A new therapeutic target against diseases caused by lipid accumulation in cells


La recerca està liderada per Carles Enrich i Carles Rentero, professors de la Unitat de Biologia Cel·lular del Departament de Biomedicina de la Facultat de Medicina i Ciències de la Salut de la UB i del Centre de Recerca Biomèdica CELLEX (IDIBAPS-UB).

La recerca està liderada per Carles Enrich i Carles Rentero, professors de la Unitat de Biologia Cel·lular del Departament de Biomedicina de la Facultat de Medicina i Ciències de la Salut de la UB i del Centre de Recerca Biomèdica CELLEX (IDIBAPS-UB).


Les cèl·lules que tenen el gen NPC1 mutat acumulen colesterol en vesícules a prop del nucli. Quan se silencia l'expressió d'AnxA6 en les cèl·lules amb NPC1 mutat, el colesterol es distribueix de manera normal per la cèl·lula a causa de l'increment de MCS entre les vesícules i el reticle endoplasmàtic. Si hi ha un excés de colesterol, la cèl·lula l'acumula als cossos lipídics, on no interferirà amb el funcionament cel·lular.

Les cèl·lules que tenen el gen NPC1 mutat acumulen colesterol en vesícules a prop del nucli. Quan se silencia l’expressió d’AnxA6 en les cèl·lules amb NPC1 mutat, el colesterol es distribueix de manera normal per la cèl·lula a causa de l’increment de MCS entre les vesícules i el reticle endoplasmàtic. Si hi ha un excés de colesterol, la cèl·lula l’acumula als cossos lipídics, on no interferirà amb el funcionament cel·lular.

Researchers from the UB and the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) found a new molecular mechanism involved in the regulation of the cholesterol movement in cells, an essential process for a proper cell functioning. The study, published in the journal Cellular and Molecular Life Sciences, also identifies the protein Annexin A6 (AnxA6) as a key factor in this regulation and as a potential therapeutical target against diseases that are caused by the accumulation of cholesterol and other lipids in endosomes, such as the Niemann-Pick disease type C1, a minority genetic disease with no cure that causes hepatic damage and a type of dementia.

The study is led by Carles Enrich and Carles Rentero, lecturers at the unit of Cell Biology in the Department of Biomedicine of the Faculty of Medicine and Health Sciences at the UB and the CELLEX Biomedical Research Center (IDIBAPS-UB). This is the result of six years of research and a collaboration with Thomas Grewal, from the University of Sydney; Elina Ikonen, from the University of Helsinki, and the research group on Lipids and Cardiovascular Pathology of the Biomedical Research Institute at Hospital Sant Pau.

Study with the CRISPR/Cas9 editing technology

Cholesterol is essential in the organization of membranes and it also modulates the vesicular trafficking, basic mechanisms for the cell functioning. To coordinate and regulate the balance, or homeostasis in cholesterol, cells have developed a molecular machinery, which is not fully understood yet. “The understanding of these mechanisms is very important to treat diseases in which there is an accumulation of cholesterol and other lipids which cause serious physiological alterations in the liver, spleen and especially the nervous system”, note Carles Enrich and Carles Rentero.

One of such diseases is Niemann-Pick type C1, caused by a mutation in the NPC1 gene, which causes the accumulation of cholesterol in the cell interior of the endosome. In order to study this mechanism, researchers used the CRISPR/Cas9 genetic editing technique to block a molecule –AnxA6 protein- in cells with the phenotype of the disease. The effect of such block resulted in the release of the endosome cholesterol, showing the essential role of this protein in the regulation of cholesterol transfer.

Increasing membrane contact sites

The results of the study also show this release occurred thanks to a significant increase of membrane contact sites (MCS), nanometric structures that can be seen through electronic microscopy. According to the authors, these membrane contact sites are just a few inside the cells of the affected patients, therefore, silencing AnxA6 induces the creation of MCS, stops the effect of the NPC1 gene mutation and redirects cholesterol towards other cell compartments, returning to cell normality.

“Results could help treating the clinical impact of the accumulation of cholesterol in Niemann-Pick and about twelve more diseases, among which are different types of cancer (pancreas, prostate, breast), in which the lipidic metabolism plays a fundamental role”, note the researchers.

A new paradigm in the study of the cholesterol cell transport

The membrane contact sites being involved in the cholesterol transport is a pioneering result in this field, since researchers thought –so far- that lipid transport was carried out through vesicles and a type of specialized proteins. “We do not know much about the functioning and dynamics of membrane contact sites, but this study goes together with recent ones and shows MCS are a new paradigm for the understanding of the regulation, transport and homeostasis of lipids, cholesterol and calcium”, conclude the researchers.

Article:

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-Cortés V.; Rye K-A.; Heeren J.; Lu A.; Pol A.; Tebar F.; Ikonen E.; Grewal T.; Enrich C. i Rentero C. “Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells”. Cellular and Molecular Life Sciences, novembre de 2019. Doi: https://doi.org/10.1007/s00018-019-03330-y

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