miR-30c in Lipid Metabolism and Atherosclerosis

In addition to miR-122, miR-30c levels also regulate circulating lipids by regulating the expression of microsomal triglyceride transfer protein (MTTP), an enzyme that lipidates Apo-B and triglycerides and is required for the secretion of plasma lipoproteins that contain Apo-B (Irani et al. 2016; Soh et al. 2013). Moreover, miR- 30c inhibits hepatic lipid synthesis. As a result, overexpression of miR-30c using lentiviral constructs or miRNA mimics significantly reduces plasma cholesterol levels and attenuates the progression of atherosclerosis (Irani et al. 2016; Soh et al.

2013). Interestingly the inhibition of MTTP expression and VLDL secretion does not influence the accumulation of lipids in the liver, suggesting that miR-30c therapies might be an interesting approach for treating patients with homozygous hypercholesterolemia.

miR-33a/miR-33b

Besides the abovementioned role of miR-33a/miR-33b in regulating HDL-C metabolism and the progression and regression of atherosclerosis, several reports have shown that miR-33 might also control VLDL metabolism (Allen et al. 2014; Goedeke et al. 2014). In this regard, Baldan and colleagues found that chronic inhibition of miR-33 in rodents enhances hepatic VLDL-C. The authors showed that targeting miR-33 in vivo increases the expression of N-ethylmaleimide- sensitive factor (NSF), an ATPase enzyme involved in intracellular trafficking and membrane fusion (Allen et al. 2014). These findings correlate with another study that shows a marked increase in circulating TAG (Goedeke et al. 2014). In agreement with these observations, genetic ablation of miR-33 in mice results in obesity, insulin resistance, hepatosteatosis, and dyslipidemia (Horie et al. 2013). Despite these results, other similar studies in mice and nonhuman primates showed no differences or even a decrease in circulating TAG (Rayner et al. 2011a). The factors that might explain these discrepancies need further investigation.

 
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