Catalan researchers have demonstrated a new molecular mechanism involved in the regulation of cholesterol movement within the cell, a process essential for proper cell function. The study, in which the Lipids and Cardiovascular Pathology Group of the Biomedical Research Institute of the Hospital de Sant Pau participates, was published in the journal Cellular and Molecular Life Sciences. This work also identifies Annex A6 protein (AnxA6) as a key factor in this regulation and a potential therapeutic target against disorders caused by the cellular accumulation of cholesterol and other lipids in endosomes. A type of disorder found in Niemann-Pick disease type C1, a rare genetic pathology without care that causes liver damage and finally a type of dementia.
The research is led by Carles Enrich and Carlos Rentero, professors of the Cellular Biology Unit of the Department of Biomedicine of the Faculty of Medicine and Health Sciences of the UB and the Center for Biomedical Research CELLEX (IDIBAPS-UB). It is the culmination of six years of research and close collaboration with Thomas Grewal (University of Sydney) and Elina Ikonen (University of Helsinki), and with the Lipids and Cardiovascular Pathology Group of the Biomedical Research Institute of the Hospital de Sant Pau.
Study with the technique of genetic editing CRISPR / CAS9
Cholesterol is fundamental for the organization of membranes and also modulates vesicular transport, basic mechanisms for cell function. To coordinate and regulate the balance -or homeostasis- of cholesterol, cells have developed sophisticated molecular machinery that is not yet fully understood. “Understanding these mechanisms is also very important to address diseases in which the accumulation of cholesterol and other lipids causes serious physiological alterations in the liver, spleen, and especially the nervous system,” explain Carles Enrich and Carlos Rentero.
One of these diseases is the Niemann-Pick C1 type, caused by a mutation in the NPC1 gene that causes the accumulation of cholesterol inside cells, in vesicles called endosomes. To study this mechanism, the researchers have used the CRISPR / CAS9 genetic editing technique, which allows blocking a molecule – the AnxA6 protein – in cells with the phenotype of the disease. The effect of this blockade was the release of cholesterol from endosomes, which demonstrates the essential role of this protein in regulating the transport of cholesterol in the cell.
Increased membrane contacts
The results of the work also show that this release occurred thanks to the significant increase in membrane contact sites (MCS), nanometric structures that can only be seen by electron microscopy. According to the authors, these membrane contacts are scarce within the cells of affected patients: thus, the silencing of the AnxA6 protein serves to induce the formation of MCS, cancel out the effects of the genetic mutation in the NPC1 gene and redirect cholesterol to other cell compartments, which restores cell normality.
“The results could significantly help treat the clinical impact of the accumulation of cholesterol from Niemann-Pick disease and at least a dozen other diseases in which lipid metabolism plays a fundamental role, among which different types of cancer (pancreas, prostate, breast),” explain the researchers.
A new paradigm in the study of the cellular transport of cholesterol
The discovery of the involvement of membrane contacts in the transport of cholesterol is a pioneering result in this field, since until now it was thought that the transport of lipids was carried out by means of vesicles and specialised proteins. “Although very little is known about the functioning and dynamics of membrane contacts, this study joins other very recent studies and shows that MCS are a new paradigm for understanding the regulation, transport and homeostasis of lipids, cholesterol and calcium,” conclude the researchers.
Article reference:
Meneses-Salas, E.; García-Melero, A. ; Kanerva, K. ; Blanco-Muñoz, P. ; Morales-Paytuvi, F.; Bonjoch, J.; Casas, J.; Egert, A.; Beevi, S. S.; Jose, J.; Llorente-Cortésn V.; Ryen K-A.Heerenn J.; Lun A.; Poln A.; Tebanr F.; Ikonenn E.; Grewaln T.; Enrichn C. i Rentero, C. “Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells”. Cellular and Molecular Life Sciences, November 2019. Doi: https://doi.org/10.1007/s00018-019-03330-y
