International Journal of Molecular Sciences

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13 pages, 2671 KiB

Open AccessArticle

The Role of Olfactomedin 2 in the Adipose Tissue–Liver Axis and Its Implication in Obesity-Associated Nonalcoholic Fatty Liver Disease

by Andrea Barrientos-Riosalido, Laia Bertran, Mercè Vilaró-Blay, Carmen Aguilar, Salomé Martínez, Marta Paris, Fàtima Sabench, David Riesco, Jessica Binetti, Daniel Del Castillo, Cristóbal Richart and Teresa Auguet

Int. J. Mol. Sci. 2023, 24(6), 5221; https://doi.org/10.3390/ijms24065221 - 9 Mar 2023

Cited by 2 | Viewed by 1464

Abstract

This study’s objective was to assess the involvement of olfactomedin 2 (OLFM2), a secreted glycoprotein related to lipid metabolism regulation, in nonalcoholic fatty liver disease (NAFLD) mediated by the adipose-tissue–liver axis. OLFM2 mRNA expression was analyzed in subcutaneous (SAT) and visceral (VAT) adipose [...] Read more.

This study’s objective was to assess the involvement of olfactomedin 2 (OLFM2), a secreted glycoprotein related to lipid metabolism regulation, in nonalcoholic fatty liver disease (NAFLD) mediated by the adipose-tissue–liver axis. OLFM2 mRNA expression was analyzed in subcutaneous (SAT) and visceral (VAT) adipose tissue by RT–qPCR. The cohort included women with normal weight (n = 16) or morbid obesity (MO, n = 60) who were subclassified into normal liver (n = 20), simple steatosis (n = 21), and nonalcoholic steatohepatitis (NASH, n = 19) groups. The results showed that OLFM2 expression in SAT was enhanced in MO individuals and in the presence of NAFLD. Specifically, OLFM2 expression in SAT was increased in mild and moderate degrees of steatosis in comparison to the absence of it. Moreover, OLFM2 expression in SAT was negatively correlated with interleukin-6 levels. On the other hand, OLFM2 expression in VAT decreased in the presence of NASH and exhibited a positive correlation with adiponectin levels. In conclusion, OLFM2 in SAT seems to be implicated in hepatic lipid accumulation. Additionally, since we previously suggested the possible implication of hepatic OLFM2 in NAFLD progression, now we propose a possible interaction between the liver and SAT, reinforcing the potential implication of this tissue in NAFLD development. Full article

(This article belongs to the Special Issue Lipid Metabolism in Pathology and Health)

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21 pages, 2375 KiB

Open AccessArticle

Overlapping and Distinct Features of Cardiac Pathology in Inherited Human and Murine Ether Lipid Deficiency

by Fabian Dorninger, Attila Kiss, Peter Rothauer, Alexander Stiglbauer-Tscholakoff, Stefan Kummer, Wedad Fallatah, Mireia Perera-Gonzalez, Ouafa Hamza, Theresa König, Michael B. Bober, Tiscar Cavallé-Garrido, Nancy E. Braverman, Sonja Forss-Petter, Christian Pifl, Jan Bauer, Reginald E. Bittner, Thomas H. Helbich, Bruno K. Podesser, Hannes Todt and Johannes Berger

Int. J. Mol. Sci. 2023, 24(3), 1884; https://doi.org/10.3390/ijms24031884 - 18 Jan 2023

Viewed by 1780

Abstract

Inherited deficiency in ether lipids, a subgroup of glycerophospholipids with unique biochemical and biophysical properties, evokes severe symptoms in humans resulting in a multi-organ syndrome. Mouse models with defects in ether lipid biosynthesis have widely been used to understand the pathophysiology of human [...] Read more.

Inherited deficiency in ether lipids, a subgroup of glycerophospholipids with unique biochemical and biophysical properties, evokes severe symptoms in humans resulting in a multi-organ syndrome. Mouse models with defects in ether lipid biosynthesis have widely been used to understand the pathophysiology of human disease and to study the roles of ether lipids in various cell types and tissues. However, little is known about the function of these lipids in cardiac tissue. Previous studies included case reports of cardiac defects in ether-lipid-deficient patients, but a systematic analysis of the impact of ether lipid deficiency on the mammalian heart is still missing. Here, we utilize a mouse model of complete ether lipid deficiency (Gnpat KO) to accomplish this task. Similar to a subgroup of human patients with rhizomelic chondrodysplasia punctata (RCDP), a fraction of Gnpat KO fetuses present with defects in ventricular septation, presumably evoked by a developmental delay. We did not detect any signs of cardiomyopathy but identified increased left ventricular end-systolic and end-diastolic pressure in middle-aged ether-lipid-deficient mice. By comprehensive electrocardiographic characterization, we consistently found reduced ventricular conduction velocity, as indicated by a prolonged QRS complex, as well as increased QRS and QT dispersion in the Gnpat KO group. Furthermore, a shift of the Wenckebach point to longer cycle lengths indicated depressed atrioventricular nodal function. To complement our findings in mice, we analyzed medical records and performed electrocardiography in ether-lipid-deficient human patients, which, in contrast to the murine phenotype, indicated a trend towards shortened QT intervals. Taken together, our findings demonstrate that the cardiac phenotype upon ether lipid deficiency is highly heterogeneous, and although the manifestations in the mouse model only partially match the abnormalities in human patients, the results add to our understanding of the physiological role of ether lipids and emphasize their importance for proper cardiac development and function. Full article

(This article belongs to the Special Issue Lipid Metabolism in Pathology and Health)

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12 pages, 1537 KiB

Open AccessArticle

Time-Dependent Effect of Sciatic Nerve Injury on Rat Plasma Lipidome

by Dmitry Senko, Anna Gorovaya, Elena Stekolshchikova, Nickolay Anikanov, Artur Fedianin, Maxim Baltin, Olga Efimova, Daria Petrova, Tatyana Baltina, Mikhail A. Lebedev, Philipp Khaitovich and Anna Tkachev

Int. J. Mol. Sci. 2022, 23(24), 15544; https://doi.org/10.3390/ijms232415544 - 8 Dec 2022

Cited by 1 | Viewed by 1762

Abstract

Neuropathic pain is a condition affecting the quality of life of a substantial part of the population, but biomarkers and treatment options are still limited. While this type of pain is caused by nerve damage, in which lipids play key roles, lipidome alterations [...] Read more.

Neuropathic pain is a condition affecting the quality of life of a substantial part of the population, but biomarkers and treatment options are still limited. While this type of pain is caused by nerve damage, in which lipids play key roles, lipidome alterations related to nerve injury remain poorly studied. Here, we assessed blood lipidome alterations in a common animal model, the rat sciatic nerve crush injury. We analyzed alterations in blood lipid abundances between seven rats with nerve injury (NI) and eight control (CL) rats in a time-course experiment. For these rats, abundances of 377 blood lipid species were assessed at three distinct time points: immediately after, two weeks, and five weeks post injury. Although we did not detect significant differences between NI and CL at the first two time points, 106 lipids were significantly altered in NI five weeks post injury. At this time point, we found increased levels of triglycerides (TGs) and lipids containing esterified palmitic acid (16:0) in the blood plasma of NI animals. Lipids containing arachidonic acid (20:4), by contrast, were significantly decreased after injury, aligning with the crucial role of arachidonic acid reported for NI. Taken together, these results indicate delayed systematic alterations in fatty acid metabolism after nerve injury, potentially reflecting nerve tissue restoration dynamics. Full article

(This article belongs to the Special Issue Lipid Metabolism in Pathology and Health)

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17 pages, 6378 KiB

Open AccessArticle

The Crystal Structure of Mouse Ces2c, a Potential Ortholog of Human CES2, Shows Structural Similarities in Substrate Regulation and Product Release to Human CES1

by Helgit Eisner, Lina Riegler-Berket, Carlos Francisco Rodriguez Gamez, Theo Sagmeister, Gabriel Chalhoub, Barbara Darnhofer, P J Jazleena, Ruth Birner-Gruenberger, Tea Pavkov-Keller, Guenter Haemmerle, Gabriele Schoiswohl and Monika Oberer

Int. J. Mol. Sci. 2022, 23(21), 13101; https://doi.org/10.3390/ijms232113101 - 28 Oct 2022

Cited by 3 | Viewed by 2422

Abstract

Members of the carboxylesterase 2 (Ces2/CES2) family have been studied intensively with respect to their hydrolytic function on (pro)drugs, whereas their physiological role in lipid and energy metabolism has been realized only within the last few years. Humans have one CES2 gene which [...] Read more.

Members of the carboxylesterase 2 (Ces2/CES2) family have been studied intensively with respect to their hydrolytic function on (pro)drugs, whereas their physiological role in lipid and energy metabolism has been realized only within the last few years. Humans have one CES2 gene which is highly expressed in liver, intestine, and kidney. Interestingly, eight homologous Ces2 (Ces2a to Ces2h) genes exist in mice and the individual roles of the corresponding proteins are incompletely understood. Mouse Ces2c (mCes2c) is suggested as potential ortholog of human CES2. Therefore, we aimed at its structural and biophysical characterization. Here, we present the first crystal structure of mCes2c to 2.12 Å resolution. The overall structure of mCes2c resembles that of the human CES1 (hCES1). The core domain adopts an α/β hydrolase-fold with S230, E347, and H459 forming a catalytic triad. Access to the active site is restricted by the cap, the flexible lid, and the regulatory domain. The conserved gate (M417) and switch (F418) residues might have a function in product release similar as suggested for hCES1. Biophysical characterization confirms that mCes2c is a monomer in solution. Thus, this study broadens our understanding of the mammalian carboxylesterase family and assists in delineating the similarities and differences of the different family members. Full article

(This article belongs to the Special Issue Lipid Metabolism in Pathology and Health)

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12 pages, 299 KiB

Open AccessArticle

Plasma Campesterol Is Positively Associated with Carotid Plaques in Asymptomatic Subjects

by Valéria Sutti Nunes, Edite Vieira Silva de Campos, Jamal Baracat, Victor França, Érica Ivana Lázaro Gomes, Raissa Peres Coelho, Edna Regina Nakandakare, Vanessa Helena Souza Zago, Eliana Cotta de Faria and Eder Carlos Rocha Quintão

Int. J. Mol. Sci. 2022, 23(19), 11997; https://doi.org/10.3390/ijms231911997 - 9 Oct 2022

Cited by 8 | Viewed by 1715

Abstract

Background: Increased cholesterol absorption and reduced synthesis are processes that have been associated with cardiovascular disease risk in a controversial way. However, most of the studies involving markers of cholesterol synthesis and absorption include conditions, such as obesity, diabetes, dyslipidemia, which can be [...] Read more.

Background: Increased cholesterol absorption and reduced synthesis are processes that have been associated with cardiovascular disease risk in a controversial way. However, most of the studies involving markers of cholesterol synthesis and absorption include conditions, such as obesity, diabetes, dyslipidemia, which can be confounding factors. The present study aimed at investigating the relationships of plasma cholesterol synthesis and absorption markers with cardiovascular disease (CVD) risk factors, cIMT (carotid intima-media thickness), and the presence of carotid plaques in asymptomatic subjects. Methods: A cross-sectional study was carried out in 270 asymptomatic individuals and anthropometrical parameters, fasting plasma lipids, glucometabolic profiles, high-sensitivity C-reactive protein (hs-CRP), markers of cholesterol synthesis (desmosterol and lathosterol), absorption (campesterol and sitosterol), cIMT, and the presence of atherosclerotic plaques were analyzed. Results: Among the selected subjects aged between 19 and 75 years, 51% were females. Age, body mass index, systolic and diastolic blood pressure, total cholesterol, non-HDL-C, triglycerides, glucose, and lathosterol/sitosterol ratios correlated positively with cIMT (p ≤ 0.05). Atherosclerotic plaques were present in 19% of the subjects. A direct association of carotid plaques with campesterol, OR = 1.71 (95% CI = 1.04–2.82, p ≤ 0.05) and inverse associations with both ratios lathosterol/campesterol, OR = 0.29 (CI = 0.11–0.80, p ≤ 0.05) and lathosterol/sitosterol, OR = 0.45 (CI = 0.22–0.95, p ≤ 0.05) were observed in univariate logistic regression analysis. Conclusions: The findings suggested that campesterol may be associated with atherosclerotic plaques and the lathosterol/campesterol or sitosterol ratios suggested an inverse association. Furthermore, synthesis and absorption of cholesterol are inverse processes, and the absorption marker, campesterol, may reflect changes in body cholesterol homeostasis with atherogenic potential. Full article

(This article belongs to the Special Issue Lipid Metabolism in Pathology and Health)

12 pages, 1195 KiB

Open AccessArticle

Alterations of Lipid Profile in Livers with Impaired Lipophagy

by Wenke Jonas, Kristin Schwerbel, Lisa Zellner, Markus Jähnert, Pascal Gottmann and Annette Schürmann

Int. J. Mol. Sci. 2022, 23(19), 11863; https://doi.org/10.3390/ijms231911863 - 6 Oct 2022

Cited by 4 | Viewed by 1676

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. Various mechanisms such as an increased uptake in fatty acids or de novo synthesis contribute to the development of steatosis and progression to more severe stages. Furthermore, it has [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. Various mechanisms such as an increased uptake in fatty acids or de novo synthesis contribute to the development of steatosis and progression to more severe stages. Furthermore, it has been shown that impaired lipophagy, the degradation of lipids by autophagic processes, contributes to NAFLD. Through an unbiased lipidome analysis of mouse livers in a genetic model of impaired lipophagy, we aimed to determine the resulting alterations in the lipidome. Observed changes overlap with those of the human disease. Overall, the entire lipid content and in particular the triacylglycerol concentration increased under conditions of impaired lipophagy. In addition, we detected a reduction in long-chain polyunsaturated fatty acids (PUFAs) and an increased ratio of n-6 PUFAs to n-3 PUFAs, which was due to the depletion of n-3 PUFAs. Although the abundance of major phospholipid classes was reduced, the ratio of phosphatidylcholines to phosphatidylethanolamines was not affected. In conclusion, this study demonstrates that impaired lipophagy contributes to the pathology of NAFLD and is associated with an altered lipid profile. However, the lipid pattern does not appear to be specific for lipophagic alterations, as it resembles mainly that described in relation to fatty liver disease. Full article

(This article belongs to the Special Issue Lipid Metabolism in Pathology and Health)

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15 pages, 3383 KiB

Open AccessArticle

Hepatocyte Proteome Alterations Induced by Individual and Combinations of Common Free Fatty Acids

by Juergen Gindlhuber, Maximilian Schinagl, Laura Liesinger, Barbara Darnhofer, Tamara Tomin, Matthias Schittmayer and Ruth Birner-Gruenberger

Int. J. Mol. Sci. 2022, 23(6), 3356; https://doi.org/10.3390/ijms23063356 - 20 Mar 2022

Cited by 3 | Viewed by 3061

Abstract

Non-alcoholic fatty liver disease is a pathology with a hard-to-detect onset and is estimated to be present in a quarter of the adult human population. To improve our understanding of the development of non-alcoholic fatty liver disease, we treated a human hepatoma cell [...] Read more.

Non-alcoholic fatty liver disease is a pathology with a hard-to-detect onset and is estimated to be present in a quarter of the adult human population. To improve our understanding of the development of non-alcoholic fatty liver disease, we treated a human hepatoma cell line model, HepG2, with increasing concentrations of common fatty acids, namely myristic, palmitic and oleic acid. To reproduce more physiologically representative conditions, we also included combinations of these fatty acids and monitored the cellular response with an in-depth proteomics approach and imaging techniques. The two saturated fatty acids initially presented a similar phenotype of a dose-dependent decrease in growth rates and impaired lipid droplet formation. Detailed analysis revealed that the drop in the growth rates was due to delayed cell-cycle progression following myristic acid treatment, whereas palmitic acid led to cellular apoptosis. In contrast, oleic acid, as well as saturated fatty acid mixtures with oleic acid, led to a dose-dependent increase in lipid droplet volume without adverse impacts on cell growth. Comparing the effects of harmful single-fatty-acid treatments and the well-tolerated fatty acid mixes on the cellular proteome, we were able to differentiate between fatty-acid-specific cellular responses and likely common lipotoxic denominators. Full article

(This article belongs to the Special Issue Lipid Metabolism in Pathology and Health)

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Review

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21 pages, 1631 KiB

Open AccessReview

Lipidomics—Paving the Road towards Better Insight and Precision Medicine in Rare Metabolic Diseases

by Martina Zandl-Lang, Barbara Plecko and Harald Köfeler

Int. J. Mol. Sci. 2023, 24(2), 1709; https://doi.org/10.3390/ijms24021709 - 15 Jan 2023

Cited by 4 | Viewed by 2733

Abstract

Even though the application of Next-Generation Sequencing (NGS) has significantly facilitated the identification of disease-associated mutations, the diagnostic rate of rare diseases is still below 50%. This causes a diagnostic odyssey and prevents specific treatment, as well as genetic counseling for further family [...] Read more.

Even though the application of Next-Generation Sequencing (NGS) has significantly facilitated the identification of disease-associated mutations, the diagnostic rate of rare diseases is still below 50%. This causes a diagnostic odyssey and prevents specific treatment, as well as genetic counseling for further family planning. Increasing the diagnostic rate and reducing the time to diagnosis in children with unclear disease are crucial for a better patient outcome and improvement of quality of life. In many cases, NGS reveals variants of unknown significance (VUS) that need further investigations. The delineation of novel (lipid) biomarkers is not only crucial to prove the pathogenicity of VUS, but provides surrogate parameters for the monitoring of disease progression and therapeutic interventions. Lipids are essential organic compounds in living organisms, serving as building blocks for cellular membranes, energy storage and signaling molecules. Among other disorders, an imbalance in lipid homeostasis can lead to chronic inflammation, vascular dysfunction and neurodegenerative diseases. Therefore, analyzing lipids in biological samples provides great insight into the underlying functional role of lipids in healthy and disease statuses. The method of choice for lipid analysis and/or huge assemblies of lipids (=lipidome) is mass spectrometry due to its high sensitivity and specificity. Due to the inherent chemical complexity of the lipidome and the consequent challenges associated with analyzing it, progress in the field of lipidomics has lagged behind other omics disciplines. However, compared to the previous decade, the output of publications on lipidomics has increased more than 17-fold within the last decade and has, therefore, become one of the fastest-growing research fields. Combining multiple omics approaches will provide a unique and efficient tool for determining pathogenicity of VUS at the functional level, and thereby identifying rare, as well as novel, genetic disorders by molecular techniques and biochemical analyses. Full article

(This article belongs to the Special Issue Lipid Metabolism in Pathology and Health)

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24 pages, 1398 KiB

Open AccessReview

Mitochondrial Fatty Acid β-Oxidation Disorders: From Disease to Lipidomic Studies—A Critical Review

by Inês M. S. Guerra, Helena B. Ferreira, Tânia Melo, Hugo Rocha, Sónia Moreira, Luísa Diogo, Maria Rosário Domingues and Ana S. P. Moreira

Int. J. Mol. Sci. 2022, 23(22), 13933; https://doi.org/10.3390/ijms232213933 - 11 Nov 2022

Cited by 12 | Viewed by 3816

Abstract

Fatty acid oxidation disorders (FAODs) are inborn errors of metabolism (IEMs) caused by defects in the fatty acid (FA) mitochondrial β-oxidation. The most common FAODs are characterized by the accumulation of medium-chain FAs and long-chain (3-hydroxy) FAs (and their carnitine derivatives), respectively. These [...] Read more.

Fatty acid oxidation disorders (FAODs) are inborn errors of metabolism (IEMs) caused by defects in the fatty acid (FA) mitochondrial β-oxidation. The most common FAODs are characterized by the accumulation of medium-chain FAs and long-chain (3-hydroxy) FAs (and their carnitine derivatives), respectively. These deregulations are associated with lipotoxicity which affects several organs and potentially leads to life-threatening complications and comorbidities. Changes in the lipidome have been associated with several diseases, including some IEMs. In FAODs, the alteration of acylcarnitines (CARs) and FA profiles have been reported in patients and animal models, but changes in polar and neutral lipid profile are still scarcely studied. In this review, we present the main findings on FA and CAR profile changes associated with FAOD pathogenesis, their correlation with oxidative damage, and the consequent disturbance of mitochondrial homeostasis. Moreover, alterations in polar and neutral lipid classes and lipid species identified so far and their possible role in FAODs are discussed. We highlight the need of mass-spectrometry-based lipidomic studies to understand (epi)lipidome remodelling in FAODs, thus allowing to elucidate the pathophysiology and the identification of possible biomarkers for disease prognosis and an evaluation of therapeutic efficacy. Full article

(This article belongs to the Special Issue Lipid Metabolism in Pathology and Health)

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8 pages, 1862 KiB

Open AccessHypothesis

An Altered Sphingolipid Profile as a Risk Factor for Progressive Neurodegeneration in Long-Chain 3-Hydroxyacyl-CoA Deficiency (LCHADD)

by Sara Tucci

Int. J. Mol. Sci. 2022, 23(13), 7144; https://doi.org/10.3390/ijms23137144 - 27 Jun 2022

Cited by 4 | Viewed by 1938

Abstract

Long-chain 3-hydroxyacyl-CoA deficiency (LCHADD) and mitochondrial trifunctional protein (MTPD) belong to a group of inherited metabolic diseases affecting the degradation of long-chain chain fatty acids. During metabolic decompensation the incomplete degradation of fatty acids results in life-threatening episodes, coma and death. Despite fast [...] Read more.

Long-chain 3-hydroxyacyl-CoA deficiency (LCHADD) and mitochondrial trifunctional protein (MTPD) belong to a group of inherited metabolic diseases affecting the degradation of long-chain chain fatty acids. During metabolic decompensation the incomplete degradation of fatty acids results in life-threatening episodes, coma and death. Despite fast identification at neonatal screening, LCHADD/MTPD present with progressive neurodegenerative symptoms originally attributed to the accumulation of toxic hydroxyl acylcarnitines and energy deficiency. Recently, it has been shown that LCHADD human fibroblasts display a disease-specific alteration of complex lipids. Accumulating fatty acids, due to defective β-oxidation, contribute to a remodeling of several lipid classes including mitochondrial cardiolipins and sphingolipids. In the last years the face of LCHADD/MTPD has changed. The reported dysregulation of complex lipids other than the simple acylcarnitines represents a novel aspect of disease development. Indeed, aberrant lipid profiles have already been associated with other neurodegenerative diseases such as Parkinson’s Disease, Alzheimer’s Disease, amyotrophic lateral sclerosis and retinopathy. Today, the physiopathology that underlies the development of the progressive neuropathic symptoms in LCHADD/MTPD is not fully understood. Here, we hypothesize an alternative disease-causing mechanism that contemplates the interaction of several factors that acting in concert contribute to the heterogeneous clinical phenotype. Full article

(This article belongs to the Special Issue Lipid Metabolism in Pathology and Health)

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