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The Role of microRNAs in Cholesterol Efflux and Hepatic Lipid Metabolism


The Role of microRNAs in Cholesterol Efflux and Hepatic Lipid Metabolism

Kathryn J Moore et al. Annu Rev Nutr.


MicroRNAs (miRNAs) represent an elegant mechanism of posttranscriptional control of gene expression that serves to fine-tune biological processes. These tiny noncoding RNAs (20-22 nucleotide) bind to the 3' untranslated region of mRNAs, thereby repressing gene expression. Recent advances in the understanding of lipid metabolism have revealed that miRNAs, particularly miR-122 and miR-33, play major roles in regulating cholesterol and fatty acid homeostasis. miR-122, the most abundant miRNA in the liver, appears to maintain the hepatic cell phenotype, and its inhibition decreases total serum cholesterol. miR-33, an intronic miRNA located with the sterol response element-binding protein (SREBP)-2 gene, regulates cholesterol efflux, fatty acid β oxidation, and high-density lipoprotein metabolism. These findings have highlighted the complexity of lipid homeostasis and the important role that miRNAs play in these processes, potentially opening new avenues for the treatment of dyslipidemias.


Figure 1
Figure 1
miRNA biogenesis pathway. miRNAs are transcribed in the nucleus by RNA polymerase from independent miRNA genes located in polycistronic transcripts or introns of protein-coding genes into primary transcripts (pri-miRNAs). Pri-miRNAs are processed in two steps in the nucleus and cytoplasm by the RNase III type endonuclease Drosha and Dicer, respectively, in complexes with dsRNA-binding domains proteins, DGCR8 and TRBP as indicated. In the canonical pathway, Drosha-DGCR8 processes the transcript to a stem-loop-structured precursor (pre-miRNA). Alternatively miRtrons, a subset of miRNAs derived from introns, may be processed into pre-miRNAs by the spliceosome and the debranching enzyme. Both canonical miRNAs and miRtrons are exported to the cytoplasm via Exportin 5, where they are further processed by Dicer-TRBP to yield ≈ 20-bp miRNA duplexes. One strand is selected to function as the mature miRNA and loaded into the RNA-induced silencing complex (RISC) containing components of the Argonaute family (Ago 1-4), while the partner miRNA* strand is preferentially degraded. A subset of miRNAs, exemplified by miR-451, are produced independently of Dicer through recognition by Ago2. The mature miRNA produced by these two mecahnisms leads to translational repression or degradation of the target mRNA. Animal miRNAs usually show only partial complementarity to the target mRNA promoting translational repression (initiation and post initiation steps) or deadenylation coupled to exonucleolytic degradation of target mRNA. mRNAs repressed by deadenylation or at the translation-initiation step can be moved to P-bodies for either degradation or storage.
Figure 2
Figure 2
miR-33 Regulates Fatty Acid Metabolism and Cholesterol Efflux Cellular stimuli that activate transcription of SREBF-1 or SREBF-2 (eg. Insulin or low-sterol, respectively) induce the co-transcription of miR-33b and miR-33a, respectivly. These pri-miRNAs are sequentially processed by Drosha and Dicer, and loaded into the RNA-induced silencing complex (RISC). As a result of binding target sites in the 3’UTR, miR-33a/b simultaneously inhibit the expression of genes involved in fatty acid metabolism (CROT, CPT1a and HADHB) and cholesterol transport (ABCA1, ABCG1 and NPC1). The outcome of miR-33 targeting of these genes is reduced fatty acid β-oxidation, reduced cholesterol efflux and reduced lipidation of apoA1 and HDL particles.
Figure 3
Figure 3
Therapeutic targeting of miR-33 and miR-122 in atherosclerosis Upon treatment with anti-miR33 inhibitors, hepatic miR-33 levels are reduced, resulting in increased expression of target genes ABCA1 and ABCG1 in the liver. This results in enhanced HDL biogenesis and an increase in circulating HDL which can promote reverse colesterol transport from tisúes, including from lesional macrophage foam cell macrophage. In addition, anti-miR-33 may directly target these lesional macrophages, upregulating ABCA1 and ABCG1 expression, further enhancing cholesterol removal from the plaque. Antagonism of miR-122, the most highly expressed miRNA in the liver, decreases circulating cholesterol, particularly LDL, via as yet unspecified mechanisms. Notably, anti-miR-122 also decreases propagation of Hepatitis C virus in the liver and is currently in clinical trial for this application.

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