Amelioration of Glucolipotoxicity-Induced Endoplasmic Reticulum Stress by a “Chemical Chaperone” in Human THP-1 Monocytes

Abstract

Chronic ER stress is emerging as a trigger that imbalances a number of systemic and arterial-wall factors and promote atherosclerosis. Macrophage apoptosis within advanced atherosclerotic lesions is also known to increase the risk of atherothrombotic disease. We hypothesize that glucolipotoxicity might mediate monocyte activation and apoptosis through ER stress. Therefore, the aims of this study are (a) to investigate whether glucolipotoxicity could impose ER stress and apoptosis in THP-1 human monocytes and (b) to investigate whether 4-Phenyl butyric acid (PBA), a chemical chaperone could resist the glucolipotoxicity-induced ER stress and apoptosis. Cells subjected to either glucolipotoxicity or tunicamycin exhibited increased ROS generation, gene and protein (PERK, GRP-78, IRE1α, and CHOP) expression of ER stress markers. In addition, these cells showed increased TRPC-6 channel expression and apoptosis as revealed by DNA damage and increased caspase-3 activity. While glucolipotoxicity/tunicamycin increased oxidative stress, ER stress, mRNA expression of TRPC-6, and programmed the THP-1 monocytes towards apoptosis, all these molecular perturbations were resisted by PBA. Since ER stress is one of the underlying causes of monocyte dysfunction in diabetes and atherosclerosis, our study emphasize that chemical chaperones such as PBA could alleviate ER stress and have potential to become novel therapeutics.

Acid Sphingomyelinase Mediates Oxidized-LDL Induced Apoptosis in Macrophage <i>via</i> Endoplasmic Reticulum Stress

“…In our present study, we proved that ox-LDL-induced upregulation of CHOP and apoptosis in macrophages could be prevented when PBA inhibited ER stress. This finding agrees well with that of a previous study 41–42) .…”

HIGD1A Regulates Oxygen Consumption, ROS Production, and AMPK Activity during Glucose Deprivation to Modulate Cell Survival and Tumor Growth

“…ROS generation during glucose deprivation can result in cell death (Gao et al, 2012; Lenin et al, 2012; Malhotra et al, 2008). AMPK can be induced by glucose deprivation and mitochondrial O 2 − production (Wu and Wei, 2012) (Mackenzie et al, 2013) to reduce total ROS via the promotion of pentose phosphate shunt-mediated NADPH production (Jeon et al, 2012).…”

Increased monocyte‐derived reactive oxygen species in type 2 diabetes: role of endoplasmic reticulum stress

“…A potential mechanism by which monocyte-derived ROS is increased in T2D is ER stress (Lenin et al , 2012). While initially a compensatory attempt to maintain cellular homeostasis, sustained ER stress and activation of the unfolded protein response (UPR) is now thought to be the basis of a number of chronic diseases of both metabolic and cardiovascular nature (Eizirik et al , 2008; Hotamisligil, 2010a; Hotamisligil, 2010b; Hummasti & Hotamisligil, 2010; Gregor & Hotamisligil, 2011; Flamment et al , 2012; Fu et al , 2012; Cao & Kaufman, 2013).…”

“…Hyperglycemia, hyperinsulinemia, and hyperlipidemia are known triggers of ER stress in various tissues and cell types (Wang et al , 2005; Jeffrey et al , 2008; Komura et al , 2010; McAlpine et al , 2010; Mozzini et al , 2015; Rajan et al , 2016; Tampakakis et al , 2016). For instance, it has been shown that exposure of human monocytes to serum free medium with high levels of glucose plus palmitic acid, a mixture intended to emulate the circulating glucolipotoxic environment of T2D, resulted in the induction of ER stress markers and ROS production (Lenin et al , 2012). …”