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Tollip Deficiency Alters Atherosclerosis and Steatosis by Disrupting Lipophagy

BACKGROUND: Compromised lipophagy with unknown mechanisms may be critically involved in the intracellular accumulation of lipids, contributing to elevated atherosclerosis and liver steatosis. We hypothesize that toll‐interacting protein (Tollip), a key innate immune molecule involved in the fusion o...

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Autores principales: Chen, Keqiang, Yuan, Ruoxi, Zhang, Yao, Geng, Shuo, Li, Liwu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532987/
https://www.ncbi.nlm.nih.gov/pubmed/28396568
http://dx.doi.org/10.1161/JAHA.116.004078
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author Chen, Keqiang
Yuan, Ruoxi
Zhang, Yao
Geng, Shuo
Li, Liwu
author_facet Chen, Keqiang
Yuan, Ruoxi
Zhang, Yao
Geng, Shuo
Li, Liwu
author_sort Chen, Keqiang
collection PubMed
description BACKGROUND: Compromised lipophagy with unknown mechanisms may be critically involved in the intracellular accumulation of lipids, contributing to elevated atherosclerosis and liver steatosis. We hypothesize that toll‐interacting protein (Tollip), a key innate immune molecule involved in the fusion of autolysosome, may play a significant role in lipophagy and modulate lipid accumulation during the pathogenesis of atherosclerosis and liver steatosis. METHODS AND RESULTS: By comparing mice fed with either a Western high‐fat diet or a regular chow diet, we observed that both atherosclerosis and liver steatosis were aggravated in apolipoprotein E–deficient (ApoE(−/−))/Tollip(−/−) mice as compared with ApoE(−/−) mice. Through electron microscopy analyses, we observed compromised fusion of lipid droplets with lysosomes within aortic macrophages as well as liver hepatocytes from ApoE(−/−)/Tollip(−/−) mice as compared with ApoE(−/−) mice. As a molecular indicator for disrupted lysosome fusion, the levels of p62 were significantly elevated in aortic and liver tissues from ApoE(−/−)/Tollip(−/−) mice. Molecules involved in facilitating lipophagy completion such as Ras‐related protein 7 and gamma‐aminobutyric acid receptor‐associated protein were reduced in ApoE(−/−)/Tollip(−/−) mice as compared with ApoE(−/−) mice. Intriguingly, ApoE(−/−)/Tollip(−/−) mice had reduced circulating levels of inflammatory cytokines such as tumor necrosis factor‐α and increased levels of transforming growth factor‐β. The reduced inflammation due to Tollip deficiency is consistent with a stable atherosclerotic plaque phenotype with increased levels of plaque collagen and smooth muscle cells in ApoE(−/−)/Tollip(−/−) mice. CONCLUSIONS: Tollip deficiency selectively leads to enlarged yet stable atherosclerotic plaques, increased circulating lipids, liver steatosis, and reduced inflammation. Compromised lipophagy and reduced expression of inflammatory mediators due to Tollip deficiency may be the underlying causes. Our data suggest that lipid accumulation and inflammation may be intertwined yet independent processes during the progression of atherosclerosis and steatosis.
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spelling pubmed-55329872017-08-14 Tollip Deficiency Alters Atherosclerosis and Steatosis by Disrupting Lipophagy Chen, Keqiang Yuan, Ruoxi Zhang, Yao Geng, Shuo Li, Liwu J Am Heart Assoc Original Research BACKGROUND: Compromised lipophagy with unknown mechanisms may be critically involved in the intracellular accumulation of lipids, contributing to elevated atherosclerosis and liver steatosis. We hypothesize that toll‐interacting protein (Tollip), a key innate immune molecule involved in the fusion of autolysosome, may play a significant role in lipophagy and modulate lipid accumulation during the pathogenesis of atherosclerosis and liver steatosis. METHODS AND RESULTS: By comparing mice fed with either a Western high‐fat diet or a regular chow diet, we observed that both atherosclerosis and liver steatosis were aggravated in apolipoprotein E–deficient (ApoE(−/−))/Tollip(−/−) mice as compared with ApoE(−/−) mice. Through electron microscopy analyses, we observed compromised fusion of lipid droplets with lysosomes within aortic macrophages as well as liver hepatocytes from ApoE(−/−)/Tollip(−/−) mice as compared with ApoE(−/−) mice. As a molecular indicator for disrupted lysosome fusion, the levels of p62 were significantly elevated in aortic and liver tissues from ApoE(−/−)/Tollip(−/−) mice. Molecules involved in facilitating lipophagy completion such as Ras‐related protein 7 and gamma‐aminobutyric acid receptor‐associated protein were reduced in ApoE(−/−)/Tollip(−/−) mice as compared with ApoE(−/−) mice. Intriguingly, ApoE(−/−)/Tollip(−/−) mice had reduced circulating levels of inflammatory cytokines such as tumor necrosis factor‐α and increased levels of transforming growth factor‐β. The reduced inflammation due to Tollip deficiency is consistent with a stable atherosclerotic plaque phenotype with increased levels of plaque collagen and smooth muscle cells in ApoE(−/−)/Tollip(−/−) mice. CONCLUSIONS: Tollip deficiency selectively leads to enlarged yet stable atherosclerotic plaques, increased circulating lipids, liver steatosis, and reduced inflammation. Compromised lipophagy and reduced expression of inflammatory mediators due to Tollip deficiency may be the underlying causes. Our data suggest that lipid accumulation and inflammation may be intertwined yet independent processes during the progression of atherosclerosis and steatosis. John Wiley and Sons Inc. 2017-04-10 /pmc/articles/PMC5532987/ /pubmed/28396568 http://dx.doi.org/10.1161/JAHA.116.004078 Text en © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Research
Chen, Keqiang
Yuan, Ruoxi
Zhang, Yao
Geng, Shuo
Li, Liwu
Tollip Deficiency Alters Atherosclerosis and Steatosis by Disrupting Lipophagy
title Tollip Deficiency Alters Atherosclerosis and Steatosis by Disrupting Lipophagy
title_full Tollip Deficiency Alters Atherosclerosis and Steatosis by Disrupting Lipophagy
title_fullStr Tollip Deficiency Alters Atherosclerosis and Steatosis by Disrupting Lipophagy
title_full_unstemmed Tollip Deficiency Alters Atherosclerosis and Steatosis by Disrupting Lipophagy
title_short Tollip Deficiency Alters Atherosclerosis and Steatosis by Disrupting Lipophagy
title_sort tollip deficiency alters atherosclerosis and steatosis by disrupting lipophagy
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532987/
https://www.ncbi.nlm.nih.gov/pubmed/28396568
http://dx.doi.org/10.1161/JAHA.116.004078
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