Phosphatidylcholine (PC) is the major component of cell membranes and is synthesized de novo in the Kennedy pathway and then undergoes extensive deacylation-reacylation remodeling via Lands' cycle (non- Kennedy pathway). The reacylation is catalyzed by lysophosphatidylcholine acyltransferase (LPCAT), which adds a polyunsaturated fatty acid at the sn-2 position. Polyunsaturated PC content influences plasma membrane structure and function. Four LPCAT isoforms have been described to date, and we determined that LPCAT3 is the major isoform in macrophages and adipocytes. Here, we hypothesize that an increase in saturated PCs in the plasma membrane of macrophages, as a consequence of Lpcat3 deficiency, promotes inflammation by activating NF?B and MAP kinase signaling and promotes inflammation-induced systemic insulin resistance and atherosclerosis (Aims 1 and 2). Lpcat3 deficiency in adipocytes might blunt insulin signaling, thereby accelerating inflammation, systemic insulin resistance and atherosclerosis (Aim 3). Lpcat3 overexpression should have the opposite effects. The outcomes of this study could lead to a novel anti- atherogenic strategy for clinical use.

Public Health Relevance

Based on very promising preliminary results, we speculate that manipulation the PC composition on the membrane of macrophages and adipocytes through LPCAT3 regulation (gene knockout or overexpression) can influence inflammation and insulin signaling, thus influencing the development of atherosclerosis. We will evaluate these processes in this application. The outcomes of this study may well lead to a novel anti-atherogenic strategy for clinical use.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL139582-03
Application #
9914073
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
2018-07-01
Project End
2022-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Suny Downstate Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
040796328
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
Lou, Bin; Liu, Qi; Hou, Jiahui et al. (2018) 2-Hydroxy-oleic acid does not activate sphingomyelin synthase activity. J Biol Chem 293:18328-18336