MiR-33 Contributes to the Regulation of Cholesterol Homeostasis

By K. Rayner, Y. Suárez, A. Dávalos, Saj Parathath, M. Fitzgerald, N. Tamehiro, E. Fisher, K. Moore, C. Fernández‐Hernando. Science, 2010

1,302 citations recorded by the source corpus.

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. A small noncoding RNA helps regulate cholesterol levels in mice. Cholesterol metabolism is tightly regulated at the cellular level. Here we show that miR-33, an intronic microRNA (miRNA) located within the gene encoding sterol-regulatory element–binding factor–2 (SREBF-2), a transcriptional regulator of cholesterol synthesis, modulates the expression of genes involved in cellular cholesterol transport. In mouse and human cells, miR-33 inhibits the expression of the adenosine triphosphate–binding cassette (ABC) transporter, ABCA1, thereby attenuating cholesterol efflux to apolipoprotein A1. In mouse macrophages, miR-33 also targets ABCG1, reducing cholesterol efflux to nascent high-density lipoprotein (HDL). Lentiviral delivery of miR-33 to mice represses ABCA1 expression in the liver, reducing circulating HDL levels. Conversely, silencing of miR-33 in vivo increases hepatic expression of ABCA1 and plasma HDL levels. Thus, miR-33 appears to regulate both HDL biogenesis in the liver and cellular cholesterol efflux.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c7c02537e9faaff79a06ab6bcfe4d86364567045

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Citations in the corpus

An overview of microRNAs (2015, background): “miR-33 has been linked to serum high density lipoprotein (HDL) and triglyceride levels, though it is not clear if this is a hepatocyte-specific event or if expression in macrophages, among other cells, is controlling lipid metabolic regulatory networks[184-187].”
Autophagy Regulates Cholesterol Efflux from Macrophage Foam Cells via Lysosomal Acid Lipase (2011, positive): “Additionally, ABCA1 expression is increased in response to cholesterol loading, both transcriptionally via the liver X receptor (LXR) (Beaven and Tontonoz, 2006) and posttranscriptionally by miR33 (Rayner et al., 2010).”
MicroRNAs in stress signaling and human disease (2012, background): “This is exemplified by miR-33 family members, which cooperate with the sterol regulatory element binding protein (SREBP) genes in which they are embedded to reduce cholesterol efflux and increase cholesterol biosynthesis (NajafiShoushtari et al., 2010; Rayner et al., 2010).”
miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling (2011, background): “We recently showed that miR-33a is cotranscribed with its host gene Srebp-2 like many intronic miRNAs, and it targets genes involved in cholesterol export, including the adenosine triphosphate binding cassette (ABC) transporters ABCA1 and ABCG1 and the endolysosomal transport protein Niemann-Pick C1”