Analysis of serum changes in response to a high fat high cholesterol diet challenge reveals metabolic biomarkers of atherosclerosis

Abstract

Atherosclerotic plaques are characterized by an accumulation of macrophages, lipids, smooth muscle cells, and fibroblasts, and, in advanced stages, necrotic debris within the arterial walls. Dietary habits such as high fat and high cholesterol (HFHC) consumption are known risk factors for atherosclerosis. However, the key metabolic contributors to diet-induced atherosclerosis are far from established. Herein, we investigate the role of a 2-year HFHC diet challenge in the metabolic changes of development and progression of atherosclerosis. We used a non-human primate (NHP) model (baboons, n = 60) fed a HFHC diet for two years and compared metabolomic profiles in serum from animals on baseline chow with serum collected after the challenge diet using two-dimensional gas chromatography time-of-flight mass-spectrometry (2D GC-ToF-MS) for untargeted metabolomic analysis, to quantify metabolites that contribute to atherosclerotic lesion formation. Further, clinical biomarkers associated with atherosclerosis, lipoprotein measures, fat indices, and arterial plaque formation (lesions) were quantified. Using two chemical derivatization (i.e., silylation) approaches, we quantified 321 metabolites belonging to 66 different metabolic pathways, which revealed significantly different metabolic profiles of HFHC diet and chow diet fed baboon sera. We found heritability of two important metabolites, lactic acid and asparagine, in the context of diet-induced metabolic changes. In addition, abundance of cholesterol, lactic acid, and asparagine were sex-dependent. Finally, 35 metabolites correlated (R 2 , 0.068–0.271, P < 0.05) with total lesion burden assessed in three arteries (aortic arch, common iliac artery, and descending aorta) which could serve as potential biomarkers pending further validation. This study demonstrates the feasibility of detecting sex-specific and heritable metabolites in NHPs with diet-induced atherosclerosis using untargeted metabolomics allowing understanding of atherosclerotic disease progression in humans.

Biocompatible chitosan-modified core-shell Fe3O4 nanocomposites for exigent removal of blood lactic acid

“…More importantly, differing from the traditional lactic acid lowering methods, Fe 3 O 4 @Chi NCs directly adsorbed lactic acid. Therefore, patients could avoid the metabolic burden from lactic acid clearance [25]. After adsorption, the FTIR spectrum of lactic acid loaded Fe 3 O 4 @Chi NCs was tested to investigate the underlying mechanism of action of lactic acid adsorption.…”

Amylin deposition activates HIF1α and 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) signaling in failing hearts of non-human primates

“…Similar to humans, NHPs spontaneously or following treatment with a high-fat diet, develop cardiovascular diseases related to obesity and T2D, thereby acting as ideal models for investigating the molecular pathogenesis of these diseases 47,65,66 . As shown previously, aggregated amylin plays important detrimental roles in the pancreas, heart, kidney, and brain of humans and HIP rats 13,19,[22][23][24][28][29][30]51 .…”

Efficacy of choline and DHA supplements or enriched environment exposure during early adult obesity in mitigating its adverse impact through aging in rats

“…Along with intimal wall changes, the tunica media of the artery also thickened due to changes in smooth muscle cells, alterations in collagen fibers and fatty streaks formation which further increases the thickness of tunica media. With an increase in thickness of tunica intima and tunica media, the arterial lumen gets narrowed that may cause decrease in blood flow through the arterial lumen ( Misra et al, 2019 ). Additionally, studies show that hydroxyproline; a content of collagen increases with age in addition to increased collagen and elastic fibers in tunica media of an artery with aging ( Tsamis, Krawiec and Vorp, 2013 ).…”

“…Fatty streaks deposition is characterized by accumulation of non-foamy and foamy macrophages in arterial wall in later stages. Further, this leads to disturbances in amino acid and lipid metabolism in hypercholesterolemia ( Misra et al, 2019 ). An altered lipid profile can cause structural changes in arterial wall leading to initial stages of atherosclerosis.…”