# The Function of Mammalian LPGAT1

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $506,256

## Abstract

Project Summary/Abstract
Disorders of fat metabolism, such as obesity, metabolic syndrome, and atherosclerosis, are characterized by
abnormal processing of fatty acids. The non-random distribution of fatty acids in phospholipids, where
saturated chains are linked to the first (sn-1) but unsaturated chains are linked to the second (sn-2) carbon
atom of the glycerol group, has important implications for membrane structure, lipid metabolism, and second
messenger functions. However, while the composition of unsaturated fatty acids in sn-2 position is controlled
by the Lands pathway, it has remained unclear what controls saturated fatty acids in sn-1 position. We have
collected preliminary data that strongly suggest an sn-1 specific remodeling pathway for saturated
fatty acids, which plays a pivotal role in the production of lipoproteins. Based on our preliminary data we
postulate that the acyltransferase LPGAT1 controls the composition of saturated fatty acids in the two most
abundant phospholipids, phosphatidylethanolamine (PE) and phosphatidylcholine (PC), and that this pathway
is critical for the regulation of the de novo synthesis of lipids in hepatocytes. To test our hypothesis and to
identify the function of LPGAT1, we will (i) establish the mechanism of phospholipid remodeling by LPGAT1
and (ii) establish the regulatory function of LPGAT1 in lipid de novo synthesis. To this end, we will define the
enzymatic reaction of LPGAT1 in vitro upon expression and purification of the enzyme (subaim 1a), determine
the effect of LPGAT1 knockout and knockdown on the lipid composition of subcellular membranes by
lipidomics analysis of tissues and organelles (subaim 1b), dissect the remodeling pathway of LPGAT1 by
tracing the metabolism of isotope-labeled substrates and by reconstituting the deacylation-reacylation cycle
(subaim 1c), determine the mechanism by which LPGAT1 remodels PC by isotope labeling studies in
hepatocytes (subaim 1d), determine how LPGAT1 affects global lipid fluxes in mice by lipidome-wide 13C-
fluxomics analysis (subaim 2a); determine the effect of LPGAT1 ablation on lipoprotein metabolism by
measuring production and clearance of lipoproteins in mice (subaim 2b), and establish whether LPGAT1
ablation protects from atherosclerosis in LDL-receptor deficient mice (subaim 2c). The proposed work is
significant because (i) it will establish a parallel concept to the Lands cycle for the remodeling of
saturated fatty acids in sn-1 position and (ii) it will identify the function of this pathway within the lipid
metabolic network. This is expected to have critical influence on the evolving concepts of phospholipid
remodeling and be directly relevant to prevalent health problems, such as obesity, metabolic syndrome, and
atherosclerosis.

## Key facts

- **NIH application ID:** 10783071
- **Project number:** 5R01HL166418-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** M Mahmood Hussain
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $506,256
- **Award type:** 5
- **Project period:** 2023-02-10 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10783071

## Citation

> US National Institutes of Health, RePORTER application 10783071, The Function of Mammalian LPGAT1 (5R01HL166418-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10783071. Licensed CC0.

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