Sorting out cholesterol metabolism: novel insights into the mechanism of endosomal trafficking of lipoprotein receptors

Abstract

This thesis highlights a crucial role for the CCC and WASH complexes in hepatic cholesterol uptake by orchestrating the endosomal recycling of LDLR, LRP1 and SR-BI. We provided novel insights into how the different CCC components interrelate to maintain the integrity of the CCC complex. We introduced somatic CRISPR/Cas9 gene editing technology, a sophisticated methodology to study the interplay between different endosomal sorting complexes in vivo. Using this technology, we found that both retriever and retromer likely participate in the CCC-WASH axis to facilitate endosomal recycling of LDLR, but not SR-BI. Moreover, we showed that hepatic retromer controls plasma TG levels independently of the CCC-WASH pathway. Overall, this thesis provides novel insights into the intricate interplay between the different protein complexes of endosomal sorting machineries in the regulation of lipid metabolism.