chemo-preventative mechanism(s)
remains elusive. Over the years, the YAP/TAZ cascade emerged as an important signal transduction pathway
in the pathogenesis of HCC, and has been shown to be modulated by changes in intracellular lipids. Stearoyl-
CoA desaturate (SCD), the rate limiting enzyme of monounsaturated fatty acids (MUFAs), is a key enzyme in
the Hippo pathway that links YAP/TAZ to sterol regulatory element binding protein 1 (SREBP1) and mTORC1 in
hepatocarcinogenesis. Using human liver bulk RNA sequencing studies of a prospective cohort of NAFLD/NASH
patients undergoing bariatric surgery, we discovered a novel regulatory role of SCD by a long non-coding
enhancer RNA. After characterizing the intracellular lipid pool with an SCD inhibitor, we next investigated the
role of SCD on the YAP/TAZ pathway using an in vitro cell culture model and demonstrate SCD-dependent
decrease on YAP protein and its target genes. Our preliminary data led us to hypothesize that SCD and
monounsaturated to saturated fatty acid ratios regulate and are a point of convergence in the YAP/TAZ,
mTORC1 and mevalonic acid pathways. In this proposal, we aim to delineate the mechanisms underpinning the
role of lipids in HCC through the YAP/TAZ pathway. In Aim 1, we will study cellular sub-types in HCC and
adjacent non-HCC human samples to identify how the YAP/TAZ pathway relates to lipid gene expression. Gene-
environment interactions with statin use will also be investigated using the Million Veteran Program, to identify
the sub-group of patients who would benefit from statin chemoprevention. In Aim 2, we test the hypothesize that
statins and the mevalonic acid pathway regulate YAP/TAZ function through Rho in hepatocytes and patient-
derived tumoroids. The effects of statin on cellular localization and phosphorylation of YAP/TAZ and the
YAP/TEAD-regulated genes will be examined. We will determine if these effects are dependent on Rho or
intracellular cholesterol/lipid metabolites. In Aim 3, the role of SCD on the regulation of YAP/TAZ, cell proliferation
and migration in a panel of hepatocytes and cancer cells will be examined. These studies will ...

## Key facts

- **NIH application ID:** 10693580
- **Project number:** 1IK2CX002593-01A1
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** Jihane Benhammou
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2028-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10693580

## Citation

> US National Institutes of Health, RePORTER application 10693580, A lipid signaling network through stearoyl Co-A desaturase regulates hepatocellular carcinogenesis through YAP/TAZ activity (1IK2CX002593-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10693580. Licensed CC0.

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