EHD2-mediated restriction of caveolar dynamics regulates cellular lipid uptake
Posted on: 4 February 2019
Preprint posted on 4 January 2019
Article now published in Proceedings of the National Academy of Sciences at http://dx.doi.org/10.1073/pnas.1918415117
Categories: cell biology, physiology
Background:
Caveolae are invaginations of the plasma membrane with a size of 50-100 nm. They are abundant in fat tissue, muscles and endothelium. They participate in transmembrane signalling pathways (1) and play a pivotal role in lipid metabolism. Knock-out of the major proteins caveolin1 and cavin1 that form caveolae leads to a disturbed lipid metabolism associated with a lack of caveolae and less body fat. Absence of caveolae leads to a defect in lipid uptake, which is characterized by increased triglycerides in the blood and severe health problems.
There is another protein that plays an important role in caveolae formation and stabilization: Eps15 homology domain containing protein 2 (EHD2). It is localized in the neck of caveolae. So far, it has been shown that knock-down of EHD2 in cell culture lead to an increased motility of caveolae. In this study the authors have generated and characterized an EHD2 knock-mouse. They have investigated changes in in lipid metabolism and also ultrastructural and dynamic changes of caveolae in the affected tissues.
Key findings:
As expected, EHD2 was highly expressed in tissues with plenty of caveolae (heart, blood vessels, brown adipose tissue). EHD2 knock-out mice had more fat surrounding the heart and in liver and muscles. Furthermore white adipocytes of KO mice were bigger compared to that of control animals. The authors continued to investigate the effect of EHD2 KO on a cellular level in cultured adipocytes of KO mice. Differentiated EHD2 KO adipocytes had more lipids and were a little larger than the control cells. The authors ruled out secondary metabolic effects by knocking down EHD2 in cultured adipocytes, which showed similar results as before. There was no effect of EHD2 KO on glucose uptake and lipophagy which led the authors to conclude that EHD2 is pivotal for coordination of fatty acid uptake.
The authors also analyzed the ultrastructure of caveolae of white and brown adipose tissue of EHD2 KO mice. Intriguingly, they found that many caveolae were not connected to the plasma membrane anymore as seen in the figure below while number and size were unchanged.
By TIRF microscopy of isolated mouse embryonic fibroblasts from EHD2 KO mice they could show that caveolar mobility and also endocytosis were increased. Furthermore, the authors provided evidence that CD36 acts as mediator for the increased fatty acid uptake in CD36 KO adipocytes. Finally, the authors could show that in obesity models EHD2 expression is reduced.
What I liked about this preprint:
With this preprint the authors have managed to investigate the function of a gene on the metabolic as well as on the cell biology level. Thereby they were able correlate a phenotype of increased lipid uptake on the organ level with striking ultrastructural and live-cell imaging data of detached and dynamic caveolae. They also use the proper controls to rule out secondary metabolic effects on lipid turnover and show that the knock-out of EHD2 alone causes this peculiar phenotype.
Questions and further directions:
It would be interesting to investigate possible changes of the actin cytoskeleton in adipocytes of EHD2 KO mice since it might be involved in the detachment of caveolae.
Future studies could focus on the signalling pathways involving EHD2 and CD36 to find other proteins involved.
Also, possible changes in the lipid composition of caveolae of EHD2 KO mice would be an interesting topic to look at.
Furthermore, I am curious if in obesity mouse models other proteins that are involved in caveolae formation are also down- or up-regulated.
Literature:
- Cheng, J. P. X. & Nichols, B. J. Caveolae: One Function or Many? Trends Cell Biol. 26, 177–189 (2016).
doi: https://doi.org/10.1242/prelights.7805
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