Abstract
Background:
High plasma cholesterol levels are a major risk factor for atherosclerosis. Plasma cholesterol can be reduced by inhibiting lipoprotein production; however, this is associated with steatosis. Previously we showed that lentiviral mediated hepatic over-expression of microRNA-30c (miR-30c) reduced hyperlipidemia and atherosclerosis in mice without causing hepatosteatosis. Since viral therapy would be formidable, we tested the hypothesis that a miR-30c oligonucleotide mimic can mitigate hyperlipidemia and atherosclerosis without causing steatosis.
Methods and results:
Delivery of a miR-30c mimic to the liver diminished Western diet-induced hypercholesterolemia in C57BL/6J wild type mice. Reductions in plasma cholesterol levels were significantly correlated with increases in hepatic miR-30c levels. Long-term dose escalation studies showed that miR-30c mimic causes sustained reductions in plasma cholesterol without increasing hepatic lipids and plasma transaminases. Further, miR-30c mimic significantly reduced hypercholesterolemia and atherosclerosis in
Apoe
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mice without causing steatosis or increasing plasma transaminases. Mechanistic studies indicated that miR-30c mimic reduced hepatic lipoprotein production, in part by reducing microsomal triglyceride transfer protein (MTP) activity. This is supported by the observation that miR-30c did not lower plasma cholesterol in liver-specific MTP deficient mice but did reduce hepatic lipid synthesis. In order to understand why there was no increase in hepatic lipids, we carried out whole transcriptome studies by RNA-sequencing. Bioinformatic analysis of the data revealed that genes down-regulated by miR-30c mimic are most significantly enriched for lipid synthesis pathways. Consistent with this finding, we showed that miR-30c mimic reduced fatty acid and glycerolipid synthesis in the liver but had no effect on hepatic β-oxidation.
Conclusions:
We conclude that miR-30c reduces plasma cholesterol by targeting MTP and prevents hepatosteatosis by repressing lipid synthesis programs in the liver. These findings suggest that increasing hepatic miR-30c levels may be a viable treatment modality for hypercholesterolemia and atherosclerosis.