# Hepatic eNOS in the regulation of NASH

> **NIH VA I01** · HARRY S. TRUMAN MEMORIAL VA HOSPITAL · 2024 · —

## Abstract

Nonalcoholic fatty liver disease (NAFLD) is a global epidemic, progresses to nonalcoholic steatohepatitis
(NASH) and fibrosis, and results in the development of hepatocellular carcinoma and increased cardiovascular
mortality. NAFLD affects greater than 30% of the general US adult population, and disturbingly, prevalence
rates appear to be greater in the military and veteran population. Unfortunately, no pharmacological therapies
are available yet to treat NASH and fibrosis, necessitating the identification of novel targets and approaches.
We have recently reported that hepatic eNOS is reduced in human patients with increasing NASH severity,
and in vivo deletion of eNOS in hepatocytes exacerbated hepatic steatosis and NASH susceptibility. Here we
present novel preliminary data demonstrating that eNOS deletion in hepatocytes upregulates the lipogenic
transcription factor sterol regulatory element binding protein 1c (SREBP1c) and the DNL regulatory proteins
acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). In addition, both hepatocyte-specific eNOS
overexpression suppressed markers of DNL, concurrent with decreased histological steatosis and
inflammation. These results clearly show in hepatocytes that eNOS depletion is deleterious for liver disease. In
contrast, we have recently made the novel preliminary observation that silencing eNOS specifically in Kupffer
cells (KCs) in vitro and in vivo dramatically suppressed KC pro-inflammatory activation status and reduced
short-term western diet induced NASH. Similarly, silencing eNOS in hepatic stellate cells (HSCs) in vitro
reduced HSC fibrogenic activation. Whereas overexpressing eNOS in KCs and HSCs increased pro-
inflammatory cytokine expression and increased HSC activation. Collectively, these data indicate that there is
an apparent dichotomy in eNOS function in hepatocytes vs. nonparenchymal cells. Therefore, we hypothesize
that hepatocyte-specific eNOS deletion transcriptionally upregulates DNL and SREBP1c and drives NAFLD
(Aim 1), while KC- and HSC- specific eNOS deletion attenuates NASH and fibrosis (Aim 2). We will
mechanistically interrogate both of these aims using gain-of-function and loss-of-function studies in vivo and in
vitro to target eNOS in hepatocytes, KCs and HSCs. These studies will establish the cell type specific
importance of eNOS and provide valuable insight into reducing the incidence of NAFLD and NASH in our
Veteran population.

## Key facts

- **NIH application ID:** 10805957
- **Project number:** 2I01BX003271-05A1
- **Recipient organization:** HARRY S. TRUMAN MEMORIAL VA HOSPITAL
- **Principal Investigator:** RANDY SCOTT RECTOR
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2017-04-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10805957

## Citation

> US National Institutes of Health, RePORTER application 10805957, Hepatic eNOS in the regulation of NASH (2I01BX003271-05A1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10805957. Licensed CC0.

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