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.

Public Health Relevance

Cardiovascular disease is the leading cause of death in the United States and diabetes is a significant risk factor for developing cardiovascular complications, suggesting novel modulators of lipid traits can have significant impact on human health. Plasma LDL cholesterol levels are a heritable risk factor for heart disease and diabetes. The majority of therapies to reduce LDL cholesterol levels are aimed at increasing hepatic expression of the LDL receptor and novel regulators of this pathway have the potential to impact clinical care.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL136543-02
Application #
9462648
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Tarling, Elizabeth J; Clifford, Bethan L; Cheng, Joan et al. (2017) RNA-binding protein ZFP36L1 maintains posttranscriptional regulation of bile acid metabolism. J Clin Invest 127:3741-3754