Inhibition of miR-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver

Abstract

MicroRNAs (miRNAs) are important regulators and potential therapeutic targets of metabolic disease. In this study we show by in vivo administration of locked nucleic acid (LNA) inhibitors that suppression of endogenous miR-29 lowers plasma cholesterol levels by ~40%, commensurate with the effect of statins, and reduces fatty acid content in the liver by ~20%. Whole transcriptome sequencing of the liver reveals 883 genes dysregulated (612 down, 271 up) by inhibition of miR-29. The set of 612 down-regulated genes are most significantly over-represented in lipid synthesis pathways. Among the up-regulated genes are the anti-lipogenic deacetylase sirtuin 1 (Sirt1) and the anti-lipogenic transcription factor aryl hydrocarbon receptor (Ahr), the latter of which we demonstrate is a direct target of miR-29. In vitro radiolabeled acetate incorporation assays confirm that pharmacologic inhibition of miR-29 significantly reduces de novo cholesterol and fatty acid synthesis. Our findings indicate that miR-29 controls hepatic lipogenic programs, likely in part through regulation of Ahr and Sirt1, and therefore may represent a candidate therapeutic target for metabolic disorders such as dyslipidemia.

Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse non-alcoholic steatohepatitis

“…Indeed, here, we identified miR-29a/b/c to be affected by Dicer1-deficiency; thus, their inhibitory effect on HMGCR mRNA and protein expression (Figure 4) was diminished by Dicer1 knockout. Specifically, we have revealed that miR29a/b/c are employing their inhibitory effects by acting via their seed region to form hybrids with the 3'-UTR of HMGCR mRNA, which is in agreement with a recently published report [49] . Excess cholesterol and 25-hydroxycholesterol decreased HMGCR expression in vitro ( Figure 5), which may be due to the increased miR-29a levels, suggesting that in normal conditions, the cells induced miR-29a expression to reduce HMGCR expression and to balance cellular cholesterol levels.…”

“…The inhibition of miR29a also slightly increased the hepatic cholesterol level [49,52] . However, when mice were fed with a high-fat diet (HFD) for 16 weeks, the inhibition of miR-29a caused a 2-fold FC accumulation in the liver of mice, more obvious than the accumulation of TG [52] .…”

A-to-I RNA Editing Up-regulates Human Dihydrofolate Reductase in Breast Cancer

“…13). In support of this prediction, a recent study reported that the 3'-UTR of human AhR was directly recognized by miR-29a in Huh-7 cells (Kurtz et al, 2015), although a functional MRE for miR-29a has not been experimentally identified. miR-29 family members, including miR-29a, are known to be down-regulated in human fibrotic livers (Roderburg et al, 2011).…”

MicroRNA Pharmacoepigenetics: Posttranscriptional Regulation Mechanisms behind Variable Drug Disposition and Strategy to Develop More Effective Therapy

“…There is also evidence suggesting that CYP enzymes might be regulated by miRNA through AHR pathways (Table 3). For instance, in vivo administration of locked nucleic acid-modified antisense miR-29 antagomir to mice altered the expression of many hepatic proteins, including the upregulation of Ahr, Cyp1a1, Cyp2b10, Cyp3a11, and Cyp4a12 (Kurtz et al, 2015). A conserved miR-29 MRE site within the 39UTR of human AHR and mouse Ahr was then validated by luciferase reporter assay, demonstrating that AHR is a direct target of miR-29.…”