Insulin Resistance as a Risk Factor for Alzheimer's Disease
André Kleinridders in Physiological Consequences of Brain Insulin Action, 2023
Ceramides comprise a family of sphingolipids that are generated from fatty acids and sphingosine. It is well known that ceramides play an important role in the structure of the cell membrane since they participate in the formation of the lipid raft. On the other hand, ceramides exert various physiological and regulatory effects on cell signalling pathways that mediate cellular growth, proliferation and senescence, among other functions (58). Interestingly, ceramides like other neurotoxic lipids can cross the BBB, contributing to the BIR and neurodegeneration. In this line, previous studies have reported that ceramide levels increase in the brain of preclinical mice models of AD and in LOAD patients (143). Likewise, ceramides exert a role in LOAD pathophysiology promoting the regulation of BACE1 and the generation and aggregation of Aβ (144, 145). Besides, ceramides which are located especially in the myelin sheath that surrounds some nerve cell axons, have also been observed in plasma, CSF and brain tissue of LOAD patients, and have also been associated with an increase in Aβ plaques (146, 147).
Cholesterol Modulation of BK (MaxiK; Slo1) Channels
Qiu-Xing Jiang in New Techniques for Studying Biomembranes, 2020
In native cellular membranes, including vascular myocytes, BK channels tend to reside within CLR-rich lipid rafts (Dopico and Tigyi, 2007; Sones et al., 2010; Dopico et al., 2012). Modification of CLR levels is expected to alter membrane microdomains, including CLR-rich lipid domains, and sphingolipid distribution (Dopico and Tigyi, 2007; Lingwood, 2011). Thus, one of the possible explanations for CLR-ethanol interaction in controlling BK channel activity arises from CLR modification of lipid rafts. However, CLR modification of BK channel ethanol sensitivity is observed in artificial bilayer systems (see below) of lipid composition that do not enable raft formation (Crowley et al., 2003; Bukiya et al., 2011b). These findings suggest that raft disruption is not a main contributor to CLR modification of the BK channel’s ethanol sensitivity.
Microalgae and Cyanobacteria as a Potential Source of Anticancer Compounds
Gokare A. Ravishankar, Ranga Rao Ambati in Handbook of Algal Technologies and Phytochemicals, 2019
Another group of dinoflagellate toxins that has potential for anticancer drug development is karlotoxins (KTX). The toxins are produced by Karlodinium veneficum, are a group of polyketide compounds with haemolytic, cytotoxic and ichthyotoxic activity (Van Wagoner et al. 2008). The structure and physiological effects of KTX resemble that of APDL. The toxins are potentially useful for lowering cholesterol or targeting cancer cells high in cholesterol (Waters et al. 2010). The mechanism of toxicity of KTX is based on the ability of the toxin to form a pore in the cell membrane, which destroys the osmotic balance, leading to cell death (Deeds et al. 2015). In addition, the mechanism of cytotoxicity of KTX is linked to its perturbation of the lipid raft of the cell membrane through its interaction with cholesterol (Waters et al. 2010). Cholesterol is known to play an important role in mediating the function of the lipid raft and accumulation of cholesterol has been reported in some solid tumors. The link between cholesterol and cancer, and the potential of KTX as an anticancer agent targeting cholesterol is an area that is worth further investigations. Cytotoxicity testing of karlotoxin 2 on NCI-60 cell panel showed that the compound was active against a wide range of cell lines, including leukemia, NSCLC, ovarian cancer and breast cancer cell lines (Waters et al. 2015).
Genistein prevents the decrease in ganglioside levels induced by amyloid-beta in the frontal cortex of rats
Published in Neurological Research, 2022
Fernanda dos Santos Petry, Juliana Bender Hoppe, Caroline Peres Klein, Bernardo Gindri dos Santos, Régis Mateus Hözer, Christianne Gazzana Salbego, Vera Maria Treis Trindade
The AD pathogenesis is closely related to changes in the lipid homeostasis, which can severely affect the physicochemical properties of cell membranes [4,5]. Gangliosides are sialic acid-containing glycosphingolipids, present in high concentrations in neuronal cell membranes, which play important roles in memory formation, neuritogenesis and synaptic transmission. Moreover, they are involved in cell differentiation and growth, ion channel modulation, and intercellular signaling [6]. Phospholipids exert structural functions in the membrane, also participating in cell signaling. Cholesterol, in turn, is an essential component for the structure and function of cell membranes, modulating their physicochemical properties and contributing to the formation of lipid rafts, specialized membrane microdomains that compartmentalize cellular processes [7]. Increasing evidence indicates that the Aβ peptide can alter the composition and structure of cell membranes, impairing neuronal functions [8,9].
An update on synthetic high-density lipoprotein-like nanoparticles for cancer therapy
Published in Expert Review of Anticancer Therapy, 2019
Stephen E. Henrich, C. Shad Thaxton
To deepen our understanding of the clinical correlation between reduced HDL-C and cancer risk with an eye toward therapy, it is important to understand the underlying biology of cholesterol homeostasis in the setting of cancer. Cholesterol is an essential component of the mammalian cell membrane and is required to maintain plasma membrane fluidity, stability, and organization [25,26]. As a result, cancer cells require a steady diet of cholesterol to enable their rapid proliferation. Cholesterol is also a precursor in the synthesis of various hormones and vitamins that are required for cell proliferation and maintenance [26–28]. Prostate cancer, breast cancer, adrenocortical carcinoma and other tumors are highly dependent upon sterol-derived hormones for their growth; and these tumors therefore often have a vociferous appetite for cholesterol [29]. Additionally, cholesterol can be found at high densities in specialized regions of the plasma membrane known as lipid rafts. These membrane microdomains serve as scaffolds for protein assemblies, and thereby regulate a host of ligand-receptor interactions and downstream intracellular signaling processes, many of which are hi-jacked in cancer cells. One instance of this is lipid raft-dependent B cell receptor signaling in B cell lymphomas, which can be inhibited by targeted reduction of cellular cholesterol [30–32]. The fact that synthetic HDLs directly induce cell death in lymphoma cells via this mechanism also provides evidence that HDLs may play a causal role in slowing the progression of malignancy in cancer patients.
Advances and challenges in understanding the role of the lipid raft proteome in human health
Published in Expert Review of Proteomics, 2018
Ahmed Mohamed, Harley Robinson, Pablo Joaquin Erramouspe, Michelle M Hill
Membrane microdomains are biophysical manifestations of lipid phase separation which occurs in cellular membranes containing a mixture of lipids.Although ‘lipid raft’ has been used to denote the liquid-ordered (less fluid) phase characterized by enriched cholesterol and sphingolipids at the plasma membrane, intracellular rafts have been well characterized as mediating lipid trafficking and inter-organellar signaling.Isolation of pure lipid rafts for proteomics remains a significant technical challenge. Additional strategies should be incorporated in the experimental design, such as comparative proteomics and/or incorporation of subcellular fractionation.Lipid rafts are implicated in numerous diseases and health conditions, with varying levels of evidence. Further research is needed to clarify the role of lipids and lipid raft proteins in pathology, to enable the development of prevention and treatment strategies.
Related Knowledge Centers
- Cell Signaling
- Glycosphingolipid
- Golgi Apparatus
- Membrane Fluidity
- Membrane Protein
- Neurotransmission
- Cell Membrane
- Receptor
- Lipid Microdomain
- Protein Targeting