Abstract 264: Adiponectin, an Atherosclerosis-Protective Hormone, Inhibits Cholesterol-Induced Activation of the Unfolded Protein Response and Apoptosis in Macrophages
In advanced atherosclerosis, macrophage (Mϕ) apoptosis leads to plaque necrosis and destabilization. Mϕ apoptosis in this setting can be triggered by excess free cholesterol (FC), which overloads the endoplasmic reticulum (ER) with FC and triggers a stress pathway known as the Unfolded Protein Response (UPR). Prolonged FC-induced UPR activation triggers apoptosis via the effector CHOP. Adiponectin (ApN) is an abundant adipocyte-derived hormone whose plasma levels fall in obesity/insulin resistance. Most importantly, ApN is found in atherosclerotic lesions, and low levels are associated with coronary artery disease in humans and atherosclerosis in mice. In studies exploring possible athero-protective mechanisms of ApN, we found that ApN is a potent suppressor of FC-induced Mϕ apoptosis. Remarkably, this action was specific for the naturally occuring high-molecular-weight form of ApN, which is the form that promotes insulin sensitization in vivo. The mechanism was not due to suppression of FC uptake or FC trafficking to the ER. Rather, ApN was a potent suppressor of FC-induced CHOP as well as CHOP induced by other UPR activators. Whereas most CHOP-suppressing agents function by relieving global ER stress at the level of the upstream UPR activators PERK and IRE1, ApN suppresses CHOP by uniquely down-regulating the intermediate UPR mediator ATF4. ApN does not suppress ATF4 mRNA or accelerate ATF4 degradation, indicating translational control. While ATF4-CHOP suppression likely explains at least part of the anti-apoptotic action of ApN, we found that ApN also potently activates STAT3, a known survival effector. Thus, ApN inhibits FC-induced Mϕ apoptosis, most likely by a combination of ATF4-CHOP suppression and STAT3 activation. These findings shed new light on how ApN affects Mϕ biology, with potential relevance to the athero-protective effects of this adipocyte hormone.