OBJECTIVE —Type 2 diabetes is often accompanied by abnormal blood lipid and lipoprotein levels, but most studies on the link between hyperlipidemia and diabetes have focused on free fatty acids (FFAs). In this study, we examined the relationship between cholesterol and insulin secretion from pancreatic β-cells that is independent of the effects of FFAs.

RESEARCH DESIGN AND METHODS —Several methods were used to modulate cholesterol levels in intact islets and cultured β-cells, including a recently developed mouse model that exhibits elevated cholesterol but normal FFA levels. Acute and metabolic alteration of cholesterol was done using pharmacological reagents.

RESULTS —We found a direct link between elevated serum cholesterol and reduced insulin secretion, with normal secretion restored by cholesterol depletion. We further demonstrate that excess cholesterol inhibits secretion by downregulation of metabolism through increased neuronal nitric oxide synthase dimerization.

CONCLUSIONS —This direct effect of cholesterol on β-cell metabolism opens a novel set of mechanisms that may contribute to β-cell dysfunction and the onset of diabetes in obese patients.

https://diabetes.diabetesjournals.org/content/diabetes/56/9/2328.full.pdf

Direct Effect of Cholesterol on Insulin Secretion: A Novel Mechanism for Pancreatic β-Cell Dysfunction

Many types of ion channel localize to cholesterol and sphingolipid-enriched regions of the plasma membrane known as lipid microdomains or ‘rafts’. The precise physiological role of these unique lipid microenvironments remains elusive due largely to difficulties associated with studying these potentially extremely small and dynamic domains. Nevertheless, increasing evidence suggests that membrane rafts regulate channel function in a number of different ways. Raft-enriched lipids such as cholesterol and sphingolipids exert effects on channel activity either through direct protein–lipid interactions or by influencing the physical properties of the bilayer. Rafts also appear to selectively recruit interacting signalling molecules to generate subcellular compartments that may be important for efficient and selective signal transduction. Direct interaction with raft-associated scaffold proteins such as caveolin can also influence channel function by altering gating kinetics or by affecting trafficking and surface expression. Selective association of ion channels with specific lipid microenvironments within the membrane is thus likely to be an important and fundamental regulatory aspect of channel physiology. This brief review highlights some of the existing evidence for raft modulation of channel function.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2010.191585

Lipid microdomains and the regulation of ion channel function.

A variety of ion channels, including members of all major ion channel families, have been shown to be regulated by changes in the level of membrane cholesterol and partition into cholesterol-rich membrane domains. In general, several types of cholesterol effects have been described. The most common effect is suppression of channel activity by an increase in membrane cholesterol, an effect that was described for several types of inwardly-rectifying K+ channels, voltage-gated K+ channels, Ca+2 sensitive K+ channels, voltage-gated Na+ channels, N-type voltage-gated Ca+2 channels and volume-regulated anion channels. In contrast, several types of ion channels, such as epithelial amiloride-sensitive Na+ channels and Transient Receptor Potential channels, as well as some of the types of inwardly-rectifying and voltage-gated K+ channels were shown to be inhibited by cholesterol depletion. Cholesterol was also shown to alter the kinetic properties and current-voltage dependence of several voltage-gated channels. Finally, maintaining membrane cholesterol level is required for coupling ion channels to signalling cascades. In terms of the mechanisms, three general mechanisms have been proposed: (i) specific interactions between cholesterol and the channel protein, (ii) changes in the physical properties of the membrane bilayer and (iii) maintaining the scaffolds for protein-protein interactions. The goal of this review is to describe systematically the role of cholesterol in regulation of the major types of ion channels and to discuss these effects in the context of the models proposed.

/pdf/cholesterol-and-ion-channels-1mr64e7how.pdf

Cholesterol and Ion Channels

A variety of lipid microdomains, including caveolae, have been shown to play an important role in both protein targetting and in controlling protein–protein interactions. There is increasing evidence for significant ion channel localization in lipid rafts. Cardiac channel subunits known to localize in lipid rafts include Kv1.4, Kv1.5, Kv2.1, Kv4, Kir2, Kir3, KATP, Nav and Cav subunits. This article reviews what is known about the occurrence and functional significance of cardiac ion channel/lipid raft interactions. Much remains to be learned about this area of potentially enormous importance to cardiac function in health and disease.

/pdf/involvement-of-lipid-rafts-and-caveolae-in-cardiac-ion-4zoyb8b5kg.pdf

Involvement of lipid rafts and caveolae in cardiac ion channel function.

https://pure.mpg.de/pubman/item/item_598924_3/component/file_598923/230368.pdf

SNAREs Prefer Liquid-disordered over “Raft” (Liquid-ordered) Domains When Reconstituted into Giant Unilamellar Vesicles

Disruption of Pancreatic β-Cell Lipid Rafts Modifies Kv2.1 Channel Gating and Insulin Exocytosis

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Disruption of Pancreatic β-Cell Lipid Rafts Modifies Kv2.1 Channel Gating and Insulin Exocytosis