Metabolites

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24 pages, 5353 KiB

Open AccessArticle

Mathematical Modelling of Material Transfer to High-Density Lipoprotein (HDL) upon Triglyceride Lipolysis by Lipoprotein Lipase: Relevance to Cardioprotective Role of HDL

by Svetlana Schekatolina, Viktoriia Lahovska, Aleksandr Bekshaev, Sergey Kontush, Wilfried Le Goff and Anatol Kontush

Metabolites 2022, 12(7), 623; https://doi.org/10.3390/metabo12070623 - 6 Jul 2022

Cited by 4 | Viewed by 1759

Abstract

High-density lipoprotein (HDL) contributes to lipolysis of triglyceride-rich lipoprotein (TGRL) by lipoprotein lipase (LPL) via acquirement of surface lipids, including free cholesterol (FC), released upon lipolysis. According to the reverse remnant-cholesterol transport (RRT) hypothesis recently developed by us, acquirement of FC by HDL [...] Read more.

High-density lipoprotein (HDL) contributes to lipolysis of triglyceride-rich lipoprotein (TGRL) by lipoprotein lipase (LPL) via acquirement of surface lipids, including free cholesterol (FC), released upon lipolysis. According to the reverse remnant-cholesterol transport (RRT) hypothesis recently developed by us, acquirement of FC by HDL is reduced at both low and extremely high HDL concentrations, potentially underlying the U-shaped relationship between HDL-cholesterol and cardiovascular disease. Mechanisms underlying impaired FC transfer however remain indeterminate. We developed a mathematical model of material transfer to HDL upon TGRL lipolysis by LPL. Consistent with experimental observations, mathematical modelling showed that surface components of TGRL, including FC, were accumulated in HDL upon lipolysis. The modelling successfully reproduced major features of cholesterol accumulation in HDL observed experimentally, notably saturation of this process over time and appearance of a maximum as a function of HDL concentration. The calculations suggested that the both phenomena resulted from competitive fluxes of FC through the HDL pool, including primarily those driven by FC concentration gradient between TGRL and HDL on the one hand and mediated by lecithin-cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) on the other hand. These findings provide novel opportunities to revisit our view of HDL in the framework of RRT. Full article

(This article belongs to the Special Issue Insights into the Alteration of Lipid Metabolisms in Cardiometabolic Diseases)

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25 pages, 2559 KiB

Open AccessArticle

Whole Exome/Genome Sequencing Joint Analysis of a Family with Oligogenic Familial Hypercholesterolemia

by Youmna Ghaleb, Sandy Elbitar, Anne Philippi, Petra El Khoury, Yara Azar, Miangaly Andrianirina, Alexia Loste, Yara Abou-Khalil, Gaël Nicolas, Marie Le Borgne, Philippe Moulin, Mathilde Di-Filippo, Sybil Charrière, Michel Farnier, Cécile Yelnick, Valérie Carreau, Jean Ferrières, Jean-Michel Lecerf, Alexa Derksen, Geneviève Bernard, Marie-Soleil Gauthier, Benoit Coulombe, Dieter Lütjohann, Bertrand Fin, Anne Boland, Robert Olaso, Jean-François Deleuze, Jean-Pierre Rabès, Catherine Boileau, Marianne Abifadel and Mathilde Varret Show full author list Hide full author list

Metabolites 2022, 12(3), 262; https://doi.org/10.3390/metabo12030262 - 18 Mar 2022

Cited by 2 | Viewed by 3510

Abstract

Autosomal Dominant Hypercholesterolemia (ADH) is a genetic disorder caused by pathogenic variants in LDLR, APOB, PCSK9 and APOE genes. We sought to identify new candidate genes responsible for the ADH phenotype in patients without pathogenic variants in the known ADH-causing genes [...] Read more.

Autosomal Dominant Hypercholesterolemia (ADH) is a genetic disorder caused by pathogenic variants in LDLR, APOB, PCSK9 and APOE genes. We sought to identify new candidate genes responsible for the ADH phenotype in patients without pathogenic variants in the known ADH-causing genes by focusing on a French family with affected and non-affected members who presented a high ADH polygenic risk score (wPRS). Linkage analysis, whole exome and whole genome sequencing resulted in the identification of variants p.(Pro398Ala) in CYP7A1, p.(Val1382Phe) in LRP6 and p.(Ser202His) in LDLRAP1. A total of 6 other variants were identified in 6 of 160 unrelated ADH probands: p.(Ala13Val) and p.(Aps347Asn) in CYP7A1; p.(Tyr972Cys), p.(Thr1479Ile) and p.(Ser1612Phe) in LRP6; and p.(Ser202LeufsTer19) in LDLRAP1. All six probands presented a moderate wPRS. Serum analyses of carriers of the p.(Pro398Ala) variant in CYP7A1 showed no differences in the synthesis of bile acids compared to the serums of non-carriers. Functional studies of the four LRP6 mutants in HEK293T cells resulted in contradictory results excluding a major effect of each variant alone. Within the family, none of the heterozygous for only the LDLRAP1 p.(Ser202His) variant presented ADH. Altogether, each variant individually does not result in elevated LDL-C; however, the oligogenic combination of two or three variants reveals the ADH phenotype. Full article

(This article belongs to the Special Issue Insights into the Alteration of Lipid Metabolisms in Cardiometabolic Diseases)

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10 pages, 1689 KiB

Open AccessCommunication

Diabetes-Induced Changes in Macrophage Biology Might Lead to Reduced Risk for Abdominal Aortic Aneurysm Development

by Giulia Chinetti, Joseph Carboni, Joseph Murdaca, Claudine Moratal, Brigitte Sibille, Juliette Raffort, Fabien Lareyre, Elixène Jean Baptiste, Réda Hassen-Khodja and Jaap G. Neels

Metabolites 2022, 12(2), 128; https://doi.org/10.3390/metabo12020128 - 29 Jan 2022

Cited by 3 | Viewed by 2340

Abstract

Type 2 diabetes patients are less likely to develop an abdominal aortic aneurysm (AAA). Since macrophages play a crucial role in AAA development, we hypothesized that this decrease in AAA risk in diabetic patients might be due to diabetes-induced changes in macrophage biology. [...] Read more.

Type 2 diabetes patients are less likely to develop an abdominal aortic aneurysm (AAA). Since macrophages play a crucial role in AAA development, we hypothesized that this decrease in AAA risk in diabetic patients might be due to diabetes-induced changes in macrophage biology. To test this hypothesis, we treated primary macrophages obtained from healthy human volunteers with serum from non-diabetic vs. diabetic AAA patients and observed differences in extracellular acidification and the expression of genes involved in glycolysis and lipid oxidation. These results suggest an increase in metabolism in macrophages treated with serum from diabetic AAA patients. Since serum samples used did not differ in glucose content, these changes are not likely to be caused by differences in glycemia. Macrophage functions have been shown to be linked to their metabolism. In line with this, our data suggest that this increase in macrophage metabolism is accompanied by a shift towards an anti-inflammatory state. Together, these results support a model where diabetes-induced changes in metabolism in macrophages might lead to a reduced risk for AAA development. Full article

(This article belongs to the Special Issue Insights into the Alteration of Lipid Metabolisms in Cardiometabolic Diseases)

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15 pages, 1859 KiB

Open AccessArticle

Lipidomic Profiling Identifies Signatures of Poor Cardiovascular Health

by Irma Magaly Rivas Serna, Michal Sitina, Gorazd B. Stokin, Jose R. Medina-Inojosa, Francisco Lopez-Jimenez, Juan P. Gonzalez-Rivas and Manlio Vinciguerra

Metabolites 2021, 11(11), 747; https://doi.org/10.3390/metabo11110747 - 29 Oct 2021

Cited by 10 | Viewed by 2855

Abstract

Ideal cardiovascular health (CVH) is defined for the presence of ideal behavioral and health metrics known to prevent cardiovascular disease (CVD). The association of circulatory phospho- and sphingo-lipids to primary reduction in cardiovascular risk is unclear. Our aim was to determine the association [...] Read more.

Ideal cardiovascular health (CVH) is defined for the presence of ideal behavioral and health metrics known to prevent cardiovascular disease (CVD). The association of circulatory phospho- and sphingo-lipids to primary reduction in cardiovascular risk is unclear. Our aim was to determine the association of CVH metrics with the circulating lipid profile of a population-based cohort. Serum sphingolipid and phospholipid species were extracted from 461 patients of the randomly selected prospective Kardiovize study based on Brno, Czech Republic. Lipids species were measured by a hyphenated mass spectrometry technique, and were associated with poor CVH scores, as defined by the American Heart Association. Phosphatidylcholine (PC), phosphatidylethanolamine (PE), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE) species were significantly lower in ideal and intermediate scores of health dietary metric, blood pressure, total cholesterol and blood fasting glucose compared to poor scores. Current smokers presented higher levels of PC, PE and LPE individual species compared to non-smokers. Ceramide (Cer) d18:1/14:0 was altered in poor blood pressure, total cholesterol and fasting blood glucose metrics. Poor cardiovascular health metric is associated with a specific phospho- and sphingolipid pattern. Circulatory lipid profiling is a potential biomarker to refine cardiovascular health status in primary prevention strategies. Full article

(This article belongs to the Special Issue Insights into the Alteration of Lipid Metabolisms in Cardiometabolic Diseases)

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13 pages, 311 KiB

Open AccessCommunication

Blood Fatty Acids Profile in MIS-C Children

by Elvira Verduci, Patrizia Risé, Elisabetta Di Profio, Laura Fiori, Sara Vizzuso, Dario Dilillo, Savina Mannarino, Elena Zoia, Valeria Calcaterra, Christian Pinna, Angelo Sala and Gianvincenzo Zuccotti

Metabolites 2021, 11(11), 721; https://doi.org/10.3390/metabo11110721 - 22 Oct 2021

Cited by 8 | Viewed by 2519

Abstract

MIS-C (multisystem inflammatory syndrome in children) linked to SARS-CoV-2 infection, is a pathological state observed in subjects younger than 21 years old with evidence of either current SARS-CoV-2 infection or exposure within the 4 weeks prior to the onset of symptoms, the presence [...] Read more.

MIS-C (multisystem inflammatory syndrome in children) linked to SARS-CoV-2 infection, is a pathological state observed in subjects younger than 21 years old with evidence of either current SARS-CoV-2 infection or exposure within the 4 weeks prior to the onset of symptoms, the presence of documented fever, elevated markers of inflammation, at least two signs of multisystem involvement, and, finally, lack of an alternative diagnosis. They share with adult COVID-19 patients the presence of altered markers of inflammation, but unlike most adults the symptoms are not pulmonary but are affecting several organs. Lipid mediators arising from polyunsaturated fatty acids (PUFA) play an important role in the inflammatory response, with arachidonic acid-derived compounds, such as prostaglandins and leukotrienes, mainly pro-inflammatory and ω3 PUFA metabolites such as resolvins and protectins, showing anti-inflammatory and pro-resolution activities. In order to assess potential alterations of these FA, we evaluated the blood fatty acid profile of MIS-C children at admission to the hospital, together with biochemical, metabolic and clinical assessment. All the patients enrolled showed altered inflammatory parameters with fibrinogen, D-dimer, NT-proBNP, ferritin, aspartate aminotransferase (AST), C-reactive protein (CRP) and TrygIndex levels over the reference values in all the subjects under observation, while albumin and HDL-cholesterol resulted below the normal range. Interestingly, linoleic acid (LA), arachidonic acid (AA) and the ω3 PUFA docosahexaenoic acid (DHA) results were lower in our study when compared to relative amounts reported in the other studies, including from our own laboratory. This significant alteration is pointing out to a potential depletion of these PUFA as a result of the systemic inflammatory condition typical of these patients, suggesting that LA- and AA-derived metabolites may play a critical role in this pathological state, while ω3 PUFA-derived pro-resolution metabolites in these subjects may not be able to provide a timely, physiological counterbalance to the formation of pro-inflammatory lipid mediators. In conclusion, this observational study provides evidence of FA alterations in MIS-C children, suggesting a significant contribution of ω6 FA to the observed inflammatory state, and supporting a potential dietary intervention to restore an appropriate balance among the FAs capable of promoting the resolution of the observed inflammatory condition. Full article

(This article belongs to the Special Issue Insights into the Alteration of Lipid Metabolisms in Cardiometabolic Diseases)

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23 pages, 4581 KiB

Open AccessArticle

Evaluation of Bioactive Metabolites and Antioxidant-Rich Extracts of Amaranths with Possible Role in Pancreatic Lipase Interaction: In Silico and In Vitro Studies

by Swati Chaturvedi and Promila Gupta

Metabolites 2021, 11(10), 676; https://doi.org/10.3390/metabo11100676 - 30 Sep 2021

Cited by 5 | Viewed by 3023

Abstract

Fat/carbohydrate-rich diet consumption or elevated secretion of pancreatic lipase (PL) in pancreatic injury results in increased fat digestion and storage. Several metabolites in plant-based diets can help achieve the requirements of nutrition and fitness together. Presently, nutritional metabolites from Amaranthus tricolor, A. [...] Read more.

Fat/carbohydrate-rich diet consumption or elevated secretion of pancreatic lipase (PL) in pancreatic injury results in increased fat digestion and storage. Several metabolites in plant-based diets can help achieve the requirements of nutrition and fitness together. Presently, nutritional metabolites from Amaranthus tricolor, A. viridis, and Achyranthes aspera were assessed and predicted for daily intake. The volatile-metabolite profiling of their extracts using GC-MS revealed various antioxidant and bioactive components. The implication of these specialized components and antioxidant-rich extracts (EC₅₀ free radical scavenging: 34.1 ± 1.5 to 166.3 ± 14.2 µg/mL; FRAP values: 12.1 ± 1.0 to 34.0 ± 2.0 µg Trolox Equivalent/mg) in lipolysis regulation by means of interaction with PL was checked by in silico docking (Betahistine and vitamins: ΔGbind −2.3 to −4.4 kcal/mol) and in vitro fluorescence quenching. Out of the various compounds and extracts tested, Betahistine, ATRA and AVLA showed better quenching the PL fluorescence. The identification of potential extracts as source of functional components contributing to nutrition and fat regulation can be improved through such study. Full article

(This article belongs to the Special Issue Insights into the Alteration of Lipid Metabolisms in Cardiometabolic Diseases)

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15 pages, 465 KiB

Open AccessArticle

In Utero Exposure to Persistent Organic Pollutants and Childhood Lipid Levels

by Maegan E. Boutot, Brian W. Whitcomb, Nadia Abdelouahab, Andrea A. Baccarelli, Amélie Boivin, Artuela Caku, Virginie Gillet, Guillaume Martinez, Jean-Charles Pasquier, Jiping Zhu, Larissa Takser, Lindsay St-Cyr and Alexander Suvorov

Metabolites 2021, 11(10), 657; https://doi.org/10.3390/metabo11100657 - 28 Sep 2021

Cited by 12 | Viewed by 2567

Abstract

Animal studies have shown that developmental exposures to polybrominated diphenyl ethers (PBDE) permanently affect blood/liver balance of lipids. No human study has evaluated associations between in utero exposures to persistent organic pollutants (POPs) and later life lipid metabolism. In this pilot, maternal plasma [...] Read more.

Animal studies have shown that developmental exposures to polybrominated diphenyl ethers (PBDE) permanently affect blood/liver balance of lipids. No human study has evaluated associations between in utero exposures to persistent organic pollutants (POPs) and later life lipid metabolism. In this pilot, maternal plasma levels of PBDEs (BDE-47, BDE-99, BDE-100, and BDE-153) and polychlorinated biphenyls (PCB-138, PCB-153, and PCB-180) were determined at delivery in participants of GESTation and Environment (GESTE) cohort. Total cholesterol (TCh), triglycerides (TG), low- and high-density lipoproteins (LDL-C and HDL-C), total lipids (TL), and PBDEs were determined in serum of 147 children at ages 6–7. General linear regression was used to estimate the relationship between maternal POPs and child lipid levels with adjustment for potential confounders, and adjustment for childhood POPs. In utero BDE-99 was associated with lower childhood levels of TG (p = 0.003), and non-significantly with HDL-C (p = 0.06) and TL (p = 0.07). Maternal PCB-138 was associated with lower childhood levels of TG (p = 0.04), LDL-C (p = 0.04), and TL (p = 0.02). Our data indicate that in utero exposures to POPs may be associated with long lasting decrease in circulating lipids in children, suggesting increased lipid accumulation in the liver, a mechanism involved in NAFLD development, consistent with previously reported animal data. Full article

(This article belongs to the Special Issue Insights into the Alteration of Lipid Metabolisms in Cardiometabolic Diseases)

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13 pages, 696 KiB

Open AccessArticle

Identification of a Variant in APOB Gene as a Major Cause of Hypobetalipoproteinemia in Lebanese Families

by Carine Ayoub, Yara Azar, Yara Abou-Khalil, Youmna Ghaleb, Sandy Elbitar, Georges Halaby, Selim Jambart, Marie-Hélène Gannagé-Yared, Cesar Yaghi, Carole Saade Riachy, Ralph El Khoury, Jean-Pierre Rabès, Mathilde Varret, Catherine Boileau, Petra El Khoury and Marianne Abifadel

Metabolites 2021, 11(9), 564; https://doi.org/10.3390/metabo11090564 - 24 Aug 2021

Cited by 5 | Viewed by 2808

Abstract

Familial hypobetalipoproteinemia (FHBL) is a codominant genetic disorder characterized by reduced plasma levels of low-density lipoprotein cholesterol and apolipoprotein B. To our knowledge, no study on FHBL in Lebanon and the Middle East region has been reported. Therefore, we conducted genetic studies in [...] Read more.

Familial hypobetalipoproteinemia (FHBL) is a codominant genetic disorder characterized by reduced plasma levels of low-density lipoprotein cholesterol and apolipoprotein B. To our knowledge, no study on FHBL in Lebanon and the Middle East region has been reported. Therefore, we conducted genetic studies in unrelated families and probands of Lebanese origin presenting with FHBL, in order to identify the causes of this disease. We found that 71% of the recruited probands and their affected relatives were heterozygous for the p.(Arg490Trp) variant in the APOB gene. Haplotype analysis showed that these patients presented the same mutant haplotype. Moreover, there was a decrease in plasma levels of PCSK9 in affected individuals compared to the non-affected and a significant positive correlation between circulating PCSK9 and ApoB levels in all studied probands and their family members. Some of the p.(Arg490Trp) carriers suffered from diabetes, hepatic steatosis or neurological problems. In conclusion, the p.(Arg490Trp) pathogenic variant seems a cause of FHBL in patients from Lebanese origin, accounting for approximately 70% of the probands with FHBL presumably as a result of a founder mutation in Lebanon. This study is crucial to guide the early diagnosis, management and prevention of the associated complications of this disease. Full article

(This article belongs to the Special Issue Insights into the Alteration of Lipid Metabolisms in Cardiometabolic Diseases)

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17 pages, 3324 KiB

Open AccessArticle

Hepatocyte Small Heterodimer Partner Mediates Sex-Specific Effects on Triglyceride Metabolism via Androgen Receptor in Male Mice

by Brian T. Palmisano, Lin Zhu, Bridget Litts, Andreanna Burman, Sophia Yu, Joshua C. Neuman, Uche Anozie, Thao N. Luu, Emery M. Edington and John M. Stafford

Metabolites 2021, 11(5), 330; https://doi.org/10.3390/metabo11050330 - 20 May 2021

Cited by 5 | Viewed by 3255

Abstract

Mechanisms of sex differences in hypertriglyceridemia remain poorly understood. Small heterodimer partner (SHP) is a nuclear receptor that regulates bile acid, glucose, and lipid metabolism. SHP also regulates transcriptional activity of sex hormone receptors and may mediate sex differences in triglyceride (TG) metabolism. [...] Read more.

Mechanisms of sex differences in hypertriglyceridemia remain poorly understood. Small heterodimer partner (SHP) is a nuclear receptor that regulates bile acid, glucose, and lipid metabolism. SHP also regulates transcriptional activity of sex hormone receptors and may mediate sex differences in triglyceride (TG) metabolism. Here, we test the hypothesis that hepatic SHP mediates sex differences in TG metabolism using hepatocyte-specific SHP knockout mice. Plasma TGs in wild-type males were higher than in wild-type females and hepatic deletion of SHP lowered plasma TGs in males but not in females, suggesting hepatic SHP mediates plasma TG metabolism in a sex-specific manner. Additionally, hepatic deletion of SHP failed to lower plasma TGs in gonadectomized male mice or in males with knockdown of the liver androgen receptor, suggesting hepatic SHP modifies plasma TG via an androgen receptor pathway. Furthermore, the TG lowering effect of hepatic deletion of SHP was caused by increased clearance of postprandial TG and accompanied with decreased plasma levels of ApoC1, an inhibitor of lipoprotein lipase activity. These data support a role for hepatic SHP in mediating sex-specific effects on plasma TG metabolism through androgen receptor signaling. Understanding how hepatic SHP regulates TG clearance may lead to novel approaches to lower plasma TGs and mitigate cardiovascular disease risk. Full article

(This article belongs to the Special Issue Insights into the Alteration of Lipid Metabolisms in Cardiometabolic Diseases)

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Review

Jump to: Research, Other

24 pages, 1715 KiB

Open AccessReview

The Reciprocal Relationship between LDL Metabolism and Type 2 Diabetes Mellitus

by Isabella Bonilha, Eric Hajduch, Beatriz Luchiari, Wilson Nadruz, Wilfried Le Goff and Andrei C. Sposito

Metabolites 2021, 11(12), 807; https://doi.org/10.3390/metabo11120807 - 28 Nov 2021

Cited by 19 | Viewed by 6574

Abstract

Type 2 diabetes mellitus and insulin resistance feature substantial modifications of the lipoprotein profile, including a higher proportion of smaller and denser low-density lipoprotein (LDL) particles. In addition, qualitative changes occur in the composition and structure of LDL, including changes in electrophoretic mobility, [...] Read more.

Type 2 diabetes mellitus and insulin resistance feature substantial modifications of the lipoprotein profile, including a higher proportion of smaller and denser low-density lipoprotein (LDL) particles. In addition, qualitative changes occur in the composition and structure of LDL, including changes in electrophoretic mobility, enrichment of LDL with triglycerides and ceramides, prolonged retention of modified LDL in plasma, increased uptake by macrophages, and the formation of foam cells. These modifications affect LDL functions and favor an increased risk of cardiovascular disease in diabetic individuals. In this review, we discuss the main findings regarding the structural and functional changes in LDL particles in diabetes pathophysiology and therapeutic strategies targeting LDL in patients with diabetes. Full article

(This article belongs to the Special Issue Insights into the Alteration of Lipid Metabolisms in Cardiometabolic Diseases)

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12 pages, 2829 KiB

Open AccessReview

How Ceramides Orchestrate Cardiometabolic Health—An Ode to Physically Active Living

by Justin Carrard, Hector Gallart-Ayala, Nadia Weber, Flora Colledge, Lukas Streese, Henner Hanssen, Christian Schmied, Julijana Ivanisevic and Arno Schmidt-Trucksäss

Metabolites 2021, 11(10), 675; https://doi.org/10.3390/metabo11100675 - 30 Sep 2021

Cited by 12 | Viewed by 5898

Abstract

Cardiometabolic diseases (CMD) represent a growing socioeconomic burden and concern for healthcare systems worldwide. Improving patients’ metabolic phenotyping in clinical practice will enable clinicians to better tailor prevention and treatment strategy to individual needs. Recently, elevated levels of specific lipid species, known as [...] Read more.

Cardiometabolic diseases (CMD) represent a growing socioeconomic burden and concern for healthcare systems worldwide. Improving patients’ metabolic phenotyping in clinical practice will enable clinicians to better tailor prevention and treatment strategy to individual needs. Recently, elevated levels of specific lipid species, known as ceramides, were shown to predict cardiometabolic outcomes beyond traditional biomarkers such as cholesterol. Preliminary data showed that physical activity, a potent, low-cost, and patient-empowering means to reduce CMD-related burden, influences ceramide levels. While a single bout of physical exercise increases circulating and muscular ceramide levels, regular exercise reduces ceramide content. Additionally, several ceramide species have been reported to be negatively associated with cardiorespiratory fitness, which is a potent health marker reflecting training level. Thus, regular exercise could optimize cardiometabolic health, partly by reversing altered ceramide profiles. This short review provides an overview of ceramide metabolism and its role in cardiometabolic health and diseases, before presenting the effects of exercise on ceramides in humans. Full article

(This article belongs to the Special Issue Insights into the Alteration of Lipid Metabolisms in Cardiometabolic Diseases)

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13 pages, 317 KiB

Open AccessReview

Acyl-Coenzyme A: Cholesterol Acyltransferase (ACAT) in Cholesterol Metabolism: From Its Discovery to Clinical Trials and the Genomics Era

by Qimin Hai and Jonathan D. Smith

Metabolites 2021, 11(8), 543; https://doi.org/10.3390/metabo11080543 - 14 Aug 2021

Cited by 18 | Viewed by 5689

Abstract

The purification and cloning of the acyl-coenzyme A: cholesterol acyltransferase (ACAT) enzymes and the sterol O-acyltransferase (SOAT) genes has opened new areas of interest in cholesterol metabolism given their profound effects on foam cell biology and intestinal lipid absorption. The generation [...] Read more.

The purification and cloning of the acyl-coenzyme A: cholesterol acyltransferase (ACAT) enzymes and the sterol O-acyltransferase (SOAT) genes has opened new areas of interest in cholesterol metabolism given their profound effects on foam cell biology and intestinal lipid absorption. The generation of mouse models deficient in Soat1 or Soat2 confirmed the importance of their gene products on cholesterol esterification and lipoprotein physiology. Although these studies supported clinical trials which used non-selective ACAT inhibitors, these trials did not report benefits, and one showed an increased risk. Early genetic studies have implicated common variants in both genes with human traits, including lipoprotein levels, coronary artery disease, and Alzheimer’s disease; however, modern genome-wide association studies have not replicated these associations. In contrast, the common SOAT1 variants are most reproducibly associated with testosterone levels. Full article

(This article belongs to the Special Issue Insights into the Alteration of Lipid Metabolisms in Cardiometabolic Diseases)

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Other

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18 pages, 1606 KiB

Open AccessHypothesis

The Lipid Energy Model: Reimagining Lipoprotein Function in the Context of Carbohydrate-Restricted Diets

by Nicholas G. Norwitz, Adrian Soto-Mota, Bob Kaplan, David S. Ludwig, Matthew Budoff, Anatol Kontush and David Feldman

Metabolites 2022, 12(5), 460; https://doi.org/10.3390/metabo12050460 - 20 May 2022

Cited by 18 | Viewed by 53706

Abstract

When lean people adopt carbohydrate-restricted diets (CRDs), they may develop a lipid profile consisting of elevated LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) with low triglycerides (TGs). The magnitude of this lipid profile correlates with BMI such that those with lower BMI exhibit larger increases [...] Read more.

When lean people adopt carbohydrate-restricted diets (CRDs), they may develop a lipid profile consisting of elevated LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) with low triglycerides (TGs). The magnitude of this lipid profile correlates with BMI such that those with lower BMI exhibit larger increases in both LDL-C and HDL-C. The inverse association between BMI and LDL-C and HDL-C change on CRD contributed to the discovery of a subset of individuals—termed Lean Mass Hyper-Responders (LMHR)—who, despite normal pre-diet LDL-C, as compared to non-LMHR (mean levels of 148 and 145 mg/dL, respectively), exhibited a pronounced hyperlipidemic response to a CRD, with mean LDL-C and HDL-C levels increasing to 320 and 99 mg/dL, respectively, in the context of mean TG of 47 mg/dL. In some LMHR, LDL-C levels may be in excess of 500 mg/dL, again, with relatively normal pre-diet LDL-C and absent of genetic findings indicative of familial hypercholesterolemia in those who have been tested. The Lipid Energy Model (LEM) attempts to explain this metabolic phenomenon by positing that, with carbohydrate restriction in lean persons, the increased dependence on fat as a metabolic substrate drives increased hepatic secretion and peripheral uptake of TG contained within very low-density lipoproteins (VLDL) by lipoprotein lipase, resulting in marked elevations of LDL-C and HDL-C, and low TG. Herein, we review the core features of the LEM. We review several existing lines of evidence supporting the model and suggest ways to test the model’s predictions. Full article

(This article belongs to the Special Issue Insights into the Alteration of Lipid Metabolisms in Cardiometabolic Diseases)

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