miR-122

The first miRNA identified as a major regulator of cholesterol metabolism was miR- 122 (Elmen et al. 2008; Esau et al. 2006; Krutzfeldt et al. 2005). This miRNA is the most abundant miRNA in the liver, accounting for at least 80% of the total miRNA content. Importantly, pharmacological inhibition of miR-122 in mice and nonhuman primates using ASOs or genetic ablation of miR-122 in mice results in a marked reduction of plasma cholesterol levels (Elmen et al. 2008; Esau et al. 2006; Krutzfeldt et al.

2005). Despite these intriguing findings, the molecular mechanisms by which miR-122 controls lipoprotein metabolism remain largely unknown. It is thought that the reduced circulating cholesterol observed in mice treated with miR-122 antagonists is mediated by a combination of different metabolic processes including inhibition of cholesterol and fatty acid biosynthesis, enhanced fatty acid oxidation, and decreased VLDL secretion (Elmen et al. 2008; Esau et al. 2006; Krutzfeldt et al. 2005). However, the direct miR-122 target genes that influence lipid metabolism remain largely unknown. While these findings suggest that the use of miR-122 inhibitors might represent a useful approach to treat dyslipidemia, two recent studies have shown that miR-122 deficiency in mice results in hepatic steatosis, fibrosis, and hepatocellular carcinoma, raising concerns about the potential therapeutic value of miR-122 inhibitors.

 
Source
< Prev   CONTENTS   Source   Next >