# Hepatic Steatosis Induced by Bioactive Lipids

> **NIH NIH F31** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $30,814

## Abstract

Project Summary
Lipid accumulation, inflammation and metabolic dysregulation are hallmarks of liver disease.
Nonalcoholic fatty liver disease(NAFLD) has recently emerged as one of the leading global
etiologies of liver disease as it affects approximately 25% of the global population. Nonalcoholic
steatohepatitis (NASH) is the inflammatory subtype of NAFLD, and approximately 40% of
patients will progress to this stage; with another subset proceeding towards carcinogenesis.
Unfortunately, many of these patients will go undetected as they progress to hepatocellular
carcinoma which has a median survival of just 11 months. It is thus crucial to better characterize
the interface between NAFLD and NASH to best improve patient outcomes. To better
understand the molecular signals driving this transition we have targeted the insulin signaling
pathway where we have established a liver specific deletion model of PTEN, the negative
regulator of the insulin signaling pathway, that recapitulates human disease progression. Our
preliminary data has shown that dysregulation in eicosanoid metabolism correlates with PTEN
loss such that prostaglandin synthesis is significantly enhanced while proresolving cyp450
associated eicosanoid synthesis is downregulated. These correlations between PTEN,
prostaglandin, and cyp450 associated protein expression levels are preserved agnostic of
PTEN deletion when examining publicly available data. The PI3K/AKT signaling pathway is
unequivocally induced upon PTEN deletion and as such we aim to further investigate the role of
AKT in driving this bioactive lipid metabolism dysregulation. Utilizing genetic knockout
hepatocytes, our data has shown that AKT regulates eicosanoid synthesis in an isoform specific
manner. Further, eicosanoid have long been implicated in playing a role in modulating
macrophage chemotaxis and polarization. Our data has also shown significant enrichment of
macrophages, and previous work demonstrated that depletion of this macrophage accumulation
via AKT2 deletion attenuated disease progression. As such, we aim to investigate the role of
AKT specific isoforms in regulating hepatic eicosanoid biosynthesis, and the effect this has on
macrophage chemotaxis and polarization in liver disease. Completion of this project will show
the potential therapeutic benefit that targeting eicosanoid signaling may have in NAFLD and
NASH. This work will also elucidate the mechanistic roles of each AKT isoform in regulating
hepatic eicosanoid metabolism and chronic inflammation to provide more insights for the
scientific community at large.

## Key facts

- **NIH application ID:** 10827280
- **Project number:** 1F31DK138790-01
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Mario Alba
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $30,814
- **Award type:** 1
- **Project period:** 2024-09-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10827280

## Citation

> US National Institutes of Health, RePORTER application 10827280, Hepatic Steatosis Induced by Bioactive Lipids (1F31DK138790-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10827280. Licensed CC0.

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