156 - Tollip controls atherogenesis through regulation of autophagy-mediated degradation of low-density lipoprotein receptor. (ID 1078)
Abstract
Background and Aims
Atherosclerosis is a chronic inflammatory disease, in which lipids accumulate in arterial walls and lead to plaque formation. This process is largely driven by the immune system and monocytes/macrophages are the main immune cells present in atherosclerotic lesions. In this context, high levels of circulating LDL induce its engulfment and retention by macrophages, forming foam cells. The modulation of LDL absorbance is thus wildly used to manage atherosclerosis. The complex process permitting the regulation of LDL is however not fully understood.
Methods
We used Apoe-/-Tollip-/- and Apoe-/- mice on normal and high cholesterol-diet
Results
We show that Tollip regulates LDL plasma levels through posttranslational modulation of LDLR. Although already known for its atheroprotective function, we found that LDLR expression by BMDM and hepatocytes are much lower in Apoe-/-Tollip-/- than in Apoe-/- mice, while the atherosclerotic lesions are significantly enhanced. Tollip being known to modulate interleukin-1 and TLRs signalization across endosomal-trafficking, we were further able to show that Tollip controls LDLR expression through regulation of endolysosome fusion with the autophagosome. We have demonstrated that inhibition of autophagy by wortmanin abrogates the effects of Tollip knockout on LDLR expression in BMDM.
Conclusions
These findings point to LDLR modulation as the key process involved in atheroprotection mediated by Tollip. These results further suggest that Tollip regulates recycling of LDLR from the endosome back to the cell surface and/or directing LDLR to autophagy-mediated degradation. Tollip have thus crucial functions in posttranscriptional regulation of LDLR expression and, in turn, in cholesterol homeostasis.
