# Post-Translational Regulation of Lipid Metabolism

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $385,000

## Abstract

ABSTRACT
Elevated plasma cholesterol, triglycerides and metabolic complications such as obesity are among
the most important risk factors for cardiovascular disease (CVD). Understanding the factors and
mechanisms that regulate plasma low-density lipoprotein (LDL) cholesterol levels is of the utmost
importance. Increasing hepatic LDL receptor (LDLR) expression leads to increased uptake of LDL
cholesterol from the circulation, and has been a successful therapeutic strategy for treating CVD and
dyslipidemia. Here, we identify a novel gene that regulates hepatic LDLR and plasma LDL cholesterol
levels that is also a locus for LDL-C levels in human Genome-wide Association Studies. In extensive
preliminary data, we show that overexpression and silencing (using antisense oligonucleotides,
ASOs) of the candidate gene in vivo also alters plasma total and LDL cholesterol levels, and
reciprocally regulates the LDLR, suggesting the mechanism of action is directly through targeting the
LDLR. In Specific Aim 1 we will determine the molecular mechanism and structural requirements of
the regulation of LDLR protein expression and plasma LDL cholesterol levels. In Specific Aim 2, we
will use complimentary in vivo gain- and loss-of-function models, including tissue-specific knockout
mice and ASOs, to determine the therapeutic potential of specific ASO silencing agents in a relevant
disease model of atherosclerosis. In the current proposal we describe a novel post-translational
pathway that modulates plasma cholesterol homeostasis. Our findings identify a novel post-
translational regulation that can be targeted with ASO silencing agents and therefore has significant
therapeutic potential.

## Key facts

- **NIH application ID:** 10136070
- **Project number:** 5R01HL136543-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Elizabeth Joanna Tarling
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136070

## Citation

> US National Institutes of Health, RePORTER application 10136070, Post-Translational Regulation of Lipid Metabolism (5R01HL136543-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10136070. Licensed CC0.

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