In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 130, No. suppl_2 ( 2014-11-25)
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.130.suppl_2.13049
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2014
detail.hit.zdb_id:
1466401-X
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