Multi-omic signatures of atherogenic dyslipidaemia: pre-clinical target identification and validation in humans

Abstract

Background Dyslipidaemia is a major risk factor for atherosclerosis and cardiovascular diseases. The molecular mechanisms that translate dyslipidaemia into atherogenesis and reliable markers of its progression are yet to be fully elucidated. To address this issue, we conducted a comprehensive metabolomic and proteomic analysis in an experimental model of dyslipidaemia and in patients with familial hypercholesterolemia (FH). Methods Liquid chromatography/mass spectrometry (LC/MS) and immunoassays were used to find out blood alterations at metabolite and protein levels in dyslipidaemic ApoE−/−/LDLR−/− mice and in FH patients to evaluate their human relevance. Results We identified 15 metabolites (inhibitors and substrates of nitric oxide synthase (NOS), low-molecular-weight antioxidants (glutamine, taurine), homocysteine, methionine, 1-methylnicotinamide, alanine and hydroxyproline) and 9 proteins (C-reactive protein, proprotein convertase subtilisin/kexin type 9, apolipoprotein C-III, soluble intercellular adhesion molecule-1, angiotensinogen, paraoxonase-1, fetuin-B, vitamin K-dependent protein S and biglycan) that differentiated FH patients from healthy controls. Most of these changes were consistently found in dyslipidaemic mice and were further amplified if mice were fed an atherogenic (Western or low-carbohydrate, high-protein) diet. Conclusions The alterations highlighted the involvement of an immune-inflammatory response system, oxidative stress, hyper-coagulation and impairment in the vascular function/regenerative capacity in response to dyslipidaemia that may also be directly engaged in development of atherosclerosis. Our study further identified potential biomarkers for an increased risk of atherosclerosis that may aid in clinical diagnosis or in the personalized treatment.

Data-Independent Acquisition Proteomics Reveals Long-Term Biomarkers in the Serum of C57BL/6J Mice Following Local High-Dose Heart Irradiation

“…This analysis also clearly showed that local heart irradiation is able to induce systemic inflammation and hypercholesterolemia in mice. These two responses are similar to those found in a multiomics study comparing atherogenic and dyslipidemic mice with wild-type mice and, more importantly, when comparing familial hypercholesterolemia patients with healthy controls (34).…”

Low-density lipoprotein receptor genotypes modify the sera metabolome of patients with homozygous familial hypercholesterolemia

“…These metabolites have been reported to act as the endogenous free radical scavenger for reactive oxygen species ( Afolabi et al., 2022 ; Chen et al., 2012 ; Watanabe et al., 2008 ). Interestingly, the decreased plasma level of taurine, methionine, and glutamine was also observed in the comparisons of LDLR null/null mice versus wild-type mice and patients with HeFH versus normolipidemic subjects ( Olkowicz et al., 2021 ). Furthermore, we also identified the elevation of serum hypoxanthine and purine was positively with null LDLR mutations.…”

“…Of note, most of these altered metabolites are not the direct production of LDLR pathways. More importantly, these metabolic alterations were implicated in multiple biological processes and closely associated with the development of atherosclerotic cardiovascular diseases ( Lauterbach et al., 2020 ; Li et al., 2015 ; Olkowicz et al., 2021 ; Saulnier-Blache et al., 2018 ). However, current knowledge of LDLR mutations-caused HoFH is limited in the datasets of clinical laboratory and genetic tests; information on metabolomic effects of LDLR genotypes are still lacking.…”

Ethinylestradiol in combined hormonal contraceptive has a broader effect on serum proteome compared with estradiol valerate: a randomized controlled trial

“…Untargeted proteomic analysis also enables the identification of interesting novel targets for future research. Fetuin-B is a relatively understudied hepatokine associated with insulin resistance, dyslipidemia, and non-alcoholic fatty liver disease ( Meex and Watt, 2017 ; Mokou et al , 2020 ; Olkowicz et al , 2021 ). Serum levels of fetuin-B increase during pregnancy but normalize after delivery ( Šimják et al , 2018 ), possibly related to hormonal changes of pregnancy.…”