High-Cholesterol Diet Decreases the Level of Phosphatidylinositol 4,5-Bisphosphate by Enhancing the Expression of Phospholipase C (PLCβ1) in Rat Brain

Abstract

Cholesterol is a critical component of eukaryotic membranes, where it contributes to regulating transmembrane signaling, cell–cell interaction, and ion transport. Dysregulation of cholesterol levels in the brain may induce neurodegenerative diseases, such as Alzheimer’s disease, Parkinson disease, and Huntington disease. We previously reported that augmenting membrane cholesterol level regulates ion channels by decreasing the level of phosphatidylinositol 4,5-bisphosphate (PIP2), which is closely related to β-amyloid (Aβ) production. In addition, cholesterol enrichment decreased PIP2 levels by increasing the expression of the β1 isoform of phospholipase C (PLC) in cultured cells. In this study, we examined the effect of a high-cholesterol diet on phospholipase C (PLCβ1) expression and PIP2 levels in rat brain. PIP2 levels were decreased in the cerebral cortex in rats on a high-cholesterol diet. Levels of PLCβ1 expression correlated with PIP2 levels. However, cholesterol and PIP2 levels were not correlated, suggesting that PIP2 level is regulated by cholesterol via PLCβ1 expression in the brain. Thus, there exists cross talk between cholesterol and PIP2 that could contribute to the pathogenesis of neurodegenerative diseases.

Facts about Fats: New Insights into the Role of Lipids in Metabolism, Disease and Therapy

“…When evaluated as a whole, these results underline that a western diet may induce similar metabolic alterations in adipose tissue and brain. Chun and Chung further confirmed the involvement of dietary lipids in brain physiology [14]. Specifically, they show experimental evidence that a high-cholesterol diet significantly decreases the expression levels of phospholipase C β1 (PLCβ1) and of phosphatidylinositol 4,5-bisphosphate (PIP 2 ).…”

Preferred Endocytosis of Amyloid Precursor Protein from Cholesterol-Enriched Lipid Raft Microdomains

“…Therefore, cholesterol has been extensively implicated in the regulation of cellular APP processing, contributing to the development of AD [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Furthermore, lipid dyshomeostasis, including elevated cholesterol levels, is a key participant in the pathogenesis of AD [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Lipid raft microdomains, enriched with cholesterol and sphingolipids, are considered as cellular processing platforms for various cell signaling and protein–protein interactions [ 24 , 25 , 26 , 27 ].…”

Endocytosis and Alzheimer’s disease

“…Changes in PIP 2 expression may also depend on the exogenous dietary factors. In an animal model, cerebral overexpression of phospholipase C (PLβC1) induced by high dietary cholesterol levels led to decreased PIP 2 expression [ 76 ]. High cholesterol levels affect the excitability of neural cells through a potential affinity for the PIP 2 transmembrane domain that stabilizes its interaction with G protein–activated inward rectifier potassium channel 2 (GIRK2) [ 77 ].…”