Cholesterol through the Looking Glass

Kristiana, Ika; Luu, Winnie; Stevenson, Julian; Cartland, Siân P.; Jessup, Wendy; Belani, Jitendra D.; Rychnovsky, Scott D.; Brown, Andrew

doi:10.1074/jbc.m112.360537

Cited by 26 publications

(13 citation statements)

References 45 publications

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“…In addition, both native cholesterol and ent -cholesterol support normal growth of a mutant mammalian cell line [54]. ent -Cholesterol is often utilized to distinguish specific interaction of cholesterol from nonspecific effects [53,55–57]. epi -Cholesterol is a diastereomer of cholesterol in which only the orientation of the hydroxyl group at carbon-3 is inverted relative to native cholesterol (Fig.…”

Section: Resultsmentioning

confidence: 99%

Stereospecific requirement of cholesterol in the function of the serotonin1A receptor

Jafurulla

Rao

Sugunan

et al. 2014

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The serotonin1A receptor is an important member of the G protein-coupled receptor (GPCR) family. It is involved in the generation and modulation of a variety of cognitive and behavioral functions, and serves as a drug target. Previous work from our laboratory has established the sensitivity of the function of the serotonin1A receptor to membrane cholesterol. Solubilization of the hippocampal serotonin1A receptor utilizing the zwitterionic detergent CHAPS is accompanied by loss of cholesterol and results in reduction in specific ligand binding. Replenishment of cholesterol to solubilized membranes restores specific ligand binding to the receptor. We utilized this strategy of sterol replenishment of solubilized membranes to explore the stereospecific stringency of cholesterol for receptor function. We used two stereoisomers of cholesterol, ent-cholesterol (enantiomer of cholesterol) and epi-cholesterol (a diastereomer of cholesterol) for this purpose. Importantly, we show here that while ent-cholesterol could replace cholesterol in supporting receptor function, epi-cholesterol could not. These results imply that the requirement of membrane cholesterol for the serotonin1A receptor function is diastereospecific, yet not enantiospecific. Our results extend and help define specificity of the interaction of membrane cholesterol with the serotonin1A receptor, and represent the first report utilizing ent-cholesterol to examine stereospecificity of GPCR-cholesterol interaction.

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Section: Resultsmentioning

confidence: 99%

Stereospecific requirement of cholesterol in the function of the serotonin1A receptor

Jafurulla

Rao

Sugunan

et al. 2014

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…The ability of sterols to induce the conformational change is associated with their ability to affect membrane properties, and nonsteroid cationic amphiphiles that alter membrane structure have a similar effect (1, 9). Similarly, the enantiomer of cholesterol is able to robustly induce conformational change and inhibit SREBP2 processing (80). This mirror image form should not bind to a specific site on a protein, but it exerts identical effects on the physical properties of the ER membrane.…”

Section: Erad Regulation Of Cholesterol Metabolismmentioning

confidence: 99%

“…Both direct cholesterol binding and bulk membrane effects appear to control squalene monooxygenase turnover (80). Squalene monooxygenase has been observed to bind a sterol probe in a large-scale screen (63), but the enantiomer of cholesterol can still stimulate degradation, albeit less potently than cholesterol (80).…”

Section: Erad Regulation Of Cholesterol Metabolismmentioning

confidence: 99%

“…Squalene monooxygenase has been observed to bind a sterol probe in a large-scale screen (63), but the enantiomer of cholesterol can still stimulate degradation, albeit less potently than cholesterol (80). Cholesterol accumulation causes a conformational change in N100, detected by altered derivatization of specific residues by polyethylene glycol maleimide (61).…”

Section: Erad Regulation Of Cholesterol Metabolismmentioning

confidence: 99%

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Endoplasmic Reticulum–Associated Degradation and Lipid Homeostasis

2016

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The endoplasmic reticulum is the port of entry for proteins into the secretory pathway and the site of synthesis for several important lipids, including cholesterol, triacylglycerol, and phospholipids. Protein production within the endoplasmic reticulum is tightly regulated by a cohort of resident machinery that coordinates the folding, modification, and deployment of secreted and integral membrane proteins. Proteins failing to attain their native conformation are degraded through the endoplasmic reticulum–associated degradation (ERAD) pathway via a series of tightly coupled steps: substrate recognition, dislocation, and ubiquitin-dependent proteasomal destruction. The same ERAD machinery also controls the flux through various metabolic pathways by coupling the turnover of metabolic enzymes to the levels of key metabolites. We review the current understanding and biological significance of ERAD-mediated regulation of lipid metabolism in mammalian cells.

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“…In addition, both native cholesterol and ent -cholesterol support normal growth of a mutant mammalian cell line (Xu et al, 2005). An interesting use of ent -cholesterol is to distinguish specific interaction of cholesterol from nonspecific effects (Mickus et al, 1992; Covey, 2009; D’Avanzo et al, 2011; Kristiana et al, 2012). On the other hand, epi -cholesterol is a diastereomer of cholesterol in which only the orientation of the hydroxyl group at carbon-3 is inverted relative to native cholesterol and is not a mirror image of cholesterol (Fig.…”

Section: Introductionmentioning

confidence: 99%

Membrane dipole potential is sensitive to cholesterol stereospecificity: Implications for receptor function

Bandari

Chakraborty

Covey³

et al. 2014

Chemistry and Physics of Lipids

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Dipole potential is the potential difference within the membrane bilayer, which originates due to the nonrandom arrangement of lipid dipoles and water molecules at the membrane interface. Cholesterol, an essential lipid in higher eukaryotic membranes, has previously been shown to increase membrane dipole potential. In this work, we explored the effect of stereoisomers of cholesterol, ent-cholesterol and epi-cholesterol, on membrane dipole potential, monitored by the dual wavelength ratiometric approach utilizing the probe di-8-ANEPPS. Our results show that cholesterol and ent-cholesterol share comparable ability in increasing membrane dipole potential. In contrast, epi-cholesterol displays a slight reduction in membrane dipole potential. Our results constitute the first report on the effect of stereoisomers of cholesterol on membrane dipole potential, and imply that an extremely subtle change in sterol structure can significantly alter the dipolar field at the membrane interface. These results assume relevance in the context of differential abilities of these stereoisomers of cholesterol in supporting the activity of the serotonin1A receptor, a representative G protein-coupled receptor. The close correlation between membrane dipole potential and receptor activity provides new insight in receptor-cholesterol interaction in terms of stereospecificity. We envision that membrane dipole potential could prove to be a sensitive indicator of lipid-protein interactions in biological membranes.

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Cholesterol through the Looking Glass

Cited by 26 publications

References 45 publications

Stereospecific requirement of cholesterol in the function of the serotonin1A receptor

Stereospecific requirement of cholesterol in the function of the serotonin1A receptor

Endoplasmic Reticulum–Associated Degradation and Lipid Homeostasis

Membrane dipole potential is sensitive to cholesterol stereospecificity: Implications for receptor function

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