Endoplasmic Reticulum Stress Affects Cholesterol Homeostasis by Inhibiting LXRα Expression in Hepatocytes and Macrophages

Abstract

Atherosclerosis (AS) is the most common cardiovascular disease, and reverse cholesterol transport (RCT) plays an important role in maintaining cholesterol homeostasis. Both endoplasmic reticulum (ER) stress and LXRα can affect the metabolism of cholesterol. However, whether ER stress can modulate cholesterol metabolism by LXRα in hepatocytes and macrophages remains unclear. Therefore, in this study, we aimed to explore the relationship between ER stress induced by tunicamycin and LXRα in hepatocytes and macrophages and clarify their possible mechanisms and roles in AS. C57BL/6 mice and Huh-7 and THP-1 cells were treated with tunicamycin and LXR-623 (an agonist of LXRα) alone or in combination. Tunicamycin-induced ER stress caused liver injury; promoted the accumulation of cholesterol and triglycerides; inhibited the expression of LXRα, ABCA1 and ABCG1 in the livers of mice, thus reducing serum high-density lipoprotein (HDL)-C, low-density lipoprotein (LDL)-C, total cholesterol and triglyceride levels; however, LXR-623 could attenuate ER stress and reverse these changes. We also obtained the same results in Huh-7 and THP-1 cells. ER stress induced by tunicamycin could clearly be reversed by activating LXRα because it promoted cholesterol efflux by enhancing the expression of ABCA1 and ABCG1 in hepatocytes and macrophages, contributing to attenuation of the development of AS.

LKB1 Regulates Vascular Macrophage Functions in Atherosclerosis

“…ER stress in macrophages is also closely related to the occurrence of atherosclerosis ( Yang B. et al, 2020 ). ER stress aggravates atherosclerosis by inducing foam cell formation, apoptosis, and the release of pro-inflammatory cytokines ( Tian et al, 2019 ; Wang T. et al, 2020 ). Increased expression of the ER stress-associated apoptosis signaling molecule C/EBP homoiogous protein (CHOP) indicates macrophage apoptosis ( Yang et al, 2020b ).…”

Relationship between protein arginine methyltransferase and cardiovascular disease (Review)

“…ABCA1 has a key role in RCT by mediating the transfer of intracellular cholesterol to apolipoprotein A1 (ApoA1). The accumulation of cholesterol in macrophages may increase the expression of ABCA1 and cooperate with ABCG1 to increase the outflow of cholesterol and promote the formation of RCT (26), which is meaningful for reducing accumulated cholesterol in the blood vessel wall (27). As an important mediator of ABCA1 and potential regulator of LXR, PRMT2 regulates LXR-mediated ABCA1 expression and ABCA1-dependent cholesterol efflux (28).…”

AGEs-Induced and Endoplasmic Reticulum Stress/Inflammation-Mediated Regulation of GLUT4 Expression and Atherogenesis in Diabetes Mellitus

“…The activation of liver X receptor (LXR), by enhancing the expression of ABCA1 and ABCG1, improves the cholesterol efflux, alleviates ER stress and reduces apoptosis and defective efferocytosis in atherosclerotic lesion [ 84 , 85 ]. The pharmacological inhibition of cholesterol esterification and the stimulus to cholesterol efflux after treating with APOA1 mimetics, or overexpressing APOA1, abrogate ER and inflammatory stress [ 86 , 87 ].…”