# Molecular Mechanisms of Stellate Cell Activation in Liver Fibrosis

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2021 · —

## Abstract

Activated HSCs (aHSCs) participate in liver fibrogenesis and promote the development of liver
tumor, the two most devastating sequela of chronic liver disease. Our rigorous efforts to screen Wnt-
β-catenin target genes in aHSCs, identified Scd (stearoyl-CoA desaturase) which encodes an ER
enzyme responsible for the synthesis of mono-unsaturated fatty acids (MUFA) and is implicated in
fatty liver, cancer and stemness. Scd is upregulated in a Wnt-dependent manner by the ability of β-
catenin to bind to SREBP-1c and potentiate nearly 10-fold SREBP-1c-induce transcription. Induction
of Scd2, an isoform dominantly expressed in HSCs is required for HSC activation and provides a
positive forward loop to amplify canonical Wnt pathway via Lrp5/6 mRNA stability. This novel loop is
initiated by SCD-generated MUFA interfering nuclear import of the mRNA binding protein HuR via
Transportin (TNPO) and Ran1 GTPase, resulting in HuR cytoplasmic accumulation, HuR binding to
Lrp5/6 mRNA 3'UTR, and their stabilization. SCD inhibition or Scd2 silencing abrogates LRP5/6
expression and stabilization of β-catenin in aHSCs, and attenuates liver fibrosis in mice. Intriguingly,
the Wnt-SCD2-LRP5/6 loop also exists in liver tumor-initiating stem-cell like cells (TICs) and Huh7
cells and is required for their self-renewal and tumor-initiating activity, establishing this novel
pathway as a functional core in both aHSCs and TICs/HCC cells. We further demonstrate that
conditional Scd2 KO in aHSCs (Scd2 cKO) incapacitates aHSCs to promote TIC-initiated tumor
growth in nude mice and suppresses tumor cell Scd2 expression and natural development of liver
tumors induced by diethyl nitrosamine (DEN) in mice. Our most recent lipidomic and transcriptomic
analyses of non-tumor liver tissues of Scd2 cKO mice, reveal global suppression of tumor-promoting
lipid reprogramming in cholesterol synthesis and eicosanoid metabolism.
 Based on these results, we hypothesize that SCD2-HuR-Wnt positive loop established by aHSCs
induces tumor-promoting lipid reprogramming in microenvironment by targeting genes involved in
cholesterol synthesis and eicosanoid generation and metabolism. To test this hypothesis and the
mechanisms of the tumor enhancer role of HSC SCD2, we will address the following aims:
Aim 1. To determine whether Scd2 conditional KO in hepatocytes prevents DEN-induced liver
tumor development by using Scd2ff;Alb-Cre vs. Scd2ff mice.
Aim 2. To determine whether HSC SCD2 enhances tumor initiation vs. tumor promotion by timing
Scd2 ablation using Scd2ff;Col1a1-Cre-ERT2.
Aim-3. To determine how SCD2 in aHSCs supports tumor promoting lipid microenvironment.
Aim 3-1. To determine the mechanism of β-catenin dependent regulation of HMGCR transcription.
Aim 3-2. To determine whether β-catenin transcriptionally stimulates FADS1/2 and LTA4H via TCF.
Aim 3-3. To determine if LTA4H mRNA is up-regulated by HuR via SCD.
Aim 3-4. To validate SCD-mediated lipid reprogramming in HCC-PDX (patient-derived ...

## Key facts

- **NIH application ID:** 10045559
- **Project number:** 5I01BX001991-07
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** HIDEKAZU TSUKAMOTO
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10045559

## Citation

> US National Institutes of Health, RePORTER application 10045559, Molecular Mechanisms of Stellate Cell Activation in Liver Fibrosis (5I01BX001991-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10045559. Licensed CC0.

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