http://www.sciencemag.org/cgi/rapidpdf/science.1189123v1.pdf
http://www.sciencemag.org/cgi/rapidpdf/science.1189123.pdf
The two papers both identified mir-33 as a regulator of cholesterol homeostasis, particularly through its inhibitory effect on ABCA1. Like some other miRs, mir33 lies within the SREBP2 intron and is cotranscribed with SREBP2, thus the regulation of cholesterol level is coordinated. It will be interesting to address mir33 function that is independent of SREBP2, which can be attained, for example, under a condition that SREBP2 proteolysis is blocked but the transcription is still responsive to cholesterol level changes. Another mir (let-7c) potentially targets CCR7, and it is shown in the screen to be affected by cholesterol change in macrophages, whereas in my screen( LXR activated vs not) there is not much change.
now a comment also comes out in the same print issue.
ReplyDeletehttp://www.sciencemag.org/cgi/content/full/328/5985/1495
Cholesterol regulation is a really interesting and seemingly unique mechanism especially at the molecular level. Question: I was looking at some of the array data and it seems that ABCA1 expression was enhanced dramatically in the LXRalpha S198A cells compared to WT. I noticed, though in Inez's paper that the LXR S198A mutation reduced ABCA1 expression for lower doses of the T-compound. I'm not sure of the details of the array but it made me think about targeting both the kinase (Ck-2?) and miR-33. Maybe combined, this would have a more impactful affect on HDL levels. Have the dynamics of mir33 and LXR regulation of ABCA1 been explored? Maybe agents that antagonize miR-33 will enhance the effect of LXR on ABCA1 expression.
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ReplyDeleteI like how the authors were able to inhibit miR-33 function and, as result, increase plasma HDL levels in mice. This demonstrates that this may be a plausible therapy in humans. Although, it is most likely that there are other miRNAs that regulate ABCA1 and that their inhibition, in addition to miR-33, could further increase plasma HDL levels. Here is why I think this...
ReplyDeleteI noticed in the paper by Najafi-Shoushtari that in liver cells, inhibition of both Drosha and Dicer can increase ABCA1 expression. However, in fibroblast IMR-90 and macrophage J774 cells, only inhibition of Drosha, but not Dicer, can increase ABCA1 protein levels. This made me ask, are there other proteins besides Dicer that can make siRNAs?
I asked a friend who is an miRNA expert and apparently there are. Cheloufi et al. Nature 2010 and Karginov et al. Mol Cell 2010 show that Ago2 can function like DIcer on certain miRNAs and that Drosha can cleave mRNAs that are not miRNAs.
Therefore, it looks like different RNAi machinery are being used to inhibit ABCA1 expression in liver vs. fibroblasts and macrophages and may explain why the authors do not see strong effects of inhibiting miR-33 on ABCA1 expression in the liver. Probably, ABCA1 is targeted by other Dicer-processed miRNA in the liver and miR-33 may not be processed by Dicer?