Judging from the amount of Lipitor® adds on TV, everyone these days is looking for ways to lower bad cholesterol (LDL) and raise good cholesterol (HDL). Now, in dueling Science Express papers, two independent research teams say that blocking miR-33 expression could give our good cholesterol a real boost.
Anders Näär and colleagues at various Massachusetts research institutions got hooked on miR-33 when they were studying sterol regulatory element-binding proteins (SREBPs). They noticed that many organisms had highly conserved miR-33 sequences in SREBP introns. Since SREBPs are transcription factors that promote cholesterol uptake and synthesis, the team figured that miR-33 must have something to do with the process.
Näär’s team used bioinformatics to identify ABCA1 as a possible miR-33 target. ABCA1 opposes SREBPs by kicking cholesterol out of cells and tissues so that the liver can either make HDL or excrete the cholesterol. The team further found that
- Cells with pre-miR-33 (excess miR-33) had low ABCA1 expression in mouse and human cells, whereas transfection with anti-miR-33 increased ABCA1 levels.
- Mutating seed sequences in miR-33 or in the ABCA1 3’UTR wiped out miR-33 effects when assayed by a luciferase reporter construct.
- Macrophages treated with a cholesterol-lowering drug had high miR-33 and SREBP expression, but low ABCA1 expression. Macrophages cultured with cholesterol had high ABCA1, which could be lowered with pre-miR-33 addition.
- When the researchers injected a locked nucleic acid-miR-33 antisense construct into mice, HDL levels went up with no apparent side-effects.
In the other Science Express paper, Kathryn Moore, Carlos Fernández-Hernando, and collaborators at Mass General Hospital, NYU, and Harvard Med found miR-33 in a genome-wide screen for miRNAs that were affected by cholesterol. They also saw that miR-33 and SREBP (aka, SREBF) were down-regulated when a lot of cholesterol was around in vivo and in vitro, and this was the opposite of ABCA1 expression.
But whereas Näär’s team didn’t find an effect of miR-33 on NPC1 (a cholesterol transporter), these researchers did. In fact, there were species-specific effects—miR-33 repressed ABCA1 in human and mouse cells, but NPC1 was much more suppressed in human cells than in mouse cells. ABCG1 (which is similar to ABCA1) was only affected in mouse cells.
The researchers say that miR-122 also is involved in cholesterol metabolism, but this miRNA is only found in the liver. miR-33, though, is expressed in lots of tissues and cells, so this may be a more global cholesterol regulator. Both groups suggest that miR-33 is a promising therapeutic target for raising good cholesterol levels.
To raise your awareness of miR-33’s effects, check out Näär et.al. Science Express, May 2010, and Fernández-Hernando et.al. Science Express May, 2010.