# Hypoxia, HIF-1, and the progression of nonalcoholic fatty liver disease in obstructive sleep apnea

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $177,552

## Abstract

PROJECT SUMMARY/ABSTRACT
The objectives of this K08 proposal are: a) To foster the development of critical scientific and professional skills
which will allow the candidate, Dr. Omar Mesarwi, to progress toward his goal of becoming an independent
physician-scientist, examining the metabolic consequences of obstructive sleep apnea (OSA); and b) To
determine how intermittent hypoxia (IH) in OSA may impact the development and progression of nonalcoholic
fatty liver disease (NAFLD). Dr. Mesarwi and his mentors at UC San Diego have designed a comprehensive
training plan that will afford Dr. Mesarwi new knowledge and research skills in the pathobiology of metabolic
dysfunction in OSA. This will be accomplished through extensive laboratory experience and coursework at UC
San Diego, which will provide Dr. Mesarwi additional expertise in experimental design, laboratory procedures,
data analysis, and scientific communication. OSA is a common condition which is characterized by recurrent
upper airway narrowing during sleep, leading to chronic IH. OSA is associated with a more severe NAFLD
phenotype, driven by IH. NAFLD is an extremely prevalent condition in which hepatic steatosis and
dysregulated glucose metabolism may ultimately lead to cirrhosis, need for transplant, and liver-related death.
The mechanisms which link OSA and NAFLD are relatively unknown. Previous animal work has demonstrated
that IH exacerbates hepatic steatosis and fibrosis in mice with diet-induced obesity, mirroring findings in human
subjects. Hepatic steatosis in experimental NAFLD reduces liver oxygen tension; it is further reduced with
superimposed IH. Hepatic steatosis also increases hypoxia inducible factor-1 (HIF-1), a regulator of the cellular
response to hypoxia. We have shown that hepatocyte HIF-1 mediates the expression of several key enzymes
of fatty acid metabolism in the liver, and the progression of liver fibrosis in experimental NAFLD. Therefore, we
hypothesize that IH in OSA may worsen the NAFLD phenotype through HIF-1 activation and its downstream
effects. We will test this hypothesis in three Specific Aims: 1) Determine the role of HIF-1 as a mediator of IH-
induced hepatic steatosis and dysregulated hepatic glucose metabolism; 2) Determine the role of HIF-1 on IH-
induced hepatic fibrosis in mice with experimental NAFLD, and the effect of antisense oligonucleotides
targeting HIF-1α in reversing liver fibrosis; and 3) Determine the role of HIF-1 and IH in mediating liver fibrosis
in other hepatic cell types. Tools available to us include cell type-specific HIF-1α knockout, which will help
localize HIF-1 effects. Major methods for this proposal include co-modeling OSA and NAFLD in rodents,
antisense knockdown of hepatic HIF-1α, RNA interference, and whole genome shotgun sequencing (RNA-
Seq). Successful implementation of these Specific Aims will provide a rigorous training program for Dr.
Mesarwi, laying the groundwork for R01 submission, and will allow us to answer a...

## Key facts

- **NIH application ID:** 10436877
- **Project number:** 5K08HL143140-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Omar Mesarwi
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $177,552
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436877

## Citation

> US National Institutes of Health, RePORTER application 10436877, Hypoxia, HIF-1, and the progression of nonalcoholic fatty liver disease in obstructive sleep apnea (5K08HL143140-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10436877. Licensed CC0.

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