Metabonomic Changes Associated with Atherosclerosis Progression for LDLR^–/– Mice

Abstract

Atherosclerosis resulting from hyperlipidemia causes many serious cardiovascular diseases. To understand the systems changes associated with pathogenesis and progression of atherosclerosis, we comprehensively analyzed the dynamic metabonomic changes in multiple biological matrices of LDLR(-/-) mice using NMR and GC-FID/MS with gene expression, clinical chemistry, and histopathological data as well. We found that 12 week "Western-type" diet (WD) treatment caused obvious aortic lesions, macrophage infiltration, and collagen level elevation in LDLR(-/-) mice accompanied by up-regulation of inflammatory factors including aortic ICAM-1, MCP-1, iNOS, MMP2, and hepatic TNFα and IL-1β. The WD-induced atherosclerosis progression was accompanied by metabonomic changes in multiple matrices including biofluids (plasma, urine) and (liver, kidney, myocardial) tissues involving multiple metabolic pathways. These included disruption of cholesterol homeostasis, disturbance of biosynthesis of amino acids and proteins, altered gut microbiota functions together with metabolisms of vitamin-B3, choline, purines, and pyrimidines. WD treatment caused down-regulation of SCD1 and promoted oxidative stress reflected by urinary allantoin elevation and decreases in hepatic PUFA-to-MUFA ratio. When switching to normal diet, atherosclerotic LDLR(-/-) mice reprogrammed their metabolisms and reversed the atherosclerosis-associated metabonomic changes to a large extent, although aortic lesions, inflammation parameters, macrophage infiltration, and collagen content were only partially alleviated. We concluded that metabolisms of fatty acids and vitamin-B3 together with gut microbiota played crucially important roles in atherosclerosis development. These findings offered essential biochemistry details of the diet-induced atherosclerosis and demonstrated effectiveness of the integrated metabonomic analysis of multiple biological matrices for understanding the molecular aspects of cardiovascular diseases.

Elucidating the mechanism by which regulating spleen and lipid method improves the state of hyperlipidaemic rats

“…The network pharmacology study showed that the LDLR target protein is associated with RSLD. Previous metabolomic studies have shown that LDLR protein deficiency causes a significant metabolic perturbation in TCA cycle, amino acid metabolism and fatty acid metabolism, and influences levels of taurine, linoleic acid, citric acid, leucine, and valine [33][34][35]. As shown in Figure 10, we observed similar changes in concentration of taurine, linoleic acid, citric acid, leucine, and valine in these related metabolic pathways.…”

Role of intestinal microbiota and metabolites on gut homeostasis and human diseases

“…Close to the completion of this manuscript, an interesting paper has been published demonstrating the link of atherosclerosis etiology with abnormal gut microbiota [206]. Studies with low-density lipoprotein receptor (LDLR) −/− mice, an atherosclerotic murine model, revealed that 12-week supplementation of high-fat diet could lead to evident aortic lesions, macrophage infiltration, and collagen level increase, concurrent with an up-regulation of inflammatory factors [206].…”

“…Studies with low-density lipoprotein receptor (LDLR) −/− mice, an atherosclerotic murine model, revealed that 12-week supplementation of high-fat diet could lead to evident aortic lesions, macrophage infiltration, and collagen level increase, concurrent with an up-regulation of inflammatory factors [206]. This finding suggests that gut microbiota, combined with metabolisms of fatty acids and vitamin B 3 , could play a profound role in the onset and development of atherosclerosis [206] (Fig. 3).…”

Influence of high-fat diet on gut microbiota

“…Li et al, reported that a ‘western-type’ diet induced atherosclerosis progression in association with altered gut microbiota functions among others. Switching to a normal diet reversed this process implicating a crucial role of gut microbiota in atherosclerosis development 25 . In addition, it was reported that atherosclerosis susceptibility may be transmitted via transplantation of gut microbiota and that this may be influenced by intestinal microbial metabolism of certain dietary nutrients producing trimethylamine N-oxide 26* .…”