# The role of lipid droplet proteins in eicosanoid production and non-alcoholic fatty liver disease > **NIH NIH K99** · UNIVERSITY OF PENNSYLVANIA · 2024 · $91,204 ## Abstract SUMMARY/ABSTRACT 1 Current estimates indicate that ~30 % of the global adult population is affected by non-alcoholic fatty liver disease 2 (NAFLD). NAFLD is associated with an increased risk of morbidity and mortality from hepatic and extra-hepatic 3 complications, such as cardiovascular disease. Recent research has identified hepatic lipid droplets (LDs) as 4 important players in NAFLD, yet their exact role in the pathogenesis and progression of this disease is not fully 5 understood. One of the key functions of hepatic LDs is to store polyunsaturated fatty acids (PUFAs) and regulate 6 the availability of arachidonic acid (AA). Recent evidence has shown that plasma levels of PUFAs and 7 eicosanoids are associated with NAFLD severity and cardiovascular disease. However, the role of LD proteins 8 in regulating PUFA metabolism and liver inflammation has not been investigated. To address this gap, the 9 principal investigator (PI) will study common genetic coding variants in two LD proteins that may alter PUFA and 10 eicosanoid metabolism and, thus, affect NAFLD progression. The first is PNPLA3-I148M which is well-known as 11 a risk factor for NAFLD and associated comorbidities. The second is PLIN2-Pro251 which has been recently 12 shown to be associated with a reduction in hepatic triglycerides in a NAFLD mouse model. The hypotheses at 13 the heart of this project are that PNPLA3-I148M augments the release of AA from the LD membrane, increasing 14 eicosanoid production, liver inflammation and NAFLD progression, whereas PLIN2-Pro251 decreases the 15 release of AA from the LD membrane, thereby reducing eicosanoid production, liver inflammation and NAFLD 16 progression. Using a genome-first approach, in the K99 phase, the PI will conduct a `recall-by-genotype' study 17 to deep phenotype subjects who are PNPLA3-I148M homozygous without liver disease, and matched controls 18 (Aim 1); in parallel, the PI will use human-derived induced pluripotent stem cells (iPSCs) differentiated to 19 hepatocyte-like cells (HLCs) to determine the role of PNPLA3-I148M on eicosanoids metabolism and LD biology 20 (Aim 2). In the R00 phase, the PI will turn her attention to PLIN2-Pro251. Further embracing a `human phenomic 21 science' approach, she will deep-phenotype subjects homozygous for PLIN2-Pro251 without liver disease, and 22 matched controls (Aim 3) and study the role of this genetic variant in eicosanoid production, VLDL secretion and 23 LD biology in human-derived HLCs (Aim 4). The PI will learn the necessary techniques to accomplish the 24 proposed research under the guidance of her mentors (Dr Rader and Dr FitzGerald) and Advisory Committee. 25 Her training will include 1) becoming proficient in designing and conducting deep phenotyping studies involving 26 genetic variants, and 2) mastering the use of iPSCs as tools to recapitulate metabolic variations observed in the 27 population. The PI will also gain a better understanding of mass spectrometry, bio... ## Key facts - **NIH application ID:** 10886876 - **Project number:** 1K99DK137029-01A1 - **Recipient organization:** UNIVERSITY OF PENNSYLVANIA - **Principal Investigator:** Eleonora Scorletti - **Activity code:** K99 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $91,204 - **Award type:** 1 - **Project period:** 2024-08-06 → 2026-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10886876 ## Citation > US National Institutes of Health, RePORTER application 10886876, The role of lipid droplet proteins in eicosanoid production and non-alcoholic fatty liver disease (1K99DK137029-01A1). Retrieved via AI Analytics 2026-06-13 from https://api.ai-analytics.org/grant/nih/10886876. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*