miR-33a/miR-33b

The miR-33 family consists of two members, miR-33a and miR-33b. These are intronic miRNAs, which are encoded within the SREBP2 and SREBP1 genes, respectively (Najafi-Shoushtari et al. 2010; Rayner et al. 2010; Marquart et al. 2010; Gerin et al. 2010; Horie et al. 2010). The SREBP1 transcription factor is regulated in response to factors such as insulin and LXR ligands and is primarily responsible for the induction of genes involved in fatty acid synthesis (Horton et al. 2002). SREBP2, on the other hand, is regulated by changes in sterol levels and is the primary factor involved in the induction of genes regulating cholesterol biosynthesis and uptake, thereby allowing cells to carefully regulate their intracellular cholesterol levels (Horton et al. 2002). miR-33a and miR-33b have been demonstrated to be co-transcribed along with their host genes, so conditions that modulate the expression of the SREBP genes result in concomitant changes in miR-33 levels (Rayner et al. 2010; Najafi-Shoushtari et al. 2010; Marquart et al. 2010). While the SREBP transcription factors have different target gene specificities, the miR-33 isotypes share the same seed sequence and are therefore believed to target the same set of genes. However, it is not clear whether slight differences in the mature sequence of these miRNAs may alter their affinity for certain targets.

The important role of miR-33 in regulating HDL-C metabolism was first revealed in studies showing that miR-33 could target the cholesterol transporters ABCA1 and ABCG1, both in hepatocytes and macrophages (Najafi-Shoushtari et al. 2010; Rayner et al. 2010; Marquart et al. 2010; Gerin et al. 2010; Horie et al. 2010). Overexpression of miR-33 reduced the expression of ABCA1 and ABCG1 in the liver of mice and decreased plasma HDL-C (Marquart et al. 2010; Najafi-Shoushtari et al. 2010; Rayner et al. 2010; Gerin et al. 2010). Conversely, antisense oligonucleotides (ASOs) that reduced miR-33 level increased the expression of ABCA1 and ABCG1 and raised plasma HDL-C (Rayner et al. 2010; Najafi- Shoushtari et al. 2010; Marquart et al. 2010). Similarly, genetic loss of miR-33 in mice was reported to increase liver ABCA1 expression and plasma HDL-C (Horie et al. 2010). Importantly, inhibition of miR-33 in nonhuman primates was also demonstrated to significantly increase plasma HDL-C (Rayner et al. 2011a; Rottiers et al. 2013). Additionally, miR-33 was found to regulate hepatic bile acid synthesis through targeting of CYP7a1 (Li et al. Hepatology 2013) and secretion via modulation of ABCB11 and ATP8B1 (Allen et al. 2012). Due to its key role in regulating the removal of cholesterol from macrophages, HDL-C biogenesis in the liver, and bile acid metabolism, miR-33 was proposed to be an important regulator of reverse cholesterol transport and the progression of atherosclerosis (Allen et al. 2012; Rayner et al. 2011b). Collectively, these data indicated that ASOs against miR-33 might be a promising therapeutic option to raise HDL-C and treat patients with atherosclerosis.

 
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