Defective insulin receptor activation and altered lipid rafts in Niemann–Pick type C disease hepatocytes

Vainio, Saara; Bykov, Igor; Hermansson, Martin; Jokitalo, Eija; Somerharju, Pentti; Ikonen, Elina

doi:10.1042/bj20050460

Cited by 58 publications

(57 citation statements)

References 46 publications

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“…Lipid rafts organize insulin signal transduction (55), and lipid raft perturbations have been suggested to participate in the pathogenesis of insulin resistance (56,57). These observations indicate that the nature of lipid rafts is different in the healthy state and the disease state.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol-dependent induction of dendrite formation by ginsenoside Rh2 in cultured melanoma cells

Ota¹

2010

Int J Mol Med

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Abstract. Herbal remedies containing root extracts of Panax ginseng are commonly used for complementary or alternative therapies. Ginsenosides, the major components of root extracts, are responsible for ginseng's pharmacological and biological effects; however, their mechanisms of action are unclear. We examined whether membrane cholesterol was involved in the mechanism of action of ginsenoside Rh2 in cultured cells. In B16 melanoma cells, Rh2 (18.5 μM) induced dendrite formation within 2 h. Depletion of cholesterol by pretreatment with 10 mM methyl-ß-cyclodextrin suppressed this effect of Rh2. Rh2 did not change the cellular cholesterol content and the immunofluorescence staining pattern of the lipid-raft-associated molecules, ganglioside GM3, Caveolin-1, Flotillin-1, and Flotillin-2, for up to 3 or 6 h. However, within 2 min of addition, Rh2 changed the fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH) but not of 1-[4-(trimethylammonio)phenyl]-6-phenyl-1,3,5-hexatriene (TMA-DPH). DPH is more sensitive than TMA-DPH to changes in the physical properties of membrane lipid bilayers regulated by cholesterol. These results suggest that Rh2 affects the physical properties of cholesterol-regulated membrane lipid bilayers and could lead to changes in cellular functions.

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Section: Discussionmentioning

confidence: 99%

Cholesterol-dependent induction of dendrite formation by ginsenoside Rh2 in cultured melanoma cells

Ota¹

2010

Int J Mol Med

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“…SCP-2) cholesterol binding proteins preferentially donate or extract cholesterol from cholesterol-rich, but not cholesterol-poor, microdomains (26,27,136,137,172). The microdomain/lipid raft concept, despite controversy in details, provides a framework for biologists studying localization and function of membrane protein receptors, transporters, and downstream signaling molecules that regulate uptake of cholesterol (86,87,, fatty acids (240)(241)(242), glucose (243)(244)(245)(246)(247)(248)(249)(250)(251)(252)(253)(254), and other activities (216,(255)(256)(257)(258)(259)(260). Cholesterol-poor microdomain preferring cholesterol analogs: BODIPY-coprostanol analog 3; BODIPY-cholesterol analog LZ110a; 22-NBD-cholesterol.…”

Section: Summary and Discussionmentioning

confidence: 99%

Fluorescence Techniques Using Dehydroergosterol to Study Cholesterol Trafficking

McIntosh

Atshaves

Huang

et al. 2008

Lipids

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Cholesterol itself has very few structural/chemical features suitable for real-time imaging in living cells. Thus, the advent of dehydroergosterol [ergosta-5,7,9(11),22-tetraen-3β-ol, DHE] the fluorescent sterol most structurally and functionally similar to cholesterol to date, has proven to be a major asset for real-time probing/elucidating the sterol environment and intracellular sterol trafficking in living organisms. DHE is a naturally-occurring, fluorescent sterol analog that faithfully mimics many of the properties of cholesterol. Because these properties are very sensitive to sterol structure and degradation, such studies require the use of extremely pure (>98%) quantities of fluorescent sterol. DHE is readily bound by cholesterol-binding proteins, is incorporated into lipoproteins (from the diet of animals or by exchange in vitro), and for real-time imaging studies is easily incorporated into cultured cells where it co-distributes with endogenous sterol. Incorporation from an ethanolic stock solution to cell culture media is effective, but this process forms an aqueous dispersion of dehydroergosterol crystals which can result in endocytic cellular uptake and distribution into lysosomes which is problematic in imaging DHE at the plasma membrane of living cells. In contrast, monomeric DHE can be incorporated from unilamellar vesicles by exchange/fusion with the plasma membrane or from DHE-methyl-β-cyclodextrin (DHE-MβCD) complexes by exchange with the plasma membrane. Both of the latter techniques can deliver large quantities of monomeric dehydroergosterol with significant distribution into the plasma membrane. The properties and behavior of DHE in protein-binding, lipoproteins, model membranes, biological membranes, lipid rafts/caveolae, and real-time imaging in living cells indicate that this naturally-occurring fluorescent sterol is a useful mimic for probing the properties of cholesterol in these systems. Keywordsdehydroergosterol; cholesterol; ergosterol; fluorescent sterols; microscopy Historical PerspectiveIn order to resolve the dynamics and factors governing cholesterol trafficking within cells, it is important to recognize that the cholesterol molecule has very few polar constituents (Fig. 1A). Consequently, cholesterol is poorly soluble in aqueous environments such as cytosol as evidenced by critical micellar concentrations of cholesterol and other sterols being very low, *To whom correspondence should be addressed: Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX 862-1433, FAX: (979) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript near 20-30 nM (1-5). The physiological impact of cholesterol's low aqueous solubility is that spontaneous cholesterol desorption from the cytofacial leaflet of the plasma membrane or lysosomal membrane into the cytosol for transfer to intracellular sites for esterification, oxidation, or secretion is extremely slow (t 1/2 3 hours-days) (6-9). Therefore, it is important to resolve factors...

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“…Mechanical disruption was verified by microscopic inspection, and the homogenate was spun at 190 ϫ g for 10 min. Subsequent isolation of plasma membrane lipids was performed as previously described (16). Lipid suspension isolated in buffer was extracted twice with 200 l of 1:1 MeOH/CHCl 3 and back-extracted once with 1 M NaCl, and the solvent was evaporated in a glass tube under a gentle stream of nitrogen.…”

Section: Imaging Of Cellular Plasma Membrane Cholesterol Withmentioning

confidence: 99%

“…Within the plasma membrane, cholesterol segregated with sphingolipids and selective proteins form distinct lipid raft complexes that act as ordered platforms for communicating signals into and out of cells (12). Dysregulation of cholesterol synthesis and transport acts as a contributing factor to pathophysiological changes (13)(14)(15)(16)(17), which are of particular importance in cardiovascular disease, chronic inflammation, and lipid disorders such as NiemannPick disease. The influence of cholesterol on NO diffusion was directly quantified in liposomal and artificial bilayer preparations.…”

mentioning

confidence: 99%

Plasma Membrane Cholesterol Content Affects Nitric Oxide Diffusion Dynamics and Signaling

Miersch

Espey

Chaube

et al. 2008

Journal of Biological Chemistry

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Nitric oxide (NO) signaling is inextricably linked to both its physical and chemical properties. Due to its preferentially hydrophobic solubility, NO molecules tend to partition from the aqueous milieu into biological membranes. We hypothesized that plasma membrane ordering provided by cholesterol further couples the physics of NO diffusion with cellular signaling. Fluorescence lifetime quenching studies with pyrene liposome preparations showed that the presence of cholesterol decreased apparent diffusion coefficients of NO ϳ20 -40%, depending on the phospholipid composition. Electrochemical measurements indicated that the diffusion rate of NO across artificial bilayer membranes were inversely related to cholesterol content. Sterol transport-defective Niemann-Pick type C1 (NPC1) fibroblasts exhibited increased plasma membrane cholesterol content but decreased activation of both intracellular soluble guanylyl cyclase and vasodilator-stimulated phosphoprotein (VASP) phosphorylation at Ser 239 induced by exogenous NO exposure relative to their normal human fibroblast (NHF) counterparts. Augmentation of plasma membrane cholesterol in NHF diminished production of both cGMP and VASP phosphorylation elicited by NO to NPC1-comparable levels. Conversely, decreasing membrane cholesterol in NPC1 resulted in the augmentation in both cGMP and VASP phosphorylation to a level similar to those observed in NHF. Increasing plasma membrane cholesterol contents in NHF, platelets, erythrocytes and tumor cells also resulted in an increased level of extracellular diaminofluorescein nitrosation following NO exposure. These findings suggest that the impact of cholesterol on membrane fluidity and microdomain structure contributes to the spatial heterogeneity of NO diffusion and signaling.As a small sized gaseous free radical, nitric oxide (NO) 2 presents unique challenges toward understanding the nature of its signaling in biological systems. Numerous levels of regulation at the level of nitric oxide synthase catalysis influence the rate of NO generation. Spatial localization of the biological signal is secondarily determined by a combination of the distinct physical and chemical properties of NO within the context of the microenvironment in which it was formed. The lifetime of NO molecules is governed chiefly by their relative abundance in relation to other radicals (1, 2), transition metal centers (3, 4), and oxygen (O 2 ) (5, 6). In addition to its very small size, the diffusional path of NO from the point of origin is affected by its preferentially hydrophobic solubility (7,8), resulting in an enrichment of NO in biological membranes relative to the aqueous milieu. In the present work, the hypothesis that cells may utilize plasma membrane cholesterol to further orchestrate spatial heterogeneity in NO biological signaling activity was tested.Cholesterol, a major lipid component of the plasma membrane in eukaryotic cells, plays an essential role in maintaining membrane fluidity and architecture (9 -11). Cells tightly control the ratio ...

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Defective insulin receptor activation and altered lipid rafts in Niemann–Pick type C disease hepatocytes

Cited by 58 publications

References 46 publications

Cholesterol-dependent induction of dendrite formation by ginsenoside Rh2 in cultured melanoma cells

Cholesterol-dependent induction of dendrite formation by ginsenoside Rh2 in cultured melanoma cells

Fluorescence Techniques Using Dehydroergosterol to Study Cholesterol Trafficking

Plasma Membrane Cholesterol Content Affects Nitric Oxide Diffusion Dynamics and Signaling

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