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Doctoral thesis
English

When immunology meets cholesterol metabolism in atherosclerosis... A match for immune-inflammatory and lipid metabolic disease?

ContributorsBaptista, Daniela
Defense date2022-05-18
Abstract

Atherosclerosis is a chronic inflammatory disease characterized by a subendothelial accumulation of lipids and the formation of a plaque which rupture is the principal cause of cardiovascular events. This process is largely driven by the immune system and high circulating low-density lipoprotein (LDL) levels. Although many studies have demonstrated the effects of hypercholesteremia on inflammatory pathways, only a few studies specifically investigated the effects of immunity on lipid metabolism.

PCSK9 is a key target for the treatment of hypercholesterolemia. PCSK9 inhibitors have been shown to reduce LDL and diminish atherosclerosis through LDL receptor (LDLR) regulation. However, the specific mechanisms regulating LDLR endosomal recycling are not completely revealed. Toll-interacting protein (Tollip) is an adaptor protein, initially described as an NF-κB signaling regulator, controlling the turnover of ubiquitinated receptors through endosomal trafficking. The present thesis revealed that Tollip controls LDL levels through posttranslational modulation of LDLR. Bone marrow-derived macrophages and hepatocytes from ApoE-/-Tollip-/- mice exhibited lower LDLR expression, whereas ApoE-/-Tollip-/- mice fed high cholesterol diet (HCD) had significantly elevated cholesterol levels and increased atherosclerotic plaques in comparison with ApoE-/- mice. These findings point that LDLR expression regulation is a key process involved in the atheroprotective effects of Tollip. Moreover, the present work demonstrated that Tollip regulates the recycling of LDLR from the endosome back to the cell surface and/or directs LDLR to autophagy-mediated degradation. Taken together our data highlight the role of Tollip, a mediator of low-grade inflammation, as an autophagic regulator of LDLR expression.

The second aspect of this thesis aims to reveal how TGF-β-producing B (BTGFβ1-/-) cells direct the immune response in atherosclerosis and impact cholesterol metabolism. Several studies have demonstrated that BTGFβ1-/- cells can suppress the immune responses in various diseases. However, the role of BTGFβ1-/- cells in atherosclerosis is largely unexplored. ApoE-/-BTGFβ1-/- mice fed HCD exhibited a pronounced increase of plasma B cells in the spleen, lymph nodes, and aorta, while immunoglobulins IgG1-oxLDL-specific levels raised significantly compared to ApoE-/- mice. In addition to direct immune-mediated effects, ApoE-/-BTGFβ1-/- mice had lower LDL and total cholesterol plasma levels, smaller atherosclerotic plaque size, and improved plaque stability compared to ApoE-/- mice. This atheroprotective effect could be partially explained by increased expression of ABCG1 in foam cells and in the liver, essential for reverse cholesterol transport; and by the reduction of scavenger receptors expression, promoting a decrease in foam cell formation. This is the first study to demonstrate that TGF-β-specific B cell deficiency in ApoE-/- mice has a beneficial effect on atherosclerotic disease and regulates plasma levels of cholesterol.

The present work demonstrates how immunity affects lipid metabolism, resulting in pronounced effects on atherosclerosis severity.

eng
Citation (ISO format)
BAPTISTA, Daniela. When immunology meets cholesterol metabolism in atherosclerosis... A match for immune-inflammatory and lipid metabolic disease? 2022. doi: 10.13097/archive-ouverte/unige:163151
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accessLevelPrivateaccessLevelPublic 08/30/2024 CC BY-NC-SA-4.0
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Creation08/30/2022 9:28:00 AM
First validation08/30/2022 9:28:00 AM
Update time03/16/2023 7:28:38 AM
Status update03/16/2023 7:28:36 AM
Last indexation02/01/2024 8:43:09 AM
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