Plasma high-density lipoprotein (HDL) levels show a strong inverse correlation with atherosclerotic vascular disease. Previous studies have demonstrated that antagonism of miR-33 in vivo increases circulating HDL and reverse cholesterol transport (RCT), thereby reducing the progression and enhancing the regression of atherosclerosis. While the efficacy of short-term anti-miR-33 treatment has been previously studied, the long-term effect of miR-33 antagonism in vivo remains to be elucidated. Here, we show that long-term therapeutic silencing of miR-33 increases circulating triglyceride (TG) levels and lipid accumulation in the liver. These adverse effects were only found when mice were fed a high-fat diet (HFD). Mechanistically, we demonstrate that chronic inhibition of miR-33 increases the expression of genes involved in fatty acid synthesis such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) in the livers of mice treated with miR-33 antisense oligonucleotides. We also report that anti-miR-33 therapy enhances the expression of nuclear transcription Y subunit gamma (NFYC), a transcriptional regulator required for DNA binding and full transcriptional activation of SREBP-responsive genes, including ACC and FAS. Taken together, these results suggest that persistent inhibition of miR-33 when mice are fed a high-fat diet (HFD) might cause deleterious effects such as moderate hepatic steatosis and hypertriglyceridemia. These unexpected findings highlight the importance of assessing the effect of chronic inhibition of miR-33 in non-human primates before we can translate this therapy to humans.
Although short-term anti-miR-33 therapy was reported to increase circulating HDL-cholesterol and reduce atherosclerosis, long-term adverse effects are here shown for the first time in mice fed a high-fat diet to result in hypertriglyceridemia and moderate hepatic steatosis.
- The effect of long-term inhibition of miR-33 was determined in mice fed a chow diet and high-fat diet.
- Chronic therapeutic silencing of miR-33 increased circulating triglycerides and lipid accumulation in the livers of mice fed a high-fat diet.
- miR-33 inhibition raised the expression of genes involved in fatty acid synthesis and lipid metabolism.
- Further studies are warranted to understand the complex gene regulatory network controlled by miR-33.