Thursday, June 17, 2010

miR-33 in Cholesterol Control

With the well-established link between serum cholesterol levels and cardiovascular disease and the availability of effective cholesterol-lowering drugs, cholesterol screening has rapidly become a routine part of health care. Yet, much remains to be learned about how cholesterol levels are regulated at the cellular level (see the Perspective by Brown et al.). Now, Najafi-Shoushtari et al. (p. 1566, published online 13 May) and Rayner et al. (p. 1570, published online 13 May) have discovered a new molecular player in cholesterol control—a small noncoding RNA that, intriguingly, is embedded within the genes coding for sterol regulatory element-binding proteins (SREBPs), transcription factors already known to regulate cholesterol levels. This microRNA, called miR-33, represses expression of the adenosine triphosphate–binding cassette transporter A1, a protein that regulates synthesis of high-density lipoprotein (HDL, or "good" cholesterol) and that helps to remove "bad" cholesterol from the blood. Reducing the levels of miR-33 in mice boosted serum HDL levels, suggesting that manipulation of this regulatory circuit might be therapeutically useful.

Close, But Not Too Close

MicroRNAs (miRNAs) in plants are generally highly complementary to their target RNAs, yet, in most animal miRNAs, only the ~8-nucleotide "seeds" sequence bases pair fully with the target, with few base pairs between the remainder of the miRNA and target. Plant miRNAs are methylated at their 3' ends, whereas animals' miRNAs are not. Ameres et al. (p. 1534; see the Perspective by Pasquinelli) noticed that, in fruit flies, miRNAs engineered to have high complementarity to target RNAs were present at reduced levels. These miRNAs were trimmed and uridylated at their 3' ends, features involved in RNA degradation. Fly small interfering RNAs, all of which are methylated at their 3' ends, were unaffected, unless the methylating enzyme, Hen1, was mutated. Thus, 3'-methylation may prevent complementarity-driven remodeling and degradation of small RNAs.