PPAR&#947 Ligand-Induced Unfolded Protein Responses in Monocytes and Macrophages

Abstract

Obesity and associated disorders such as Type-2 Diabetes (T2D) and atherosclerosis are associated with elevated levels of circulating oxidized low-density lipoprotein (oxLDL). High
levels of oxLDL lead to cell dysfunction and apoptosis, a phenomenon known as lipotoxicity. Disturbing endoplasmic reticulum (ER) function results in ER stress and unfolded protein response (UPR), which tends to restore ER homeostasis but switches to apoptosis when ER stress is prolonged. In the present study the lipotoxic effect of oxLDL was investigated on a monocyte/macrophage cell lines. The results demonstrate that oxLDL could induce ER stress and activation of the UPR pathway in mnocyte/macrophage cell lines as evident of the activation/up-regulation of ER stress/UPR genes. Cholesterol does not seem to exert effects in intact cells in our experiments; in contrast oxLDL did induce ER stress and UPR. In microsomal fractions, cholesterol but not oxLDL inhibit the ER Ca2+-ATPase activity. Gene expression analysis showed that macrophages express high levels of the oxLDL scavenger receptor CD36, than monocytes and oxLDL induced macrophage apoptosis via caspase-3/7 activation. The observations that oxLDL can induce UPRs in macrophages, and that cholesterol inhibit ER Ca2+-ATPase activity, suggest that cholesterol may be the oxLDL component responsible for macrophage lipotoxic ER stress effects as seen in obesity. As disrupted cellular Ca2+
homeostasis/ER stress may be linked to macrophage lipotoxicity this data may enhance our understanding of the diverse effects of oxLDL, particularly in the context of obesity, type 2 diabetes
and metabolic syndrome.