Abstract 13049: Microrna-33, Located Within Srebf2 Intron, Regulate Fatty Acid Synthesis via Targeting SREBP-1 in vivo
Introduction: MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote degradation. Recent reports, including ours, indicated that miR-33 located within the intron of sterol regulatory element binding protein (SREBP) 2 controls cholesterol homeostasis and can be a possible therapeutic target for treating atherosclerosis. Unexpectedly, miR-33 deficient (miR-33-/-) mice fed high fat diet (HFD) developed severe fatty liver and the mechanisms were investigated.
Methods and Results: The liver weight of miR-33-/- mice were about 1.5 times heavier than that of miR-33+/+ mice and histological examination revealed that miR-33-/- mice developed severe fatty liver under HFD feeding. In order to determine the cause of the fatty liver observed in miR-33-/- mice fed HFD, we analysed the gene expression profiles using the liver of miR-33+/+ and miR-33-/- mice fed normal chow at the age of 16 weeks when they didn’t show fatty liver. As a result, genes involved in fatty acid metabolism were upregulated in miR-33-/- mice. Among them we found SREBP-1 as a new potential target gene of miR-33 in silico and confirmed that miR-33 targets the 3’UTR of SREBP-1 in
vitro. The expression of SREBP-1 and de novo fatty acid production were significantly increased in the liver of miR-33-/- mice. We further intercrossed miR-33-/- mice with Srebf1+/- mice and fed them HFD. Hepatic steatosis was reversed in miR-33-/-Srebf1+/- mice compared with miR-33-/-Srebf1+/+ mice by histological analysis and measurement of triglyceride levels. The expression levels of genes involved in fatty acid synthesis, including Scd1, Fasn, Acc1, and Pparg were increased in miR-33-/-Srebf1+/+ mice compared with miR-33+/+Srebf1+/+ mice, and those increase were reversed in miR-33-/-Srebf1+/- mice.
Conclusions: miR-33 regulates lipogenic pathway via regulating SREBP-1 as a novel target in vivo. In sterol-depleted conditions, acetyl-CoA might be preferred as a substrate for cholesterol production and not for fatty acid production by the downregulation of SREBP-1 through the upregulation of miR-33. Conversely, in cholesterol-rich condition, acetyl-CoA might be preferred as a substrate for fatty acid production through the downregulation of miR-33.
Author Disclosures: T. Nishino: None. T. Horie: None. O. Baba: None. Y. Kuwabara: None. T. Nakao: None. M. Nishiga: None. S. Usami: None. M. Izuhara: None. Y. Ide: None. F. Nakazeki: None. S. Koyama: None. M. Yokode: None. T. Kita: None. T. Kimura: None. K. Ono: None.
- © 2014 by American Heart Association, Inc.