Cholesterol interactions with phospholipids in membranes

doi:10.1016/S0163-7827(01)00020-0

Progress in Lipid Research

Volume 41, Issue 1, January 2002, Pages 66-97

https://doi.org/10.1016/S0163-7827(01)00020-0 Get rights and content

Abstract

Mammalian cell membranes are composed of a complex array of glycerophospholipids and sphingolipids that vary in head-group and acyl-chain composition. In a given cell type, membrane phospholipids may amount to more than a thousand molecular species. The complexity of phospholipid and sphingolipid structures is most likely a consequence of their diverse roles in membrane dynamics, protein regulation, signal transduction and secretion. This review is mainly focused on two of the major classes of membrane phospholipids in eukaryotic organisms, sphingomyelins and phosphatidylcholines. These phospholipid classes constitute more than 50% of membrane phospholipids. Cholesterol is most likely to associate with these lipids in the membranes of the cells. We discuss the synthesis and distribution in the cell of these lipids, how they are believed to interact with each other, and what cellular consequences such interactions may have. We also include a discussion about findings in the recent literature regarding cholesterol/phospholipid interactions in model membrane systems. Finally, we look at the recent trends in computer and molecular dynamics simulations regarding phospholipid and cholesterol/phospholipid behavior in bilayer membranes.

Section snippets

Molecular structure of choline-containing phospholipids

The structures of both phosphatidylcholine and sphingomyelin include the same hydrophilic phosphorylcholine head group, which is zwitterionic at neutral pH. Both lipids also contain two long hydrocarbon chains, which form the hydrophobic domain of these amphiphiles (Fig. 1). The conformation and the charge distribution are quite similar in these phospholipids, but they are certainly chemically different [1]. The differences arise from the fact that phosphatidylcholine has a glycerol backbone to

Cholesterol

Even if phospholipids and sphingolipids build up the matrix of cellular membranes, sterols are essential components of these membranes. In contrast to the amazing diversity of phospholipid species, mammalian cells contain one major sterol, cholesterol, which is absolutely required for viability and cell proliferation [62], [63]. Sterols differ from the other membrane lipid classes, and in principal consist of pure hydrocarbon in the form of a steroid ring structure. The maximal solubility of

Is there coordinate regulation of cholesterol and choline-containing phospholipids?

The early work by Patton in 1970 revealed a positive correlation between cellular cholesterol and sphingomyelin levels in rat liver hepatocytes [129], and since then a considerable amount of studies have concentrated on unravelling the effects of sphingomyelin on cellular cholesterol homeostasis, and also the effects of cholesterol on sphingomyelin homeostasis (for recent reviews see Refs. [130], [131], [132], [133]). The coordinated effects of phosphatidylcholine and cholesterol on each

Cholesterol/phospholipid interactions in artificial model membranes

Biological membranes contain a heterogeneous mixture of phospholipids differing from each other with respect to their head-group structure, hydrocarbon chain length, degree of unsaturation of the acyl chains, and mode of attachment of the hydrocarbon chains. Due to this complexity, it is difficult to ascertain the physical properties and functional roles of individual lipids and their mode of interaction with other lipids in natural membranes. Therefore model systems consisting of phospholipids

What lies in the future?

The enormous complexity of the molecular structure of biological membranes is becoming increasingly apparent, but the ultimate goal to fully understand how membrane components interact and how different events affect membrane dynamics will be hard to achieve. Currently there is an intense effort to study rafts in membranes because of their biological interest, and focused experiments during the next few years will probably substantially increase our understanding of how lipids in membranes form

Acknowledgements

The financial support from the Academy of Finland, the Sigrid Juselius Foundation, the Magnus Ehrnrooth Foundation, the Medicinska Understödföreningen Liv och Hälsa Foundation, Svenska Kulturfonden, the Oskar Öflund Foundation, the Borg Foundation, the Walter and Lisi Wahl Foundation, and from the Åbo Akademi University is gratefully acknowledged.

References (281)

Y. Barenholz et al.
Chem Phys Lipids
(1999)
Y. Barenholz et al.
Biochim Biophys Acta
(1980)
E. Yechiel et al.
J Biol Chem.
(1985)
M.R. Morrow
Singh, D,. Lu, D,. Grant, C.W. Biophys J.
(1995)
K. Hanada et al.
J Biol Chem.
(1992)
A.H. Merrill et al.
Toxicol Appl Pharmacol.
(1997)
H. Vesper et al.
J Nutr
(1999)
W.-D. Marggraf et al.
Biochim Biophys Acta
(1987)
R.N. Kolesnick
Prog Lipid Res.
(1991)
M. Koval et al.
Biochim Biophys Acta
(1991)

A.H. Futerman et al.

J Biol Chem.

(1990)

K.J. Kallen et al.

Biochim Biophys Acta

(1994)

G. van Meer et al.

Biochim Biophys Acta

(2000)

A. Huwiler et al.

Biochim Biophys Acta

(2000)

Y. Lange et al.

J Biol Chem.

(1989)

A.J. Verkleij et al.

Biochim Biophys Acta

(1973)

C.M. Linardic et al.

J Biol Chem.

(1994)

T. Levade et al.

Chem Phys Lipids

(1999)

Y.A. Hannun

J Biol Chem.

(1994)

D.K. Perry et al.

Biochim Biophys Acta

(1998)

C. Kent et al.

Trends Biochem Sci.

(1999)

J.H. Exton

Biochim Biophys Acta

(1994)

J.T. Dodge et al.

J Lipid Res.

(1967)

C.W. Haest

Biochim Biophys Acta

(1982)

E.M. Bevers et al.

Biochim Biophys Acta

(1999)

D.L. Daleke et al.

Biochim Biophys Acta

(2000)

E.M. Bevers et al.

Biochim Biophys Acta

(1983)

Y. Tanaka et al.

J Biol Chem.

(1983)

L. Chernomordik

Chem Phys Lipids

(1996)

R.M. Epand

Biochim Biophys Acta

(1998)

J. Huang et al.

Biochimica et Biophysica Acta

(1999)

O.G. Mouritsen et al.

Chem Phys Lipids

(1994)

P.L. Yeagle

Biochim Biophys Acta

(1985)

J.M. Boggs

Biochim Biophys Acta

(1987)

P.R. Maulik et al.

Biophys J.

(1996)

R.A. Demel et al.

Biochim Biophys Acta

(1976)

D. Needham et al.

Biophys J.

(1990)

P.L. Yeagle

Biochimie

(1991)

Y. Lange et al.

Curr Opin Struct Biol.

(1998)

J.P. Incardona et al.

Curr Opin Cell Biol.

(2000)

C.J. Fielding et al.

Biochim Biophys Acta

(2000)

R.E. Brown

J Cell Sci.

(1998)

Nyholm T, Slotte JP. Langmuir...

Barenholz Y. In: Shinitzky M, editor. Physiology of membrane fluidity, Boca Raton (FL, USA): CRC Press, 1984. p....

S. Clejan

Methods Mol Biol.

(1998)

B. Ramstedt et al.

Eur J Biochem.

(1999)

T.J. McIntosh et al.

Biochemistry

(1992)

Cullis PR, Fenske DB, Hope MJ. In: Vance DE, Vance JE, editors. Biochemistry of lipids, lipoproteins and membranes....

D.R. Voelker et al.

Biochemistry

(1982)

Merrill AHJ, Sweeley CC. In: Vance DE, Vance JE, editors. Biochemistry of lipids, lipoproteins and membranes. Amsterdam...

Cited by (914)

Fumonisin B<inf>1</inf> protects against long-chained polyunsaturated fatty acid-induced cell death in HepG2 cells – implications for cancer promotion
2024, Biochimica et Biophysica Acta - Biomembranes
Fumonisin B₁ (FB₁), a food-borne mycotoxin, is a cancer promoter in rodent liver and augments proliferation of initiated cells while inhibiting the growth of normal hepatocytes by disrupting lipid biosynthesis at various levels. HepG2 cancer cells exhibited resistance to FB₁-induced toxic effects presumably due to their low content of polyunsaturated fatty acids (PUFA) even though FB₁-typical lipid changes were observed, e.g. significantly increased phosphatidylethanolamine (PE), decreased sphingomyelin and cholesterol content, increased sphinganine (Sa) and sphinganine/sphingosine ratio, increased C18:1ω-9, decreased C20:4ω-6 content in PE and decreased C20:4ω-6_PC/PE ratio. Increasing PUFA content of HepG2 cells with phosphatidylcholine (PC) vesicles containing C20:4ω-6 (SAPC) or C22:6ω-3 (SDPC) disrupted cell survival, cellular redox status and induced oxidative stress and apoptosis. A partially protective effect of FB₁ was evident in PUFA-enriched HepG2 cells which may be related to the FB₁-induced reduction in oxidative stress and the disruption of key cell membrane constituents indicative of a resistant lipid phenotype. Interactions between different ω-6 and ω-3 PUFA, membrane constituents including cholesterol, and the glycerophospho- and sphingolipids and FB₁ in this cell model provide further support for the resistant lipid phenotype and its role in the complex cellular effects underlying the cancer promoting potential of the fumonisins.
Recent advances in organelle-targeted organic photosensitizers for efficient photodynamic therapy
2024, Coordination Chemistry Reviews
Photodynamic therapy (PDT) is a long known, FDA approved, and highly promising therapeutic modality, which is still developing. Photosensitizers (PSs) are at the core of PDT action and a worldwide effort has been put to develop PSs having multiple functionalities. In the design of new generation PSs, an attractive approach is to target organelles to get an exceptional therapeutic outcome as damaging these vital subcellular compartments improve the photocytotoxic effect of the PSs. To this end, small molecule organic PSs are suitable candidates due to ease of chemical modification, which allows simple implementation of the organelle targeting units on the PS structure. Furthermore, they hold unique characteristics such as low dark toxicity, high reactive oxygen species (ROS) generation capacity, biocompatibility, and tunable photophysical and photochemical properties. Accordingly, a wide variety of organelle-targeted organic PSs have been developed and proved to be highly successful both in therapeutic action and bioimaging applications. In this review article, we have summarized the recent advances in organelle localizing organic-based PSs by discussing the design principles, organelle targeting strategies and related bio-applications in detail. PSs targeting seven different organelles have been included. We have also highlighted the current challenges and gave a comprehensive outlook for the future of organelle-targeted PSs.
Marine weeds against fungal phytopathogens - Current agronomical implications and intriguing perspectives for a sustainable future
2024, Physiological and Molecular Plant Pathology
Controlling plant diseases is essential to the long-term viability of agriculture. As the most significant global agricultural liability, fungal phytopathogens infect a widespread array of host plants and epitomize a substantial menace to plant species. Appropriate solutions are needed in contemporary agriculture to solve the current trend of agricultural and food insecurity challenges. The use of bioproducts, including seaweeds, is one potential lever to encourage this transition. Alginates, laminarins, ulvans, phenols, and carrageneans are seaweed metabolites and chemicals that have been shown to have direct antifungal properties. These substances limit the growth of the fungi by breaking down their cell walls and causing oxidative stress. This provides considerable disease control in plants at an early stage and substantially lowers the incidence of disease. It is believed that by starting a cross-talk between the defense pathway and phytohormone, seaweed oligosaccharides and ulvans stimulate synthesis of plant protective compounds as well as physiological changes that prevent pathogen entry like lignification or accumulate cell wall degrading enzymes (chitinase or glucanase) or antimicrobial compounds (phenols, salicylic acid) at the sites of infection. This activates the ethylene, jasmonic, and salicylic acid pathways, which in turn increases the synthesis of several plant defense chemicals and activates pathogenesis-related genes (PR 1–3). Effective disease management has been facilitated by increased oxidative enzyme production to avoid oxidative stress induced by pathogen entry also. Rather than a single mechanism for disease control, seaweed compounds instigate a cascade of reactions that activate plant defense offering multifold resistance and protection against phytopathogenic fungi. This substantially facilitates a benign environment for plant growth, positively influencing the nutritional status of plant products and yield, in an economic as well as sustainable manner.
Emerging roles and therapeutic potentials of sphingolipids in pathophysiology: emphasis on fatty acyl heterogeneity
2024, Journal of Genetics and Genomics
Sphingolipids not only exert structural roles in cellular membranes, but also act as signaling molecules in various physiological and pathological processes. A myriad of studies have shown that abnormal levels of sphingolipids and their metabolic enzymes are associated with a variety of human diseases. Moreover, blood sphingolipids can also be used as biomarkers for disease diagnosis. This review summarizes the biosynthesis, metabolism, and pathological roles of sphingolipids, with emphasis on the biosynthesis of ceramide, the precursor for the biosynthesis of complex sphingolipids with different fatty acyl chains. The possibility of using sphingolipids for disease prediction, diagnosis, and treatment is also discussed. Targeting endogenous ceramides and complex sphingolipids along with their specific fatty acyl chain to promote future drug development will also be discussed.
In situ interaction between the hormone 17α-ethynylestradiol and the liquid-ordered phase composed of the lipid rafts sphingomyelin and cholesterol
2024, Bioorganic Chemistry
Hormone treatments are frequently associated with cardiovascular diseases and cancers in women. Additionally, the detrimental effects of their presence as contaminants in water remain a concern. The transport of hormones through cell membranes is essential for their biological action, but investigating cell permeability is challenging owing to the experimental difficulty in dealing with whole cells. In this paper, we study the interaction of the synthetic hormone 17α-ethynylestradiol (EE2) with membrane models containing the key raft components sphingomyelin (SM) and cholesterol (Chol). The models consisted of Langmuir monolayers and giant unilamellar vesicles (GUVs) that represent bilayers. EE2 induced expansion of SM monolayers upon interacting with the non-hydrated amide group of SM head, but it had practically no effect on SM GUVs because these group are not available for interaction in bilayers. In contrast, EE2 interacted with hydrated phosphate group ( ${P O}_{2}^{-}$ ) and amide group of SM/Chol mixture monolayer, which could explain the loss in phase contrast of liquid-ordered GUVs suggesting pore formation. A comparison with reported EE2 effects on GUVs in the fluid phase, for which no loss in phase contrast was observed, indicates that the liquid-ordered phase consisting of lipid rafts is relevant to be associated with the changes on cell permeability caused by the hormones.
Improved production of Bacillus subtilis cholesterol oxidase by optimization of process parameters using response surface methodology
2023, Journal of Genetic Engineering and Biotechnology
Cholesterol oxidase has numerous biomedical and industrial applications. In the current study, a new bacterial strain was isolated from sewage and was selected for its high potency for cholesterol degradation (%) and production of high cholesterol oxidase activity (U/OD₆₀₀).
Based on the sequence of 16S rRNA gene, the bacterium was identified as Bacillus subtilis. The fermentation conditions affecting cholesterol degradation (%) and the activity of cholesterol oxidase (U/OD₆₀₀) of B. subtilis were optimized through fractional factorial design (FFD) and response surface methodology (RSM). According to this sequential optimization approach, 80.152% cholesterol degradation was achieved by setting the concentrations of cholesterol, inoculum size, and magnesium sulphate at 0.05 g/l, 6%, and 0.05 g/l, respectively. Moreover, 85.461 U of cholesterol oxidase/OD₆₀₀ were attained by adjusting the fermentation conditions at initial pH, 6; volume of the fermentation medium, 15 ml/flask; and concentration of cholesterol, 0.05 g/l. The optimization process improved cholesterol degradation (%) and the activity of cholesterol oxidase (U/OD₆₀₀) by 139% and 154%, respectively. No cholesterol was detected in the spectroscopic analysis of the optimized fermented medium via gas chromatography-mass spectroscopy (GC–MS).
The current study provides principal information for the development of efficient production of cholesterol oxidase by B. subtilis that could be used in various applications.

View all citing articles on Scopus

View full text

ReviewCholesterol interactions with phospholipids in membranes

Abstract

Section snippets

Molecular structure of choline-containing phospholipids

Cholesterol

Is there coordinate regulation of cholesterol and choline-containing phospholipids?

Cholesterol/phospholipid interactions in artificial model membranes

What lies in the future?

Acknowledgements

Chem Phys Lipids

Biochim Biophys Acta

J Biol Chem.

Singh, D,. Lu, D,. Grant, C.W. Biophys J.

J Biol Chem.

Toxicol Appl Pharmacol.

J Nutr

Biochim Biophys Acta

Prog Lipid Res.

Biochim Biophys Acta

J Biol Chem.

Biochim Biophys Acta

Biochim Biophys Acta

Biochim Biophys Acta

J Biol Chem.

Biochim Biophys Acta

J Biol Chem.

Chem Phys Lipids

J Biol Chem.

Biochim Biophys Acta

Trends Biochem Sci.

Biochim Biophys Acta

J Lipid Res.

Biochim Biophys Acta

Biochim Biophys Acta

Biochim Biophys Acta

Biochim Biophys Acta

J Biol Chem.

Chem Phys Lipids

Biochim Biophys Acta

Biochimica et Biophysica Acta

Chem Phys Lipids

Biochim Biophys Acta

Biochim Biophys Acta

Biophys J.

Biochim Biophys Acta

Biophys J.

Biochimie

Curr Opin Struct Biol.

Curr Opin Cell Biol.

Biochim Biophys Acta

J Cell Sci.

Methods Mol Biol.

Eur J Biochem.

Biochemistry

Biochemistry

Review
Cholesterol interactions with phospholipids in membranes