Accurate regulation of cholesterol/lipid homeostasis is essential to human health. Indeed, high circulating LDL- to-HDL ratios and elevated triglycerides are associated with metabolic syndrome, type II diabetes, and cardiovascular disease (CVD). An improved understanding of the regulatory mechanisms governing circulating levels of HDL and triglycerides could yield novel therapeutic avenues to combat cardiometabolic disorders. We recently made the surprising discovery that the human SREBP-1 and -2 genes encoding key transcriptional regulators of cholesterol/lipid biosynthesis harbor intronic microRNAs (miR-33b and miR-33a, respectively). Intriguingly, miR-33a/b represent key inhibitors of the ABCA1 cholesterol transporter and HDL synthesis to boost intracellular cholesterol levels, and injection of antisense oligonucleotides directed against miR-33a significantly increases HDL levels in mice on a western-type diet. We propose here to test the hypothesis that miR-33a/b represent central regulators of multiple aspects of mammalian cholesterol/lipid metabolism, in close cooperation with the SREBP host genes. Both in vitro cell culture and in vivo studies in mice and non-human primates will provide key mechanistic insights into the role of miR-33a/b in targeting entire pathways guiding lipid and energy homeostasis, and whether miR-33a/b may be suitable for therapeutic targeting to raise circulating HDL and lower plasma triglycerides in metabolic syndrome patients.

Public Health Relevance

Low circulating high-density lipoprotein (HDL) and elevated triglycerides are associated with cardiovascular disorders, however, treatment options are limited. The proposed studies will test the hypothesis that microRNAs miR-33a/b may significantly contribute to low HDL and high triglycerides by coordinately regulating entire pathways governing cholesterol/lipid production and trafficking, in concert with their host genes, the SREBPs. Studies in mice and non-human primates will examine the feasibility of therapeutic targeting of miR- 33a/b to raise circulating HDL and lower triglycerides.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK094184-03
Application #
8501444
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Blondel, Olivier
Project Start
2011-09-24
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$392,805
Indirect Cost
$167,055
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Naar, Anders M (2013) Anti-atherosclerosis or No Anti-atherosclerosis: That is the miR-33 question. Arterioscler Thromb Vasc Biol 33:447-8
Rottiers, Veerle; Naar, Anders M (2012) MicroRNAs in metabolism and metabolic disorders. Nat Rev Mol Cell Biol 13:239-50