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Cholesterol and Sugar Uptake Mechanisms

Periodic Reporting for period 3 - CSUMECH (Cholesterol and Sugar Uptake Mechanisms)

Reporting period: 2018-07-01 to 2019-12-31

Cardiovascular disease, diabetes and cancer have a dramatic impact on modern society, and in great part are related to uptake of cholesterol and sugar. We still know surprisingly little about the molecular details of the processes that goes on in this essential part of human basic metabolism. Our work addresses cholesterol and sugar transport and aims to elucidate the molecular mechanism of cholesterol and sugar uptake in humans. It moves the frontiers of the field by shifting the focus to molecular studies in vitro allowing hitherto untried structural and biochemical experiments to be performed.
Cholesterol uptake from the intestine is mediated by the membrane protein NPC1L1. Despite extensive research, the molecular mechanism of NPC1L1-dependent cholesterol uptake still remains largely unknown. Facilitated sugar transport in humans is made possible by sugar transporters called GLUTs, and every cell possesses these sugar transport systems. For all these uptake systems structural information is lacking to address important mechanistic questions to help elucidate their molecular mechanism. An improved understanding of cholesterol and sugar homeostasis has tremendous potential for improving general public health, and furthermore this proposal will help to uncover general principles of endocytotic uptake and facilitated diffusion systems at the molecular level.
Using structural biology methods we have published the binding mode of the human sugar transporter GLUT1 to important small-molecule inhibitors (most prominently cytochalasin B) that have been used in research for decades. Furthermore these results gives clues towards new drug designs that could inhibit cellular sugar uptake. We are now pushing these results further towards a mechanistic model for how sugar transport might be regulated.
Work towards elucidating the mechanisms behind sterol homeostasis is still ongoing.
At the end of the grant period, we expect to have published a more detailed description of how sugar is moved across cellular membranes, both in humans and other organisms.
We also expect to have the first detailed atomic description of how sterol are integrated into the cellular membrane using the NPC1/NPC2 homeostasis system.