A role for smooth endoplasmic reticulum membrane cholesterol ester in determining the intracellular location and regulation of sterol-regulatory-element-binding protein-2

Iddon, Christopher; Wilkinson, Jane; Bennett, Andrew J.; Bennett, J. R.; Salter, Andrew M.; Higgins, Joan A.

doi:10.1042/0264-6021:3580415

Cited by 8 publications

(6 citation statements)

References 48 publications

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“…In conclusion, our results clearly show suppression of protein aggregation by bile acids through enhancement of α-crystallin chaperone activity; its biological significance is further supported by our recent findings that treatment of TUDCA suppressed the UPR and delayed LEC death in galactose-fed rat lenses (Mulhern et al 2007), suggesting that bile acids may also enhance and retain the chaperone activity of Bip in the cholesterol-producing ER membrane (Ridsdale et al 2006;Iddon et al 2001). Bip is a chaperone protein in the ER of LECs that recognizes unfolded proteins and suppresses prolonged ER stress.…”

Section: Discussionsupporting

confidence: 70%

Cholesterol-derived bile acids enhance the chaperone activity of α-crystallins

Song

Liang

Mulhern

et al. 2011

Cell Stress and Chaperones

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Human lens membranes contain the highest cholesterol concentration of any known biological membranes, but it significantly decreases with age. Oxygenation of cholesterol generates numerous forms of oxysterols (bile acids). We previously showed that two forms of the bile acid components-ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA)-suppressed lens epithelial cell death and alleviated cataract formation in galactosemic rat lenses. We investigated whether these compounds also suppress the thermal aggregation of human lens crystallins. Total water-soluble (WS) proteins were prepared from human lenses, and recombinant human crystallins (αA-, αB-, βB2-, and γC-crystallin) were generated by a prokaryotic expression system and purified by liquid chromatography. The light scattering of proteins in the presence or absence of UDCA or TUDCA was measured using a spectrofluorometer set at Ex/Em=400/ 400 nm. Protein blot analysis was conducted for detection of α-crystallins in the human lens WS proteins. High concentrations of UDCA and TUDCA significantly suppressed thermal aggregation of total lens WS proteins, which contained a low level of αA-/αB-crystallin. Spectroscopic analysis with each recombinant human lens crystallin indicated that the bile acids did not suppress the thermal aggregation of γC-, βB2-, αA-, or αB-crystallin. Combination of α-crystallin and bile acid (either UDCA or TUDCA) suppressed thermal aggregation of each individual crystallin as well as a non-crystallin protein, insulin. These results suggest that UDCA or TUDCA protects the chaperone activity of α-crystallin. It is believed that these two naturally occurring intermediate waste products in the lens enhance the chaperone activity of α-crystallin. This finding may lead to the development of UDCA and TUDCA as anticataract agents.

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Section: Discussionsupporting

confidence: 70%

Cholesterol-derived bile acids enhance the chaperone activity of α-crystallins

Song

Liang

Mulhern

et al. 2011

Cell Stress and Chaperones

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“…This point raises the question of the physiological role of this particular cell type in the proximal region of the epididymal duct. Apical cells are as previously demonstrated in hamster ( 22 ). In parallel, apoE expression, an apoprotein acceptor of effl uxed cholesterol, was also investigated and no change at all was recorded (data not shown).…”

Section: Ce Accumulation Enhances Apoptosis In Segment 1 Epithelial Cmentioning

confidence: 81%

LXR and ABCA1 control cholesterol homeostasis in the proximal mouse epididymis in a cell-specific manner

Ouvrier¹,

Cadet²,

Vernet³

et al. 2009

Journal of Lipid Research

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This article is available online at http://www.jlr.org tozoa to fully mature cells ( 1 , 2 ). Principal aspects of epididymal transformation include functional maturation, sperm concentration, storage of the spermatozoa in a quiescent state, and removal of degenerating cells. Functional maturation of these spermatozoa requires interaction of sperm with luminal fl uid, whose composition is regulated by absorption and secretion activities of the epididymal epithelium ( 3 ).The sperm plasma membrane is the site of dramatic changes throughout the development of these cells, and, in the epididymis, the remodeling process includes important modifi cations in lipid composition as well as repositioning of lipid and protein components to different membrane domains ( 4 ). The lipid composition of mammalian spermatozoa is specifi c with a large amount of plasmalogen phospholipids (PLs), a high content of long-chain PUFAs, mostly arachidonic acid (20:4, n-6), docosapentaenoic acid (22:5, n-3), and docosahexaenoic acid (22:6, n-3), and relatively low cholesterol:PL ratios ranging from 0.24 for caput epididymidis sperm to 0.29 for cauda epididymidis sperm in mice ( 5 ). This ratio is an indicator of membrane fl uidity, and although it is quite stable during epididymal transit, membrane fl uidity was shown to increase during this step ( 6 ). Earlier work showed a significant decrease of the two major PLs, phosphatidylcholine and phosphatidylethanolamine, in mouse spermatozoa from cauda epididymidis compared with those from caput epididymidis ( 5 ). During epididymal maturation, stearic acid (C18:0) decreased also, whereas palmitic acid (C16:0) increased. Among the PUFAs, docosapentaenoic and docosahexaenoic acids rose signifi cantly in the cauda epididymidis. Cholesterol content also declined by roughly 65% during epididymal maturation ( 5 ). These modifi cations have been supposed to prepare sperm cells for capacitation and acrosome reaction that take place in the Abstract Mammalian spermatozoa undergo important plasma membrane maturation steps during epididymal transit. Among these, changes in lipids and cholesterol are of particular interest as they are necessary for fertilization. However, molecular mechanisms regulating these transformations inside the epididymis are still poorly understood. Liver X receptors (LXRs), the nuclear receptors for oxysterols, are of major importance in intracellular cholesterol homeostasis, and LXR ؊ / ؊ -defi cient male mice have already been shown to have reduced fertility at an age of 5 months and complete sterility for 9-month-old animals. This sterility phenotype is associated with testes and caput epididymides epithelial defects. The research presented here was aimed at investigating how LXRs act in the male caput epididymidis by analyzing key actors in cholesterol homeostasis. We show that accumulation of cholesteryl esters in LXR The epididymis is an essential organ for reproductive physiology as sperm cells start the process of posttesticular maturation during their transit in this or...

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“…However, levels of inflammatory cytokines are not modified between the HC and the LC groups. The cleavage of SREBP-2 can also be influenced by the concentration of cholesterol esters (CE) specifically in the smooth ER fraction, but not by the total amount of CE in the cell (Iddon et al, 2001). However, the precise mechanism involved in the modulation of the nSREBP-2 expression in response to changes in maternal cholesterol remains to be explored.…”

Section: Discussionmentioning

confidence: 99%

Impact of maternal circulating cholesterol and gestational diabetes mellitus on lipid metabolism in human term placenta

Marseille-Tremblay

Éthier-Chiasson

Forest

et al. 2007

Molecular Reproduction Devel

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Maternal hypercholesterolemia (HC) during pregnancy and gestational diabetes mellitus (GDM) are associated with disturbance of fetal development which may also modify key features of placental functions. In this study, we evaluated the impact of maternal hypercholesterolemia on placental cholesterol and lipid metabolism in 59 women classified in two groups according to the median concentration of plasma total cholesterol (6.42 mM). The impact of GDM was also evaluated on the metabolism of placentas obtained from 7 insulin-treated GDM and 7 non-GDM women. We showed that high maternal circulating cholesterol is associated with a significant increase in the LDL-cholesterol, ApoB-100 and triglyceride concentrations in the maternal blood. However the level of cholesterol in the venous cord blood and placenta remains unchanged in response to modification in maternal cholesterol profile. The levels of Fatty acid synthase (FAS) and SREBP-2 expressions in placenta are significantly increased in the HC group while expression of both sterol regulatory element-binding proteins-1 (SREBP-1) and HMG-CoA reductase (HMGR) are not modified. GDM is not associated with modification in the maternal lipid profile but it increases the concentration of inflammatory cytokines (IL-1beta and TNF-alpha) in placenta which correlates with a dramatic induction of FAS expression without affecting the expression of mature SREBPs proteins. In conclusion, our study suggests that in placenta, expressions of key proteins involved in de novo lipid synthesis are affected by changes in maternal metabolism (HC and GDM) that may subsequently affect fetal development.

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A role for smooth endoplasmic reticulum membrane cholesterol ester in determining the intracellular location and regulation of sterol-regulatory-element-binding protein-2

Cited by 8 publications

References 48 publications

Cholesterol-derived bile acids enhance the chaperone activity of α-crystallins

Cholesterol-derived bile acids enhance the chaperone activity of α-crystallins

LXR and ABCA1 control cholesterol homeostasis in the proximal mouse epididymis in a cell-specific manner

Impact of maternal circulating cholesterol and gestational diabetes mellitus on lipid metabolism in human term placenta

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