# Hepatic eNOS and Mitochondrial Function in NASH

> **NIH VA I01** · HARRY S. TRUMAN MEMORIAL VA HOSPITAL · 2020 · —

## Abstract

Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of liver pathologies from simple steatosis to
nonalcoholic steatohepatitis (NASH; hepatic inflammation and fibrosis) and cirrhosis. NAFLD affects greater
than 30% of the general US adult population, and disturbingly, prevalence rates of NAFLD and NASH appear
to be greater in the military and veteran population. NASH is directly linked to increased liver-related,
cardiovascular disease and all-cause mortality and also the need for liver transplantation. Previous studies
from our group and others indicate that mitochondrial dysfunction is linked to NASH development and
progression. Unfortunately, mechanism(s) that regulate hepatic mitochondrial function and increased
susceptibility to NASH are largely unknown. Our group has recently demonstrated that normal endothelial
nitric oxide synthase (eNOS) activation is lost in an obese rat model during the transition to NASH, and that
systemic NOS inhibition causes hepatic mitochondrial dysfunction and accelerates NAFLD progression to
NASH. These studies form the overall hypothesis of this proposal, that hepatic eNOS and eNOS-derived nitric
oxide (NO) are critical in maintaining normal hepatic mitochondrial function and quality control in the prevention
of NASH. While it is well established that eNOS and NO regulate peroxisome proliferator-activated gamma
co-activator alpha (PGC-1α), a co-activator of nuclear transcriptional factors that control mitochondrial
biogenesis, we have recently collected novel preliminary data that eNOS deficiency also causes a dramatic
reduction nuclear factor-E2-related factor-2 (NRF2/NFE2L2) and in markers of hepatic autophagy and
mitophagy, the cellular processes responsible for clearance of damage organelles and mitochondria. The loss
of mitophagy in eNOS deficiency occur in conjunction with increased H2O2 emission, reduced anti-oxidative
capacity, and susceptibility to western diet (high fat, sucrose, cholesterol) induced NASH. We will utilize
dietary, pharmacological, and in vivo and in vitro molecular approaches (gain and loss of function studies) to
mechanistically examine the novel links between hepatocellular eNOS and mitophagy in the development and
progression of NASH. The specific aims will: (1) determine the role of hepatocellular eNOS in susceptibility to
NASH, (2) test if targeting NRF2 and BNIP3 increases mitophagy and rescues NASH, and (3) test if
upregulation in mitochondrial-targeted antioxidant defense alleviates western diet induced NASH. These
studies will provide insight into reducing the incidence of NASH in our Veteran population.

## Key facts

- **NIH application ID:** 9898232
- **Project number:** 5I01BX003271-04
- **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:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898232

## Citation

> US National Institutes of Health, RePORTER application 9898232, Hepatic eNOS and Mitochondrial Function in NASH (5I01BX003271-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898232. Licensed CC0.

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