Flotillins play an essential role in Niemann-Pick C1-like 1-mediated cholesterol uptake

Ge, Liang; Qi, Wei; Wang, Limin; Miao, Hong‐Hua; Qu, Yuanzhi; Li, Bo-Liang; Song, Bao-Liang

doi:10.1073/pnas.1014434108

Cited by 141 publications

(145 citation statements)

References 28 publications

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“…Although there is now a considerable body of evidence supporting a role for flotillins in endocytosis, the mechanistic details of how they act are still not clear. Recent data suggests that endocytosis of the membrane proteins NPC1L1, APP and DAT (SLC6A3), all previously believed to be internalised through clathrin-coated pits, is dependent on flotillin (Cremona et al, 2011;Ge et al, 2011;Schneider et al, 2008). This can be explained in different ways as depicted here.…”

Section: New Insights and New Cargoesmentioning

confidence: 87%

The roles of flotillin microdomains – endocytosis and beyond

Otto

Nichols

2011

Journal of Cell Science

236

222

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SummaryFlotillins are membrane proteins that form microdomains in the plasma membrane of all mammalian cell types studied to date. They span the evolutionary spectrum, with proteins related to flotillins present in bacteria, fungi, plants and metazoans, which suggests that they perform important, and probably conserved, functions. Flotillins have been implicated in myriad processes that include endocytosis, signal transduction and regulation of the cortical cytoskeleton, yet the molecular mechanisms that underlie flotillin function in these different cases are still poorly understood. In this Commentary, we will provide an introduction to these intriguing proteins, summarise their proposed functions and discuss in greater detail some recent insights into the role of flotillin microdomains in endocytosis that have been provided by several independent studies. Finally, we will focus on the questions that are raised by these new experiments and their implications for future studies.

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Section: New Insights and New Cargoesmentioning

confidence: 87%

The roles of flotillin microdomains – endocytosis and beyond

Otto

Nichols

2011

Journal of Cell Science

236

222

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“…Recent publications have revealed a role for flotillins in the endocytosis of the Alzheimer amyloid precursor protein (APP), the amyloidogenic processing of which requires its endocytosis (75). In addition, Niemann-Pick C1-like 1 (NPC1L1), an important mediator of the uptake of dietary cholesterol, relies on flotillins for its endocytosis, and depletion of flotillins drastically reduces cholesterol uptake in cultured cells (76). Curiously, APP, NPC1L1 and DAT are all endocytosed by means of clathrin mediated endocytosis, whereas flotillins as raft associated proteins have been rather suggested to define a non-clathrin endocytosis pathway, and there is very little colocalization between clathrin and flotillins (13).…”

Section: Flotillins In Endocytosismentioning

confidence: 99%

Function of Flotillins in Receptor Tyrosine Kinase Signaling and Endocytosis: Role of Tyrosine Phosphorylation and Oligomerization

Kurrle¹,

John²,

Meister³

et al. 2012

Protein Phosphorylation in Human Health

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“…16,17) In terms of cholesterol uptake via NPC1L1, it has been reported that the N-terminal domain of NPC1L1 binds cholesterol and promotes formation of cholesterol-enriched membrane microdomains comprising lipid raft proteins flotillin-1 and flotillin-2. 8,18) Clathrin is then recruited to internalize the NPC1L1-flotillin-cholesterol membrane microdomains. Cholesterol binding the N-terminal domain of NPC1L1 released the region of a specific amino acids sequence, YVNXXF (where X stands for any amino acids) and enabled to bind Numb, a clathrin adaptor.…”

Section: Effect Of Cholesterol In Lipid Emulsion Particles On the Uptmentioning

confidence: 99%

An Approach to Improve Intestinal Absorption of Poorly Absorbed Water-Insoluble Components <i>via</i> Niemann–Pick C1-Like 1

Takekawa

Sato

Yamaki

et al. 2016

Biological & Pharmaceutical Bulletin

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Dietary and biliary cholesterol absorption contributes to the maintenance of tight control of cholesterol homeostasis. Cholesterol is present as mixed micelles formed by bile salts and phospholipids in the intestinal lumen. Recently, Niemann-Pick C1-Like 1 (NPC1L1) transporter was identified as being critical for cholesterol absorption. However, the uptake mechanism of an enveloped substrate of NPC1L1 in whole lipid emulsion particles remains unclear. In this study, we investigated the uptake mechanism of a substrate of NPC1L1 in lipid emulsion particles. We also investigated whether these particles containing cholesterol can improve the intestinal absorption of other lipophilic components via NPC1L1. The uptake of lysophosphatidylcholine (LPC)-4,4-difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-3a,4a-diaza-s-indacene-3-propionic acid saccinimidyl ester (BODIPY), a fluorescently labeled phospholipid, in lipid emulsion particles containing cholesterol (1 µM) was significantly increased compared to that without cholesterol in Caco-2 cells. On the other hand, its increased uptake was significantly inhibited by ezetimibe, a selective inhibitor of NPC1L1. These results suggested that not only cholesterol but also some components in lipid emulsion particles are taken up into enterocytes via NPC1L1. We also examined an approach to improve intestinal absorption of a poorly absorbed water-insoluble component, coenzyme Q10 (CoQ10), by this mechanism. The uptake of CoQ10 in lipid emulsion particles containing cholesterol was significantly increased compared to that without cholesterol. Its increased uptake was significantly inhibited by ezetimibe. Though it is still not clear whether CoQ10 is a substrate of NPC1L1, there is a potential for improvement of the absorption of poorly absorbed components by lipid emulsion particles containing cholesterol.Key words Niemann-Pick C1-Like 1; absorption; cholesterol; emulsion; coenzyme Q10Intestinal absorption is an important process in the maintenance of homeostasis in the body. Cholesterol homeostasis is a highly regulated balance of de novo synthesis, dietary cholesterol absorption, and biliary clearance and excretion. Although the cholesterol uptake mechanism in the intestinal lumen is not fully understood, the identification of ezetimibe as a selective inhibitor of intestinal cholesterol absorption suggested that these processes are mediated by a specific transport system rather than by passive diffusion.1) In 2004, Altmann et al. identified Niemann-Pick C1-Like 1 (NPC1L1) as an apically localized sterol transporter in the small intestine.2) NPC1L1 is highly expressed in the small intestine, particularly in the upper intestine.2,3) NPC1L1 protein has 13 predicted transmembrane domains and extensive N-linked glycosylation sites located within the extracellular loops and it contains a sterol sensing domain (SSD).4) It has predicted that the substrates of NPC1L1 have sterol domains and have been mainly thought to transport the substance involving the sterol structure.Cholesterol is pre...

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Flotillins play an essential role in Niemann-Pick C1-like 1-mediated cholesterol uptake

Cited by 141 publications

References 28 publications

The roles of flotillin microdomains – endocytosis and beyond

The roles of flotillin microdomains – endocytosis and beyond

Function of Flotillins in Receptor Tyrosine Kinase Signaling and Endocytosis: Role of Tyrosine Phosphorylation and Oligomerization

An Approach to Improve Intestinal Absorption of Poorly Absorbed Water-Insoluble Components <i>via</i> Niemann–Pick C1-Like 1

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