Abstract
Involvement of high cholesterol and oxidative stress in cardiovascular diseases is well studied, as it can be hypothesized that various products originated from lipid peroxidation, such as oxysterols, or affected protein expression might lead to cardiomyocyte damage followed by the pathological modifications. Although oxidation of excessive cholesterol to oxysterols in elevated stress conditions is identified by a number of studies, the role of a high cholesterol diet in regulating fatty acid and oxysterol accumulation, together with scavenger receptor mRNA levels, in the heart remains little investigated. Our study provides a detailed analysis of the changes in fatty acid, oxysterol, and scavenger receptor profiles and its relation with histological alterations in the heart tissue. We evaluated alterations of fatty acid composition, by the GC-MS method, while 4β-, 25-, and 27-hydroxycholesterol and 7-ketocholesterol levels by means of LC-MS/MS in high cholesterol diet-fed rabbits. Additionally, a number of proteins related to lipid metabolism and scavenger receptor mRNA expressions were evaluated by Western blotting and RT-PCR. According to our in vivo results, a high cholesterol diet enhances a number of unsaturated fatty acids, oxysterols, and LXRα, in addition to CD36, CD68, CD204, and SR-F1 expressions while α-tocopherol supplementation decreases LXRα and SR expressions together with an increase in 27-hydroxycholesterol and ABCA1 levels. Our results indicated that the high cholesterol diet modulates proteins related to lipid metabolism, which might result in the malfunction of the heart and α-tocopherol shows its beneficial effects. We believe that this work will lead the generation of different theories in the development of heart diseases.
Highlights
Cholesterol is a key component in regulating various cell functions, including the permeability and fluidity of membrane, steroid hormone synthesis, and bile acids
We have identified that both sterol regulatory element-binding protein 1c (SREBP1c) and LXRα expressions were significantly induced which were reduced to control levels by α-tocopherol supplementation (Figures 5(a) and 5(b)), no band formation of cleaved SREBP1c was observed that was correlated with decreased palmitate levels by a high cholesterol diet
Based on our hypercholesterolemic rabbit model, we showed that the 2% cholesterol diet and α-tocopherol supplementation for 8 weeks might be associated with changed free fatty acid and oxysterol compositions, proteins related to lipid metabolism, and scavenger receptors in parallel to histological alterations
Summary
Cholesterol is a key component in regulating various cell functions, including the permeability and fluidity of membrane, steroid hormone synthesis, and bile acids. After the delivery of cholesterol into the cell via lipoprotein or scavenger receptors (SRs), it might be tranferred to (i) endoplasmic reticulum (ER), inducing the sequestration of sterol regulatory element-binding proteins (SREBPs) to reduce the synthesis and uptake of cholesterol, (ii) plasma membrane, enhancing the efflux of cholesterol (known as reverse cholesterol transport (RCT)) through ATP-binding cassette transporter A1 (ABCA1), and (iii) mitochondrial sterol 27-hydroxylase (CYP27A1), increasing endogenous production of 27-hydroxycholesterol followed by the activation of liver X receptors (LXRs) [1]. Generation of oxygenated cholesterol products (oxysterols) inside the cell is majorly produced either as a result of the free radical attacks or enzymatic reactions and known as an essential reaction in cholesterol-mediated tissue damage [2]. 7-ketocholesterol is one of the major oxysterols found increased in the plasma of patients with
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