# MicroRNAs regulating plasma LDL and HDL

> **NIH VA I01** · VA NEW YORK HARBOR HLTHCARE/SYS/BROOKLYN · 2020 · —

## Abstract

Plasma high LDL and low HDL cholesterol levels are risk factors for cardiovascular diseases. MicroRNAs
(miRs), small non-coding endogenous RNAs, target multiple pathways and regulate physiologic functions.
Because miRs modulate diverse biological pathways, we hypothesized that miRs exist in nature that
might simultaneously lower LDL and increase HDL. To discover them, we screened a human miRs library
and identified miR-1200 that decreased apoB (LDL scaffold protein) and increased apoAI (major HDL
protein) secretion from human hepatoma cells. We propose to find out how miR-1200 decreases apoB
secretion, increases apoAI secretion, and enhances hepatic fatty acid oxidation (FAO) to modulate plasma
lipoproteins and reduce atherosclerosis without causing hepatosteatosis in mice.
Aim 1: Physiological mechanisms modulating plasma lipoproteins and atherosclerosis in mice. (A)
We will interrogate the effects of miR-1200 on plasma lipoproteins and atherosclerosis in Apoe–/– and Ldlr–/–
mice. Further comprehensive changes in weight gain, VO2, VCO2, activity and feeding parameters as well
as in plasma lipids, lipoproteins, glucose, cytokines, chemokines and transaminases will be determined.
Accretions of miR-1200 in different tissues and its consequences on target and control genes, hepatic
lipids, lipid synthesis and fatty acid oxidation (FAO) will be studied. Additionally, we will evaluate whether
miR-1200 is able to prevent diet induced obesity in wild type mice fed a high fat diet. (B) We will evaluate
the hypothesis that miR-1200 regulates hepatic apoB and apoAI secretion to modulate plasma LDL and
HDL levels. (C) We will test the hypothesis that miR-1200 modulates plasma LDL and HDL levels, and
hepatic FAO by regulating APOB, BCL11B and NCOR1 gene expression. (D) We will ask if the elevated
HDL is competent in cholesterol efflux and reverse cholesterol transport and is anti-inflammatory and anti-
oxidant. We foresee that increasing hepatic miR-1200 levels will (1) reduce plasma LDL, (2) augment HDL,
(3) increase reverse cholesterol transport, and (4) enhance FAO. Via these mechanisms, miR-1200 will
reduce atherosclerosis and diet-induced obesity.
Aim 2: Molecular mechanisms regulating lipid metabolism by miR-1200: (A) Mechanisms decreasing
apoB secretion: We will (1) measure mRNA and protein levels in human primary hepatocytes transfected
with miR-1200 or Control miR, (2) determine if miR-1200 interacts with seed sequence to enhance
posttranscriptional degradation of apoB mRNA. (B) Mechanisms increasing apoAI secretion: We
hypothesize that miR-1200 reduces BCL11B expression, a repressor, to increase ApoaI transcription.
Experiments will be conducted to (1) establish that BCL11B is regulated by miR-1200, (2) demonstrate if
BCL11B represses apoAI expression, (3) identify the binding site(s) for BCL11B in the ApoaI promoter, and
(4) determine whether BCL11B binds less to the ApoaI promoter in miR-1200–expressing cells. These
studies will identify a novel ...

## Key facts

- **NIH application ID:** 9933788
- **Project number:** 5I01BX004113-03
- **Recipient organization:** VA NEW YORK HARBOR HLTHCARE/SYS/BROOKLYN
- **Principal Investigator:** M Mahmood Hussain
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933788

## Citation

> US National Institutes of Health, RePORTER application 9933788, MicroRNAs regulating plasma LDL and HDL (5I01BX004113-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9933788. Licensed CC0.

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