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• W2905108129 abstract "In the present issue of Acta Physiologica, Zhao et al1 published an article, in which they investigate how the extracellular matrix protein CCN1 regulates cholesterol efflux from macrophages in atherosclerotic plaques and biliary excretion of cholesterol in the liver. The development of atherosclerotic plaques is a primarily inflammatory process, which is triggered by well-established risk factors including arterial hypertension, diabetes, hypercholesterolaemia and smoking. The latter two act together during the formation of a particularly atherogenic molecule: oxidized low-density lipoprotein (oxLDL). OxLDL accumulates at sites of prolonged endothelial damage and is eventually taken up by macrophages, which then turn into foam cells through cholesterol overload.2 This process triggers inflammation and oxidative stress leading to increased oxidation of LDL to oxLDL. Local remodelling processes, such as fibrosis and calcification, finally shape atherosclerotic plaques. An important rescue mechanism during this process is cholesterol efflux from macrophages via ABC transport proteins in order to maintain cholesterol homeostasis and to prevent foam cell formation.3 Additionally, reverse cholesterol transport, for example, through high density lipoproteins, from the peripheral plaque site to the liver reduces local cholesterol accumulation and therefore counteracts plaque formation. In the liver, cholesterol is stored and can finally be removed from the organism via biliary excretion. Failure of hepatic cholesterol elimination mechanisms leads to cholesterol overload and strongly promotes atherosclerotic plaque development, independent from dietary cholesterol intake. The extracellular matrix protein CCN1 is the first member of the CCN family, which consist of six multifunctional proteins with typically four functional domains: the insulin-like growth factor binding protein domain, the von Willebrand factor type C repeat domain, the thrombospondin type 1 repeat domain and the carboxyl-terminal domain. The presence of these four domains make the CCN proteins a unique group with large interactive potential through direct binding. CCN extracellular matrix proteins are secreted by various cells and are thought to exert their function mainly through interaction with other extracellular proteins and proteoglycans, such as integrins and cytokines. While the role of CCN1 as a regulator of cardiovascular development has been established soon after its discovery, recent research links CCN1 to acute and chronic inflammatory processes.4 In the context of atherosclerosis, CCN1 has been proven to contribute to leucocyte migration, neointima formation and endothelial apoptosis.5, 6 In a set of elegant experiments, Zhao et al have now established that (a) CCN1 secretion by macrophages is increased upon oxLDL stimulation and (b) that CCN1 reduces cholesterol efflux from macrophages leading to foam cell formation in vitro. The relevance of these results was confirmed in vivo in ApolipoproteinE knockout mice, showing that systemic CCN1 treatment increases inflammatory cytokine levels and atherosclerotic plaque formation. Interestingly, CCN1 treatment also leads to increased plasma levels of various lipids in the treated animals. The authors were able to explain this finding by showing that CCN1 impairs cholesterol elimination through the liver and leads to accumulation of cholesterol in hepatocytes. Consequently, CCN1 influences the cholesterol metabolism through two potentially additive mechanisms—locally in macrophages at the plaque site and systemically in the liver, which can explain the relatively strong induction of atherosclerotic lesions by CCN1. Noteworthy, a positive feedback loop can be inferred by integration of the presented data: OxLDL augments CCN1 secretion and thereby induces foam cell formation and local inflammation. At the same time, CCN1 reduces hepatic cholesterol excretion leading to increased plasma cholesterol levels, which promotes the formation of atherosclerotic plaques, where LDL is oxidized during local inflammation and oxidative stress. OxLDL then again triggers CNN1 secretion (Figure 1). The results of Zhao et al are complementary to data of Shi et al,7 who showed that another member of the CCN family, CCN3, negatively regulates foam cell formation and thereby acts as an atheroprotective factor. CCN1 and CCN3 have previously been shown to mediate opposite effects on cellular proliferation in a different context.8 This illustrates the complex interactions of the multivalent CCN extracellular matrix proteins. In a recently published review article Perbal describes the members of the CCN1 family as part of a team, which act together as a centralized communication network.9 Therefore, it would be a reasonable approach to study at least the first three CCN family members together, to obtain the full picture of CCN-based regulatory mechanisms. Additionally, the timing of the expression and its regulation are key elements to understand the function of the CCN proteins. For example, during embryonic development CNN extracellular matrix proteins are highly expressed and tightly regulated. Disruption of this orchestrated process leads to embryonic death owing to insufficient placental vascularization as well as compromised vessel integrity. In consequence, our understanding of the role of CCN family members in the regulation of the cholesterol metabolism remains incomplete. First, a simultaneous examination of various CCN family members in a reasonably good timely resolution covering the processes from macrophage stimulation by oxLDL to foam cell transformation in vitro would be necessary. Second, validation in an atheroprone in vivo model with tissue specific inducible genetic loss of function of different CCN family members could enlighten the role of CCN proteins in atherogenesis. Although this is certainly difficult to achieve, the demonstrated results are highly encouraging to go the extra mile to obtain novel treatment options to fight atherosclerosis. None to declare." @default.
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• W2905108129 date "2019-01-09" @default.
• W2905108129 modified "2023-09-27" @default.
• W2905108129 title "CCN1 regulates cholesterol metabolism—OxLDL enters the matrix" @default.
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• W2905108129 doi "https://doi.org/10.1111/apha.13239" @default.
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