# Novel insights into the molecular and cellular mechanism regulating lipid metabolism and atherosclerosis

> **NIH NIH R35** · YALE UNIVERSITY · 2021 · $850,059

## Abstract

PROJECT SUMMARY
Alterations in the control of cholesterol homeostasis can lead to pathological processes, including
atherosclerosis, the most common cause of mortality in Western societies. Epidemiological studies have
identified many environmental and genetic factors that contribute to atherogenesis. In particular, high levels
of low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C)
are associated with increased cardiovascular disease (CVD) risk. In addition to protein coding genes, non-
coding RNAs including microRNAs (miRNAs) have recently shown to play a key role in regulating gene
expression. Alteration in miRNAs expression has been associated to numerous diseases including CVD.
Our previous work has demonstrated the importance of miRNAs in regulating HDL-C and LDL-C. In
particular, work from our group and others identified miR-33a/b and miR-148a as key regulators of cellular
cholesterol efflux and uptake, HDL biogenesis and LDL clearance. While these studies highlight the
therapeutic potential of manipulating miRNAs to control circulating HDL-C and LDL-C, the effect of both
miRNAs in controlling lipid and glucose metabolism remains poorly understood.
To investigate in depth the molecular mechanism by which miR-33a/b and miR-148a regulate glucose and
lipid metabolism, we have recently developed a number of unique mouse models that will allow us to define
the contribution of miR-33 and miR-148a in controlling lipid metabolism and atherogenesis in vivo. Using
cutting-edge techniques, we will identify the regulatory network through which miR-33a/b and miR-148a
regulate lipid metabolism both in vitro and in vivo, and assess the potential therapeutic value of anti-miR-
33a/b and antimiR-148a therapy for treating cardiometabolic diseases including atherosclerosis and
metabolic syndrome. Additionally, we will continue our efforts to identify and characterize novel non-coding
RNAs, including long non-coding RNAs (lncRNAs) that regulate lipid metabolism and other processes that
influence the development of CVD.
In another different topic, we will also study the molecular mechanisms that regulate the initial steps of
atherogenesis. We hypothesize that Cav-1/caveolae expression is regulated by flow and mediates LDL
infiltration and retention in atheroprone areas leading to the progression of atherosclerosis. Using unique
animal models and innovative electron microscopy technics we aim to characterize how this process is
regulated.

## Key facts

- **NIH application ID:** 10102267
- **Project number:** 5R35HL135820-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Carlos Fernandez Hernando
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $850,059
- **Award type:** 5
- **Project period:** 2017-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102267

## Citation

> US National Institutes of Health, RePORTER application 10102267, Novel insights into the molecular and cellular mechanism regulating lipid metabolism and atherosclerosis (5R35HL135820-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10102267. Licensed CC0.

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