# Effect of SMSr on VLDL metabolism and atherosclerosis

> **NIH VA I01** · VA NEW YORK HARBOR HLTHCARE/SYS/BROOKLYN · 2024 · —

## Abstract

Summary
Atherosclerosis contributes significantly to cardiac related morbidity and mortality in the aging population of
veterans. Plasma low density lipoprotein (LDL) and its precursor very low density lipoprotein (VLDL) are two
atherogenic lipoproteins. LDL initiates atherosclerosis through its retention in the subendothelial space of
arterial walls. Statin-mediated LDL lowering is now the mainstay of cardiovascular disease treatment.
However, despite the efficacy, there are many instances of unresponsiveness and intolerance. There is thus
an urgent need for additional approaches for lowering plasma LDL, preferably acting synergistically with
statins. Blocking liver VLDL secretion and promoting LDL clearance have long been recognized as an
effective LDL lowering strategies. Those are different from the use of statins. It is known for a long time that
plasma phosphatidylethanolamine (PE) level is a better predictor for human atherosclerosis. However, how
to regulate PE and what is the mechanism linking PE with atherosclerosis are not quite understood. PE is
one of the important lipid components on VLDL and LDL, and its level influences the development of
atherogenesis in animal models. Thus, study PE regulation may provide an important clue for lowering
VLDL and LDL, and for a new treatment of human atherosclerosis.
 Sphingomyelin synthase (SMS) gene family has three members: SMS1 and SMS2 have SM
synthase activity, while SMS-related protein (SMSr) has no SM synthase activity but has ceramide
phosphorylethanolamine (CPE) synthase activity in test tubes. Although SMSr is ubiquitously expressed in
all tested tissues, the CPE levels in most of mammalian tissues or cells are undetectable under chow or
high fat/cholesterol diets. Therefore, SMSr is not a functional CPE synthase in vivo and its real biological
function need to be elucidated. From the CPE synthase reaction, we notice that SMSr should have a
potential PE-PLC activity, i.e. hydrolyzing PE into diacylglycerol and phosphorylethanolamine, which could
be involved in tissue PE steady state regulation. Based on preliminary results of this study, we then
hypothesize that SMSr is a functional PE-PLC in vivo. Given the fact that PE levels are involved in VLDL
production, LDL clearance, and the development of atherosclerosis, SMSr/PE-PLC should be a novel and
promising target for lowering LDL. We have three specific aims: 1. Investigate whether SMSr is a
functional PE-PLC. 2. Evaluate the effects of blocking SMSr/PE-PLC on VLDL production and LDL
clearance. 3. Examine the role of SMSr/PE-PLC deficiency in the development of atherosclerosis. Insights
gained from the proposed studies will allow us to evaluate SMSr/PE-PLC as a target for preventing and
treating human atherosclerosis.

## Key facts

- **NIH application ID:** 10726573
- **Project number:** 5I01BX000900-11
- **Recipient organization:** VA NEW YORK HARBOR HLTHCARE/SYS/BROOKLYN
- **Principal Investigator:** XIAN-CHENG JIANG
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2011-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10726573

## Citation

> US National Institutes of Health, RePORTER application 10726573, Effect of SMSr on VLDL metabolism and atherosclerosis (5I01BX000900-11). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10726573. Licensed CC0.

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