Fig 4 - uploaded by Manuel C Peitsch
Content may be subject to copyright.
Lipoprotein structure and cholesterol metabolism and transport. A) Schematic representation of a lipoprotein particle. Lipoproteins have a spherical geometry with a monolayer of amphipathic lipids and proteins encircling a core of neutral lipids. Apolipoproteins (orange or purple) embedded in the phospholipid layer confer structural and functional properties to the molecule (specific transporter of VLDL; LDL or HDL). The lipoprotein contain TG, FFA, FC, and PL. B) Cholesterol synthesized in hepatocytes is transported as VLDL to the blood circulation. The VLDL contain TG, fatty acids, free cholesterol and phospholipids. VLDL particles are transported by B100 apolipoproteins. VLDL is then remodeled and transformed into IDL and LDL by the action of LPL in the blood circulation. The cholesterol could also be transported by chylomicrons. Chylomicrons are synthesized by the enterocyted cells in the intestine tissue after diet absorption or bile acids re-absorption. The chylomicrons transport the cholesterol from intestine to the circulation via the Apolipoprotein B48. LPL triggers the transformation chylomicrons into remnants with the release of free fatty acids (FFA) in the circulation. These FFA will be stored in adipose tissue in the form of TGs or could be oxidized by non-hepatic tissues such as muscles. LDL particles and remnants are removed from the circulation through interactions with LDL receptors. The excess of cholesterol can be cleared from tissue via the reverse cholesterol transport (RCT) via the ApoA1 lipoprotein. ApoA1 is synthesized in hepatocytes and released from the liver as lipid-poor ApoA1. These particles bind to ATP-binding cassette A1 (ABCA1) transport proteins located on the surface of peripheral cells, leading to the transfer of unesterified FC. The ApoA1 accumulates free cholesterol and FFA, the particles and become mature high density lipoproteins (HDL) by the action of lecithin-cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) to become mature HDL. HDL particles are then cleared from the bloodstream by scavenger receptor B1 (SRB1) expressed by hepatocytes. ApoB100: ApoA1: Apolipoprotein A1; Apolipoprotein B100; ApoB48: Apolipoprotein B48; VLDL: Very Low Density Lipoprotein; IDL: Intermediate Low Density Lipoprotein; LDL: Low Density Lipoprotein; LPL: Lipoprotein Lipase; FFA: Free Fatty Acids; ABCA1: ATP-binding cassette A1; FC: Free cholesterol; CETP: cholesteryl ester transfer protein; LCAT: Lecithin-Cholesterol Acyltransferase; SRB1: scavenger receptor B1; TG: Triglycerides; TG: Triglycerides: FC: PL: Phospholipids.
Source publication
Atherosclerosis is a progressive inflammatory thickening of the arterial wall resulting from increased cellularity and the accumulation of lipids, cellular debris, and extracellular matrix. Conventional determinations of plasma lipoproteins have resulted in a wealth of clinical data documenting the correlation between low- and high-density lipoprot...
Citations
... After showing that the lipid storage architecture within adipocytes differed in differentiated lipodema adipocytes, we next wanted to assess their lipid composition. Adipocyte lipid composition has been shown to contribute to several clinical disorders including obesity and cancer [25][26][27]. Therefore, to characterize the lipid profiles of adipocytes in lipedema, we used a non-targeted lipidomics approach, focusing on the profile of low molecular Fig. 1 Transcriptional profiling of adipose tissue from lipedema (LED) and non-lipedema (non-LED) patients. ...
... weight (m/z 300-3000) ionizable lipid molecules, and multivariate statistics to compare the lipid molecules in lipedema adipocytes against controls. Liquid chromatography mass spectrometry (LCMS) data acquisition identified 928 putative lipid species based on accurate mass [26,27]. PCA analysis revealed distinct clusters for each of the adipocyte groups, suggesting a unique lipedema adipocyte lipidomic signature ( Fig. 3a and Supplementary Fig. 3a). ...
Objectives
Lipedema, a poorly understood chronic disease of adipose hyper-deposition, is often mistaken for obesity and causes significant impairment to mobility and quality-of-life. To identify molecular mechanisms underpinning lipedema, we employed comprehensive omics-based comparative analyses of whole tissue, adipocyte precursors (adipose-derived stem cells (ADSCs)), and adipocytes from patients with or without lipedema.
Methods
We compared whole-tissues, ADSCs, and adipocytes from body mass index–matched lipedema ( n = 14) and unaffected ( n = 10) patients using comprehensive global lipidomic and metabolomic analyses, transcriptional profiling, and functional assays.
Results
Transcriptional profiling revealed >4400 significant differences in lipedema tissue, with altered levels of mRNAs involved in critical signaling and cell function-regulating pathways (e.g., lipid metabolism and cell-cycle/proliferation). Functional assays showed accelerated ADSC proliferation and differentiation in lipedema. Profiling lipedema adipocytes revealed >900 changes in lipid composition and >600 differentially altered metabolites. Transcriptional profiling of lipedema ADSCs and non-lipedema ADSCs revealed significant differential expression of >3400 genes including some involved in extracellular matrix and cell-cycle/proliferation signaling pathways. One upregulated gene in lipedema ADSCs, Bub1 , encodes a cell-cycle regulator, central to the kinetochore complex, which regulates several histone proteins involved in cell proliferation. Downstream signaling analysis of lipedema ADSCs demonstrated enhanced activation of histone H2A, a key cell proliferation driver and Bub1 target. Critically, hyperproliferation exhibited by lipedema ADSCs was inhibited by the small molecule Bub1 inhibitor 2OH-BNPP1 and by CRISPR/Cas9-mediated Bub1 gene depletion.
Conclusion
We found significant differences in gene expression, and lipid and metabolite profiles, in tissue, ADSCs, and adipocytes from lipedema patients compared to non-affected controls. Functional assays demonstrated that dysregulated Bub1 signaling drives increased proliferation of lipedema ADSCs, suggesting a potential mechanism for enhanced adipogenesis in lipedema. Importantly, our characterization of signaling networks driving lipedema identifies potential molecular targets, including Bub1, for novel lipedema therapeutics.
... As a matter of fact, adipogenesis may be implicated in the treatment of various human disease. For instance, adipogenesis models could be utilized for lipidomics studies in various clinically relevant areas, including diabetes [124,125], cardiovascular disease [126,127], prostate cancer [128,129], and psychiatric diseases such as schizophrenia [128]. ...
Adipose tissue is contemplated as a dynamic organ that plays key roles in the human body. Adipogenesis is the process by which adipocytes develop from adipose-derived stem cells to form the adipose tissue. Adipose-derived stem cells' differentiation serves well beyond the simple goal of producing new adipocytes. Indeed, with the current immense biotechnological advances, the most critical role of adipose-derived stem cells remains their tremendous potential in the field of regenerative medicine. This review focuses on examining the physiological importance of adipogenesis, the current approaches that are employed to model this tightly controlled phenomenon, and the crucial role of adipogenesis in elucidating the pathophysiology and potential treatment modalities of human diseases. The future of adipogenesis is centered around its crucial role in regenerative and personalized medicine.
... Even though some lipidomic studies were conducted in animal models that mimic human exposure to toxicants, the data derived from such studies provide clues about the different classes of lipids that are enriched in coronary artery plaques in humans. This information will be useful for identifying a set of lipid biomarkers in human studies (200). ...
Obesity, diabetes, and hypertension have increased by epidemic proportions in recent years among African Americans in comparison to Whites resulting in significant adverse cardiovascular disease (CVD) disparities. Today, African Americans are 30% more likely to die of heart disease than Whites and twice as likely to have a stroke. The causes of these disparities are not yet well-understood. Improved methods for identifying underlying risk factors is a critical first step toward reducing Black:White CVD disparities. This article will focus on environmental exposures in the external environment and how they can lead to changes at the cellular, molecular, and organ level to increase the personal risk for CVD and lead to population level CVD racial disparities. The external environment is defined in three broad domains: natural (air, water, land), built (places you live, work, and play) and social (social, demographic, economic, and political). We will describe how environmental exposures in the natural, built, and social environments “get under the skin” to affect gene expression though epigenetic, pan-omics, and related mechanisms that lead to increased risk for adverse CVD health outcomes and population level disparities. We also will examine the important role of metabolomics, proteomics, transcriptomics, genomics, and epigenomics in understanding how exposures in the natural, built, and social environments lead to CVD disparities with implications for clinical, public health, and policy interventions. In this review, we apply an exposome approach to Black:White CVD racial disparities. The exposome is a measure of all the exposures of an individual across the life course and the relationship of those exposures to health effects. The exposome represents the totality of exogenous (external) and endogenous (internal) exposures from conception onwards, simultaneously distinguishing, characterizing, and quantifying etiologic, mediating, moderating, and co-occurring risk and protective factors and their relationship to disease. Specifically, it assesses the biological mechanisms and underlying pathways through which chemical and non-chemical environmental exposures are associated with CVD onset, progression and outcomes. The exposome is a promising approach for understanding the complex relationships among environment, behavior, biology, genetics, and disease phenotypes that underlie population level, Black: White CVD disparities.
... In the last few years, a lot of studies have investigated the diagnostic potential of biomarkers in cardiovascular diseases (Duffy and Hameed 2015). International recommendations highlight the clinical use of troponin, hs-CRP, and NT-proBNP (ESC Guideline 2016), but there are other new biomarker discoveries, e.g., microRNA (Lopez et al. 2015), apolipoprotein-E, and other lipid-based markers (LDL/HDL ratio, sphingolipids) (De Leon et al. 2015) in relation to these disorders. In the background of the intensive biomarker research is the fact that until today, there is no single cardiac biomarker available, which is absolutely specific to different conditions, or relevant both in diagnostics and prognostics. ...
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic and multifunctional neuropeptide having neurotrophic, neuroprotective, and general cytoprotective actions in a variety of tissues based on its anti-apoptotic, anti-inflammatory, and antioxidant effects. Several studies have demonstrated its cardioprotective effects in vitro and in various animal models. However, few data are available on the presence of PACAP in human cardiac tissues and its role in the pathomechanism and progression of different cardiac disorders, particularly heart failure. Earlier, our research group has shown PAC1 receptor immunoreactivity in human heart tissue samples and we have found significantly elevated PACAP27- and PACAP38-like immunoreactivity in ischemic cardiac samples compared to valvular abnormalities with radioimmunoassay. In the last few years, numerous studies examined the presence and the changes of PACAP levels in different human tissue samples and biological fluids to show alterations in different physiological and pathological conditions. Therefore, the aim of the present study was to measure the alterations of blood PACAP levels in chronic heart failure caused by primary dilated cardiomyopathy or ischemic cardiomyopathy and to examine the possible relationship between serum levels of PACAP, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and systolic left ventricular function, the most reliable biomarkers of heart failure. In the group of mild heart failure patients, a significant strong negative correlation was detected. Furthermore, in moderate heart failure, we found a significant moderate negative correlation between PACAP and NT-proBNP levels only in ischemic subgroup. Positive correlation was found between serum PACAP level and ejection fraction only in patients with heart failure due to ischemic cardiomyopathy but not in patients with primary dilated cardiomyopathy. In summary, remarkable differences were observed between the ischemic and non-ischemic heart failure suggesting that PACAP might play an important role in the pathomechanism and progression of ischemic heart failure and it might be a potential biomarker of cardiac diseases in the future.
... Another important application is screening of newborns for inborn metabolic disorders [340][341][342] (e.g., fatty acid oxidation defects, organic acidemia, amino acid metabolism, and urea cycle defects), which can lead to the development of new diagnostic tests. Lipidomics techniques have been established to detect and monitor the development of cardiovascular disease, [343][344][345] diabetes, 346,347 inflammatory diseases, 348,349 Alzheimer's disease, 350 The contribution of systems biology to personalized medicine is undeniable. Network approaches, in particular, may provide a more elegant way to stratify subjects and explain different responses to individual drugs, and to identify the best combination of drugs to treat each patient 280 by comparisons with molecular signatures. ...
Traditional reductionist approaches play a crucial role in our understanding of biology and medicine, but they cannot explain the full complexity of biological phenomena and human disease. Systems biology combines recent high-throughput profiling technologies—such as transcriptomics, proteomics, and metabolomics—with computational modeling to capture, summarize, and understand this complexity. In this article, we provide a detailed overview of these experimental profiling technologies and computational modeling approaches. Several case studies illustrate how system approaches are already effectively used in toxicology assessment, drug development, diagnostics, and personalized medicine. Overall, this article provides the foundations to further integrate systems biology approaches into biomedical research.
... Recent studies are focused in lipids-based biomarker discovery, such as in cancer (Perrotti et al. 2016), nutrition and metabolism (Newsholme 2016), cardiovascular disease (De Leon et al. 2015), such as those associated to reproduction features including polycystic ovarian syndrome (Cordeiro et al. 2015a), ovarian endometriosis (Cordeiro et al. 2015b), poor responders (Cataldi et al. 2013), predictor of pregnancy (Montani et al. 2012), endometrial receptivity (Vilella et al. 2013) and so on. ...
... Several factors may influence lipid homeostasis in a given sample. Among them are intrinsic factors such as the physicochemical properties, lipid concentrations and compartmentalization of lipids, as well as extrinsic factors, such as responses to exogenous stimuli (De Leon et al. 2015), which could explain the changes observed in lipid profiles of the FF from women undergoing different stimulation protocols. Although clinical parameters were not statistically different, there was a clear difference in the lipids expression between groups. ...
IntroductionOvulation induction protocols are key components for performing assisted reproduction treatments successfully. The importance of adding exogenous LH to the controlled ovarian stimulation protocols in young women is still a matter of discussion in the clinical practice. Objective
To estimate how LH addition to controlled ovarian stimulation protocols may affect the follicular fluid lipid profile of women undergoing in vitro fertilization treatment. Methods
We conducted the study using 28 self-paired samples, 14 per group. The patients received FSH during their first cycle of ovarian stimulation (FSH group). If the treatment did not result in pregnancy, the same patients returned for a new cycle and received stimulus with the addition of LH to the previous protocol (Low-dose-LH group). Lipidomics analysis was performed by UPLC-MSE mass spectrometry. The software Progenesis QI was used to identify potential lipid biomarkers. Statistical analysis was performed using the SPSS 18.0 and MetaboAnalyst 2.0 software. ResultsThe analysis of clinical data showed no statistically significant differences between groups, in contrast to lipidomic analysis. Concerning lipidomic profile, the lipids differentially expressed in FSH group belong to the following subclasses:triacylglycerols; branched fatty acids and diacylglycerophosphoethanolamines; while in Low-dose-LH group the subclasses are gangliosides; acylglycerophosphoethanolamines; triacylglycerols; acylglycerophosphoserines; GalNAcβ1-3Galα1-4Galβ1-4Glc-(Globo series); amino fatty acids; triacylglycerols and prostaglandins. Conclusion
The differences found between the groups may contribute to the establishment of potential therapeutical targets based on LH-associated lipid biomarkers aiming to individualize treatments and obtain reproductive success.
... Metabolomics, with the study of the metabolites of diseases of the CNS, has become useful to explain numerous aspects: information about disease mechanisms, identification of prognoses, diagnoses, and substitute markers for a disease state; the capacity for disease sub-classification based on metabolite profiles; identification of biomarkers for drug-response phenotypes, and for those that develop metabolites related to side effects (pharmacometabolomics); and the addition of important data in the development and discovery processes of new drugs [45]. Beside psychiatry and neurology, lipid biomarkers have been extensively introduced to the study of many other diseases, especially in cancer [46,47], vascular disease [48] , diabetes mellitus [49,50] and so on. ...
... While the lung is the direct target organ of cigarette smoke where COPD develops, smoking has also been associated with several systemic effects: for example, smoking has been clearly linked to cardiovascular diseases, including coronary artery disease, peripheral arterial disease, and abdominal aortic aneurysm [9][10][11]. The main pathophysiological mechanisms of atherogenesis, which is thought to underlie all cardiovascular diseases, include (a) activation and dysfunction of the endothelium; (b) induction of a proinflammatory and procoagulative state; and (c) induction of proatherogenic serum lipid profiles and lipid oxidation products [12,13]. ...
... The reported effects of smoking and COPD on blood lipid profiles include increased levels of low-density lipoprotein and very-low-density lipoprotein (LDL + VLDL) cholesterol and triacylglycerol (TAG), decreased levels of high-density lipoprotein (HDL) cholesterol in smokers [12], and decreased levels of ω-3 polyunsaturated fatty acids (PUFAs) in smokers and COPD patients [14][15][16] (see Section 3.1 for further discussion). Recent progress in mass-spectrometry-based lipidomics methods has enabled the increasingly comprehensive characterization of lipidome profiles [17][18][19]. ...
... In addition, various effects of smoking and COPD on blood lipid profiles have been reported. For example, cigarette smoking has been linked to high levels of LDL + VLDL cholesterol and TAG, decreased HDL cholesterol levels [12], and COPD has been linked to lower levels of ω-3 PUFAs [14][15][16]. Several recent lipidomics studies uncovered additional potential lipid alterations in the plasma of smokers compared with non-smokers: Wang-Sattler et al. [20] identified increased levels of several glycerophospholipids and decreased levels of plasmalogens in smokers compared with never-and former smokers. ...
Smoking is a major risk factor for several diseases including chronic obstructive pulmonary disease (COPD). To better understand the systemic effects of cigarette smoke exposure and mild to moderate COPD-and to support future biomarker development-we profiled the serum lipidomes of healthy smokers, smokers with mild to moderate COPD (GOLD stages 1 and 2), former smokers, and never-smokers (n = 40 per group) (ClinicalTrials.gov registration: NCT01780298). Serum lipidome profiling was conducted with untargeted and targeted mass spectrometry-based lipidomics. Guided by weighted lipid co-expression network analysis, we identified three main trends comparing smokers, especially those with COPD, with non-smokers: a general increase in glycero(phospho)lipids, including triglycerols; changes in fatty acid desaturation (decrease in ?-3 polyunsaturated fatty acids, and an increase in monounsaturated fatty acids); and an imbalance in eicosanoids (increase in 11,12- and 14,15-DHETs (dihydroxyeicosatrienoic acids), and a decrease in 9- and 13-HODEs (hydroxyoctadecadienoic acids)). The lipidome profiles supported classification of study subjects as smokers or non-smokers, but were not sufficient to distinguish between smokers with and without COPD. Overall, our study yielded further insights into the complex interplay between smoke exposure, lung disease, and systemic alterations in serum lipid profiles.
... Other plasma lipidome studies pinpointed individual molecules or entire lipid classes whose abundance was specifically altered in obesity 3 , type 1 4 and type 2 5 diabetes, insulin resistance 6 , hypertension 7 , cardiovascular disease 8,9 , Alzheimer's disease 10 and schizophrenia 11,12 . Associating lipidome changes with diseases progression shed light on their molecular mechanisms and metabolic consequences and lead to the identification of promising biomarkers 13 , means of dietary intervention 14 , or tools for monitoring the efficacy of lipid homeostasis correction through therapeutic or surgical treatments 15,16 . ...
Lipidomics of human blood plasma is an emerging biomarker discovery approach that compares lipid profiles under pathological and physiologically normal conditions, but how a healthy lipidome varies within the population is poorly understood. By quantifying 281 molecular species from 27 major lipid classes in the plasma of 71 healthy young Caucasians whose 35 clinical blood test and anthropometric indices matched the medical norm, we provided a comprehensive, expandable and clinically relevant resource of reference molar concentrations of individual lipids. We established that gender is a major lipidomic factor, whose impact is strongly enhanced by hormonal contraceptives and mediated by sex hormone-binding globulin. In lipidomics epidemiological studies should avoid mixed-gender cohorts and females taking hormonal contraceptives should be considered as a separate sub-cohort. Within a gender-restricted cohort lipidomics revealed a compositional signature that indicates the predisposition towards an early development of metabolic syndrome in ca. 25% of healthy male individuals suggesting a healthy plasma lipidome as resource for early biomarker discovery.
... Apoe −/− mouse models are also appropriate to investigate the atherosclerotic effects of other pollutants such as combustion emissions and ambient air fine particulate matter [92][93][94], which induce inflammatory responses and generate reactive oxygen species. Thus, as previously described [94], Apoe −/− mice have been used in a diverse range of inhalation toxicology studies. ...
... Apoe −/− mouse models are also appropriate to investigate the atherosclerotic effects of other pollutants such as combustion emissions and ambient air fine particulate matter [92][93][94], which induce inflammatory responses and generate reactive oxygen species. Thus, as previously described [94], Apoe −/− mice have been used in a diverse range of inhalation toxicology studies. These studies have assessed exposure to motor vehicle emissions, environmental air particles, and mainstream and sidestream CS, with or without the effects of a high-fat diet. ...
... The CS-dependent increase of plasma and aortic lipid levels was reversed following smoking cessation, with a consequent decrease of most lipid concentrations, including total cholesterol, VLDL, phosphatidylcholine, and sphingomyelin [116,117]. More recently, by using a systems toxicology approach, exposure effects were investigated using the classical toxicological endpoints related to both atherosclerosis and respiratory diseases, such as physiology and histology, combined with in depth molecular characterization of the transcriptome, proteome and lipidome [19,94]. ...
Atherosclerosis-prone apolipoprotein E-deficient (Apoe(-/-)) mice display poor lipoprotein clearance with subsequent accumulation of cholesterol ester-enriched particles in the blood, which promote the development of atherosclerotic plaques. Therefore, the Apoe(-/-) mouse model is well established for the study of human atherosclerosis. The systemic proinflammatory status of Apoe(-/-) mice also makes them good candidates for studying chronic obstructive pulmonary disease, characterized by pulmonary inflammation, airway obstruction, and emphysema, and which shares several risk factors with cardiovascular diseases, including smoking. Herein, we review the results from published studies using Apoe(-/-) mice, with a particular focus on work conducted in the context of cigarette smoke inhalation studies. The findings from these studies highlight the suitability of this animal model for researching the effects of cigarette smoking on atherosclerosis and emphysema.
