Pathological Crosstalk Between Oxidized LDL and ER Stress in Human Diseases: A Comprehensive Review

Abstract

The oxidative modification of the major cholesterol carrying lipoprotein, oxLDL, is a biomarker as well as a pathological factor in cardiovascular diseases (CVD), type 2 diabetes mellitus (T2DM), obesity and other metabolic diseases. Perturbed cellular homeostasis due to physiological, pathological and pharmacological factors hinder the proper functioning of the endoplasmic reticulum (ER), which is the major hub for protein folding and processing, lipid biosynthesis and calcium storage, thereby leading to ER stress. The cellular response to ER stress is marked by a defensive mechanism called unfolded protein response (UPR), wherein the cell adapts strategies that favor survival. Under conditions of excessive ER stress, when the survival mechanisms fail to restore balance, UPR switches to apoptosis and eliminates the defective cells. ER stress is a major hallmark in metabolic syndromes such as diabetes, non-alcoholic fatty liver disease (NAFLD), neurological and cardiovascular diseases. Though the pathological link between oxLDL and ER stress in cardiovascular diseases is well-documented, its involvement in other diseases is still largely unexplored. This review provides a deep insight into the common mechanisms in the pathogenicity of diseases involving oxLDL and ER stress as key players. In addition, the potential therapeutic intervention of the targets implicated in the pathogenic processes are also explored.

Current View on the Mechanisms of Alcohol-Mediated Toxicity

“…This happens mainly in the liver and pancreas [78]. In addition, some of these processes have been implicated as mediators (5) The acetylCoA formed may be used in the tricarboxylic cycle or diverted to de novo fatty acid synthesis. AcetylCoA availability modulates many substrate-level protein acetylation modifications [77].…”

“…In addition to acute intoxications, which often require urgent care attention, especially in young people, the danger of alcohol consumption lies primarily in alcohol addiction, leading to chronic abuse and organ damage. Affected organs/systems include the liver [2], the cardiovascular system [3], the endocrine system [4], the metabolism of basic nutrients [5], the neural system [6,7], or the gastrointestinal tract [8]. Although the mentioned organs/systems perform different functions, the distribution and metabolization of ethanol in organs/systems are variable.…”

Oxidized LDLs as Signaling Molecules

“…In the brain, an increase in oxLDLs has been associated with hyperlipidemia and impaired blood-brain barrier, which could contribute to neurodegenerative events and vascular dementia [181,182]. In this context, increased serum oxLDL levels have been detected in Alzheimer's patients and have been suggested as biomarkers for the disease (reviewed in [125]). In cultured embryonic neurons, astrocytes, and microglia, both oxLDLs and oxHDLs induced lethal oxidative stress that was amplified by amyloid-beta or glutamate [183,184].…”

“…In addition to oxLDLs, CD36 has numerous other ligands with important physiological functions ranging from the detection of flavors in olfactory epithelial cells to the phagocytosis of pathogens and to the regulation of lipid uptake and storage [ 117 , 119 , 120 ]. Of relevance may be the competition of these ligands with oxLDLs for CD36 binding, the ligand-induced downregulation of CD36 on the cell surface [ 34 , 67 , 121 , 122 , 123 , 124 ], and the CD36-mediated induction of endoplasmic reticulum stress by oxLDLs in various cell types [ 125 ].…”

“…In both breast and ovarian cancer, patients showed increased oxLDL levels compared to controls, suggesting a possible role of oxLDLs in the process of malignancy [ 125 , 177 ]. Certainly, in human breast mammary epithelial cells, oxLDLs triggered the upregulation of proliferative and pro-inflammatory signaling.…”