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Emerging Role of Lipids in Metabolism and Disease – 2nd Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (15 May 2021) | Viewed by 79237

Special Issue Editors

Prof. Dr. Valentina Pallottini

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Guest Editor
Department of Science, University Roma Tre, Viale Marconi, 446 Rome, Italy
Interests: cholesterol metabolism; HMG-CoA reductase; neurodegeneration; neurodevelopmental diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Marco Segatto

E-Mail Website
Guest Editor
Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche, Italy
Interests: cholesterol; brain; neurotrophins; skeletal muscle; inflammation; signal transduction; autophagy; neurodegeneration
Special Issues, Collections and Topics in MDPI journals
Dr. Antimo Cutone

E-Mail Website
Guest Editor
Department of Biosciences and Territory, University of Molise, 86090 Pesche, Italy
Interests: lactoferrin; iron homeostasis; iron-proteins; inflammation; oxidative stress; ferroportin; yeast; membrane proteins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

We are very pleased to announce the second edition of the Special Issue “Emerging Role of Lipids in Metabolism and Disease”. 

Although initially regarded as a passive method of energy storage, lipids are now considered molecules with pivotal structural and functional roles. Notably, they serve as integral components of cellular membranes and act as crucial messengers in the regulation of cell homeostasis. In recent years, the role of lipids in homeostasis maintenance, derived from both nutrition and endogenous biosynthesis, has attracted the interest of several researchers because of its involvement in human health. Altered lipid metabolism is at the root of several diseases affecting different organs and tissues. For instance, metabolic syndrome and cardiovascular disease are closely related to these metabolic dysfunctions. Moreover, connections with misbalances of cholesterol homeostasis in neurodegenerative and neurodevelopmental disorders have also been demonstrated.

The second edition of this Special Issue is aimed at gathering research papers focused on this topic and, therefore, bring to the forefront new insights into physiopathological aspects of lipid disorders. Papers from different experts in the field will provide an interdisciplinary approach that will identify how the manipulation of lipid metabolism can represent a very attractive target for designing novel therapeutic targets to counteract several pathologies.

Prof. Dr. Valentina Pallottini
Dr. Marco Segatto
Dr. Antimo Cutone
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Cholesterol
  • Fatty acids
  • Lipoproteins
  • Lipids
  • Metabolism
  • Metabolic diseases
  • Neurodegeneration and lipids
  • Neurodevelopment and lipids
  • Lipid signaling
  • Lipids and inflammation
  • Lipids in cancer
  • Cardiovascular diseases
  • Lipid rafts
  • Post-translational lipid modifications
  • Polyunsaturated fatty acids
  • Cannabinoids
  • Eicosanoids

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Published Papers (20 papers)

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Research

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13 pages, 3914 KiB  
Article
Vitamin D3 Enriches Ceramide Content in Exosomes Released by Embryonic Hippocampal Cells
by Carmela Conte, Samuela Cataldi, Cataldo Arcuri, Alessandra Mirarchi, Andrea Lazzarini, Mercedes Garcia-Gil, Tommaso Beccari, Francesco Curcio and Elisabetta Albi
Int. J. Mol. Sci. 2021, 22(17), 9287; https://doi.org/10.3390/ijms22179287 - 27 Aug 2021
Cited by 8 | Viewed by 1890
Abstract
The release of exosomes can lead to cell–cell communication. Nutrients such as vitamin D3 and sphingolipids have important roles in many cellular functions, including proliferation, differentiation, senescence, and cancer. However, the specific composition of sphingolipids in exosomes and their changes induced by vitamin [...] Read more.
The release of exosomes can lead to cell–cell communication. Nutrients such as vitamin D3 and sphingolipids have important roles in many cellular functions, including proliferation, differentiation, senescence, and cancer. However, the specific composition of sphingolipids in exosomes and their changes induced by vitamin D3 treatment have not been elucidated. Here, we initially observed neutral sphingomyelinase and vitamin D receptors in exosomes released from HN9.10 embryonic hippocampal cells. Using ultrafast liquid chromatography tandem mass spectrometry, we showed that exosomes are rich in sphingomyelin species compared to whole cells. To interrogate the possible functions of vitamin D3, we established the optimal conditions of cell treatment and we analyzed exosome composition. Vitamin D3 was identified as responsible for the vitamin D receptor loss, for the increase in neutral sphingomyelinase content and sphingomyelin changes. As a consequence, the generation of ceramide upon vitamin D3 treatment was evident. Incubation of the cells with neutral sphingomyelinase, or the same concentration of ceramide produced in exosomes was necessary and sufficient to stimulate embryonic hippocampal cell differentiation, as vitamin D3. This is the first time that exosome ceramide is interrogated for mediate the effect of vitamin D3 in inducing cell differentiation. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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18 pages, 1330 KiB  
Article
Novel Insight in Idiopathic Normal Pressure Hydrocephalus (iNPH) Biomarker Discovery in CSF
by Enrica Torretta, Beatrice Arosio, Pietro Barbacini, Daniele Capitanio, Paolo Dionigi Rossi, Manuela Moriggi, Mario Clerici, Daniela Mari, Matteo Cesari and Cecilia Gelfi
Int. J. Mol. Sci. 2021, 22(15), 8034; https://doi.org/10.3390/ijms22158034 - 27 Jul 2021
Cited by 9 | Viewed by 2980
Abstract
Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disease, causing motor and cognitive dysfunction and dementia. iNPH and Alzheimer’s disease (AD) share similar molecular characteristics, including amyloid deposition, t-tau and p-tau dysregulation; however, the disease is under-diagnosed and under-treated. The aim [...] Read more.
Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disease, causing motor and cognitive dysfunction and dementia. iNPH and Alzheimer’s disease (AD) share similar molecular characteristics, including amyloid deposition, t-tau and p-tau dysregulation; however, the disease is under-diagnosed and under-treated. The aim was to identify a panel of sphingolipids and proteins in CSF to diagnose iNPH at onset compared to aged subjects with cognitive integrity (C) and AD patients by adopting multiple reaction monitoring mass spectrometry (MRM-MS) for sphingolipid quantitative assessment and advanced high-resolution liquid chromatography–tandem mass spectrometry (LC–MS/MS) for proteomic analysis. The results indicated that iNPH are characterized by an increase in very long chains Cer C22:0, Cer C24:0 and Cer C24:1 and of acute-phase proteins, immunoglobulins and complement component fragments. Proteins involved in synaptic signaling, axogenesis, including BACE1, APP, SEZ6L and SEZ6L2; secretory proteins (CHGA, SCG3 and VGF); glycosylation proteins (POMGNT1 and DAG1); and proteins involved in lipid metabolism (APOH and LCAT) were statistically lower in iNPH. In conclusion, at the disease onset, several factors contribute to maintaining cell homeostasis, and the protective role of very long chains sphingolipids counteract overexpression of amyloidogenic and neurotoxic proteins. Monitoring specific very long chain Cers will improve the early diagnosis and can promote patient follow-up. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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16 pages, 2506 KiB  
Article
Complex Alterations of Fatty Acid Metabolism and Phospholipidome Uncovered in Isolated Colon Cancer Epithelial Cells
by Jiřina Hofmanová, Josef Slavík, Miroslav Ciganek, Petra Ovesná, Zuzana Tylichová, Martina Karasová, Ondřej Zapletal, Nicol Straková, Jiřina Procházková, Jan Bouchal, Zdeněk Kolář, Jiří Ehrmann, Monika Levková, Zlatka Hušková, Pavel Skalický, Alois Kozubík, Miroslav Machala and Jan Vondráček
Int. J. Mol. Sci. 2021, 22(13), 6650; https://doi.org/10.3390/ijms22136650 - 22 Jun 2021
Cited by 20 | Viewed by 2855
Abstract
The development of colon cancer, one of the most common malignancies, is accompanied with numerous lipid alterations. However, analyses of whole tumor samples may not always provide an accurate description of specific changes occurring directly in tumor epithelial cells. Here, we analyzed in [...] Read more.
The development of colon cancer, one of the most common malignancies, is accompanied with numerous lipid alterations. However, analyses of whole tumor samples may not always provide an accurate description of specific changes occurring directly in tumor epithelial cells. Here, we analyzed in detail the phospholipid (PL), lysophospholipid (lysoPL), and fatty acid (FA) profiles of purified EpCAM+ cells, isolated from tumor and adjacent non-tumor tissues of colon cancer patients. We found that a number of FAs increased significantly in isolated tumor cells, which also included a number of long polyunsaturated FAs. Higher levels of FAs were associated with increased expression of FA synthesis genes, as well as with altered expression of enzymes involved in FA elongation and desaturation, including particularly fatty acid synthase, stearoyl-CoA desaturase, fatty acid desaturase 2 and ELOVL5 fatty acid elongase 5 We identified significant changes in ratios of specific lysoPLs and corresponding PLs. A number of lysophosphatidylcholine and lysophosphatidylethanolamine species, containing long-chain and very-long chain FAs, often with high numbers of double bonds, were significantly upregulated in tumor cells. Increased de novo synthesis of very long-chain FAs, or, altered uptake or incorporation of these FAs into specific lysoPLs in tumor cells, may thus contribute to reprogramming of cellular phospholipidome and membrane alterations observed in colon cancer. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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18 pages, 1949 KiB  
Article
Liver Lipids of Patients with Hepatitis B and C and Associated Hepatocellular Carcinoma
by Elisabeth M. Haberl, Thomas S. Weiss, Georg Peschel, Kilian Weigand, Nikolai Köhler, Josch K. Pauling, Jürgen J. Wenzel, Marcus Höring, Sabrina Krautbauer, Gerhard Liebisch and Christa Buechler
Int. J. Mol. Sci. 2021, 22(10), 5297; https://doi.org/10.3390/ijms22105297 - 18 May 2021
Cited by 7 | Viewed by 2381
Abstract
Hepatocellular carcinoma (HCC) still remains a difficult to cure malignancy. In recent years, the focus has shifted to lipid metabolism for the treatment of HCC. Very little is known about hepatitis B virus (HBV) and C virus (HCV)-related hepatic lipid disturbances in non-malignant [...] Read more.
Hepatocellular carcinoma (HCC) still remains a difficult to cure malignancy. In recent years, the focus has shifted to lipid metabolism for the treatment of HCC. Very little is known about hepatitis B virus (HBV) and C virus (HCV)-related hepatic lipid disturbances in non-malignant and cancer tissues. The present study showed that triacylglycerol and cholesterol concentrations were similar in tumor adjacent HBV and HCV liver, and were not induced in the HCC tissues. Higher levels of free cholesterol, polyunsaturated phospholipids and diacylglycerol species were noted in non-tumorous HBV compared to HCV liver. Moreover, polyunsaturated phospholipids and diacylglycerols, and ceramides declined in tumors of HBV infected patients. All of these lipids remained unchanged in HCV-related HCC. In HCV tumors, polyunsaturated phosphatidylinositol levels were even induced. There were no associations of these lipid classes in non-tumor tissues with hepatic inflammation and fibrosis scores. Moreover, these lipids did not correlate with tumor grade or T-stage in HCC tissues. Lipid reprogramming of the three analysed HBV/HCV related tumors mostly resembled HBV-HCC. Indeed, lipid composition of non-tumorous HCV tissue, HCV tumors, HBV tumors and HBV/HCV tumors was highly similar. The tumor suppressor protein p53 regulates lipid metabolism. The p53 and p53S392 protein levels were induced in the tumors of HBV, HCV and double infected patients, and this was significant in HBV infection. Negative correlation of tumor p53 protein with free cholesterol indicates a role of p53 in cholesterol metabolism. In summary, the current study suggests that therapeutic strategies to target lipid metabolism in chronic viral hepatitis and associated cancers have to consider disease etiology. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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12 pages, 3052 KiB  
Article
A Soluble Epoxide Hydrolase Inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) Urea, Ameliorates Experimental Autoimmune Encephalomyelitis
by Deepa Jonnalagadda, Debin Wan, Jerold Chun, Bruce D. Hammock and Yasuyuki Kihara
Int. J. Mol. Sci. 2021, 22(9), 4650; https://doi.org/10.3390/ijms22094650 - 28 Apr 2021
Cited by 10 | Viewed by 2753
Abstract
Polyunsaturated fatty acids (PUFAs) are essential FAs for human health. Cytochrome P450 oxygenates PUFAs to produce anti-inflammatory and pain-resolving epoxy fatty acids (EpFAs) and other oxylipins whose epoxide ring is opened by the soluble epoxide hydrolase (sEH/Ephx2), resulting in the formation [...] Read more.
Polyunsaturated fatty acids (PUFAs) are essential FAs for human health. Cytochrome P450 oxygenates PUFAs to produce anti-inflammatory and pain-resolving epoxy fatty acids (EpFAs) and other oxylipins whose epoxide ring is opened by the soluble epoxide hydrolase (sEH/Ephx2), resulting in the formation of toxic and pro-inflammatory vicinal diols (dihydroxy-FAs). Pharmacological inhibition of sEH is a promising strategy for the treatment of pain, inflammation, cardiovascular diseases, and other conditions. We tested the efficacy of a potent, selective sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), in an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Prophylactic TPPU treatment significantly ameliorated EAE without affecting circulating white blood cell counts. TPPU accumulated in the spinal cords (SCs), which was correlated with plasma TPPU concentration. Targeted lipidomics in EAE SCs and plasma identified that TPPU blocked production of dihydroxy-FAs efficiently and increased some EpFA species including 12(13)-epoxy-octadecenoic acid (12(13)-EpOME) and 17(18)-epoxy-eicosatrienoic acid (17(18)-EpETE). TPPU did not alter levels of cyclooxygenase (COX-1/2) metabolites, while it increased 12-hydroxyeicosatetraenoic acid (12-HETE) and other 12/15-lipoxygenase metabolites. These analytical results are consistent with sEH inhibitors that reduce neuroinflammation and accelerate anti-inflammatory responses, providing the possibility that sEH inhibitors could be used as a disease modifying therapy, as well as for MS-associated pain relief. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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19 pages, 4669 KiB  
Article
Early Lipid Raft-Related Changes: Interplay between Unilateral Denervation and Hindlimb Suspension
by Irina G. Bryndina, Maria N. Shalagina, Vladimir A. Protopopov, Alexey V. Sekunov, Andrey L. Zefirov, Guzalia F. Zakirjanova and Alexey M. Petrov
Int. J. Mol. Sci. 2021, 22(5), 2239; https://doi.org/10.3390/ijms22052239 - 24 Feb 2021
Cited by 6 | Viewed by 2213
Abstract
Muscle disuse and denervation leads to muscle atrophy, but underlying mechanisms can be different. Previously, we have found ceramide (Cer) accumulation and lipid raft disruption after acute hindlimb suspension (HS), a model of muscle disuse. Herein, using biochemical and fluorescent approaches the influence [...] Read more.
Muscle disuse and denervation leads to muscle atrophy, but underlying mechanisms can be different. Previously, we have found ceramide (Cer) accumulation and lipid raft disruption after acute hindlimb suspension (HS), a model of muscle disuse. Herein, using biochemical and fluorescent approaches the influence of unilateral denervation itself and in combination with short-term HS on membrane-related parameters of rat soleus muscle was studied. Denervation increased immunoexpression of sphingomyelinase and Cer in plasmalemmal regions, but decreased Cer content in the raft fraction and enhanced lipid raft integrity. Preliminary denervation suppressed (1) HS-induced Cer accumulation in plasmalemmal regions, shown for both nonraft and raft-fractions; (2) HS-mediated decrease in lipid raft integrity. Similar to denervation, inhibition of the sciatic nerve afferents with capsaicin itself increased Cer plasmalemmal immunoexpression, but attenuated the membrane-related effects of HS. Finally, both denervation and capsaicin treatment increased immunoexpression of proapoptotic protein Bax and inhibited HS-driven increase in antiapoptotic protein Bcl-2. Thus, denervation can increase lipid raft formation and attenuate HS-induced alterations probably due to decrease of Cer levels in the raft fraction. The effects of denervation could be at least partially caused by the loss of afferentation. The study points to the importance of motor and afferent inputs in control of Cer distribution and thereby stability of lipid rafts in the junctional and extrajunctional membranes of the muscle. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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14 pages, 2848 KiB  
Article
Targeting Fat Oxidation in Mouse Prostate Cancer Decreases Tumor Growth and Stimulates Anti-Cancer Immunity
by Amanda Guth, Emily Monk, Rajesh Agarwal, Bryan C. Bergman, Karin A. Zemski-Berry, Angela Minic, Kimberly Jordan and Isabel R. Schlaepfer
Int. J. Mol. Sci. 2020, 21(24), 9660; https://doi.org/10.3390/ijms21249660 - 18 Dec 2020
Cited by 9 | Viewed by 3991
Abstract
Lipid catabolism represents an Achilles heel in prostate cancer (PCa) that can be exploited for therapy. CPT1A regulates the entry of fatty acids into the mitochondria for beta-oxidation and its inhibition has been shown to decrease PCa growth. In this study, we examined [...] Read more.
Lipid catabolism represents an Achilles heel in prostate cancer (PCa) that can be exploited for therapy. CPT1A regulates the entry of fatty acids into the mitochondria for beta-oxidation and its inhibition has been shown to decrease PCa growth. In this study, we examined the pharmacological blockade of lipid oxidation with ranolazine in TRAMPC1 PCa models. Oral administration of ranolazine (100 mg/Kg for 21 days) resulted in decreased tumor CD8+ T-cells Tim3 content, increased macrophages, and decreased blood myeloid immunosuppressive monocytes. Using multispectral staining, drug treatments increased infiltration of CD8+ T-cells and dendritic cells compared to vehicle. Functional studies with spleen cells of drug-treated tumors co-cultured with TRAMPC1 cells showed increased ex vivo T-cell cytotoxic activity, suggesting an anti-tumoral response. Lastly, a decrease in CD4+ and CD8+ T-cells expressing PD1 was observed when exhausted spleen cells were incubated with TRAMPC1 Cpt1a-KD compared to the control cells. These data indicated that genetically blocking the ability of the tumor cells to oxidize lipid can change the activation status of the neighboring T-cells. This study provides new knowledge of the role of lipid catabolism in the intercommunication of tumor and immune cells, which can be extrapolated to other cancers with high CPT1A expression. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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16 pages, 4129 KiB  
Article
Comparison of PPAR Ligands as Modulators of Resolution of Inflammation, via Their Influence on Cytokines and Oxylipins Release in Astrocytes
by Dmitry V. Chistyakov, Alina A. Astakhova, Sergei V. Goriainov and Marina G. Sergeeva
Int. J. Mol. Sci. 2020, 21(24), 9577; https://doi.org/10.3390/ijms21249577 - 16 Dec 2020
Cited by 23 | Viewed by 2989
Abstract
Neuroinflammation is a key process of many neurodegenerative diseases and other brain disturbances, and astrocytes play an essential role in neuroinflammation. Therefore, the regulation of astrocyte responses for inflammatory stimuli, using small molecules, is a potential therapeutic strategy. We investigated the potency of [...] Read more.
Neuroinflammation is a key process of many neurodegenerative diseases and other brain disturbances, and astrocytes play an essential role in neuroinflammation. Therefore, the regulation of astrocyte responses for inflammatory stimuli, using small molecules, is a potential therapeutic strategy. We investigated the potency of peroxisome proliferator-activated receptor (PPAR) ligands to modulate the stimulating effect of lipopolysaccharide (LPS) in the primary rat astrocytes on (1) polyunsaturated fatty acid (PUFAs) derivative (oxylipins) synthesis; (2) cytokines TNFα and interleukin-10 (IL-10) release; (3) p38, JNK, ERK mitogen-activated protein kinase (MAPKs) phosphorylation. Astrocytes were exposed to LPS alone or in combination with the PPAR ligands: PPARα (fenofibrate, GW6471); PPARβ (GW501516, GSK0660); PPARγ (rosiglitazone, GW9662). We detected 28 oxylipins with mass spectrometry (UPLC-MS/MS), classified according to their metabolic pathways: cyclooxygenase (COX), cytochrome P450 monooxygenases (CYP), lipoxygenase (LOX) and PUFAs: arachidonic (AA), docosahexaenoic (DHA), eicosapentaenoic (EPA). All tested PPAR ligands decrease COX-derived oxylipins; both PPARβ ligands possessed the strongest effect. The PPARβ agonist, GW501516 is a strong inducer of pro-resolution substances, derivatives of DHA: 4-HDoHE, 11-HDoHE, 17-HDoHE. All tested PPAR ligands decreased the release of the proinflammatory cytokine, TNFα. The PPARβ agonist GW501516 and the PPARγ agonist, rosiglitazone induced the IL-10 release of the anti-inflammatory cytokine, IL-10; the cytokine index, (IL-10/TNFα) was more for GW501516. The PPARβ ligands, GW501516 and GSK0660, are also the strongest inhibitors of LPS-induced phosphorylation of p38, JNK, ERK MAPKs. Overall, our data revealed that the PPARβ ligands are a potential pro-resolution and anti-inflammatory drug for targeting glia-mediated neuroinflammation. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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17 pages, 2677 KiB  
Article
FAHFAs Regulate the Proliferation of C2C12 Myoblasts and Induce a Shift toward a More Oxidative Phenotype in Mouse Skeletal Muscle
by Melha Benlebna, Laurence Balas, Laurence Pessemesse, Béatrice Bonafos, Gilles Fouret, Laura Pavlin, Bénédicte Goustard, Sylvie Gaillet, Thierry Durand, Charles Coudray, Christine Feillet-Coudray and François Casas
Int. J. Mol. Sci. 2020, 21(23), 9046; https://doi.org/10.3390/ijms21239046 - 28 Nov 2020
Cited by 8 | Viewed by 2007
Abstract
Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are endogenous lipids reported to have antidiabetic and anti-inflammatory effects. Since skeletal muscle is a major target for insulin, the aim of this study is to explore for the first time the influence of [...] Read more.
Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are endogenous lipids reported to have antidiabetic and anti-inflammatory effects. Since skeletal muscle is a major target for insulin, the aim of this study is to explore for the first time the influence of several FAHFAs in C2C12 myoblasts and in skeletal muscle phenotype in mice. Here, we show that eleven FAHFAs belonging to different families inhibit C2C12 myoblast proliferation. In addition, all FAHFAs decreased mitochondrial cytochrome c oxidase activity without affecting reactive oxygen species production and the mitochondrial network. During C2C12 myoblasts differentiation, we found that two of the most active lipids, 9-PAHPA and 9-OAHPA, did not significantly affect the fusion index and the expression of myosin heavy chains. However, we found that three months’ intake of 9-PAHPA or 9-OAHPA in mice increased the expression of more oxidative myosin in skeletal muscle without affecting skeletal muscle mass, number, and mean fiber area, mitochondrial activity, and oxidative stress parameters. In conclusion, our study indicated that the eleven FAHFAs tested decreased the proliferation rate of C2C12 myoblasts, probably through the inhibition of mitochondrial activity. In addition, we found that 9-PAHPA or 9-OAHPA supplementation in mice induced a switch toward a more oxidative contractile phenotype of skeletal muscle. These data suggest that the increase in insulin sensitivity previously described for these two FAHFAs is of muscular origin. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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16 pages, 2484 KiB  
Article
Inhibitor of Hyaluronic Acid Synthesis 4-Methylumbelliferone as an Anti-Inflammatory Modulator of LPS-Mediated Astrocyte Responses
by Dmitry V. Chistyakov, Arina I. Nikolskaya, Sergei V. Goriainov, Alina A. Astakhova and Marina G. Sergeeva
Int. J. Mol. Sci. 2020, 21(21), 8203; https://doi.org/10.3390/ijms21218203 - 02 Nov 2020
Cited by 10 | Viewed by 4447
Abstract
Astrocytes are glial cells that play an important role in neuroinflammation. Astrocytes respond to many pro-inflammatory stimuli, including lipopolysaccharide (LPS), an agonist of Toll-like receptor 4 (TLR4). Regulatory specificities of inflammatory signaling pathways are still largely unknown due to the ectodermal origin of [...] Read more.
Astrocytes are glial cells that play an important role in neuroinflammation. Astrocytes respond to many pro-inflammatory stimuli, including lipopolysaccharide (LPS), an agonist of Toll-like receptor 4 (TLR4). Regulatory specificities of inflammatory signaling pathways are still largely unknown due to the ectodermal origin of astrocytes. Recently, we have shown that hyaluronic acid (HA) may form part of astrocyte inflammatory responses. Therefore, we tested 4-methylumbelliferone (4-MU), a specific inhibitor of HA synthesis, as a possible regulator of LPS-mediated responses. Rat primary astrocytes were treated with LPS with and without 4-MU and gene expression levels of inflammatory (interleukins 1β, (IL-1β), 6, (IL-6), tumor necrosis factor alpha TNFα,) and resolution interleukin 10 (IL-10) markers were evaluated via real-time PCR and western blot. The release of cytokines and HA was determined by ELISA. Oxylipin profiles were measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. Our data show that 4-MU (i) has anti-inflammatory effects in the course of TLR4 activation, decreasing the cytokines level TNFα, IL-6 and IL-1β and increasing IL-10, (ii) downregulates prostaglandin synthesis but not via cyclooxygenases COX-1 and COX-2 pathways, (iii) modulates HA synthesis and decreases LPS-induced HA synthase mRNA expression (HAS-1, HAS-2) but does not have an influence on HAS-3, HYAL1 and HYAL2 mRNAs; (iv) the effects of 4-MU are predominantly revealed via JNK but not p38, ERK mitogen-activated protein kinases (MAPKs) or nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathways. For the first time, it is shown that 4-MU possesses the useful potential to regulate an inflammatory astrocyte response. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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Review

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16 pages, 9323 KiB  
Review
The Immunometabolic Roles of Various Fatty Acids in Macrophages and Lymphocytes
by Jose Cesar Rosa Neto, Philip C. Calder, Rui Curi, Philip Newsholme, Jaswinder K. Sethi and Loreana S. Silveira
Int. J. Mol. Sci. 2021, 22(16), 8460; https://doi.org/10.3390/ijms22168460 - 06 Aug 2021
Cited by 17 | Viewed by 4997
Abstract
Macrophages and lymphocytes demonstrate metabolic plasticity, which is dependent partly on their state of activation and partly on the availability of various energy yielding and biosynthetic substrates (fatty acids, glucose, and amino acids). These substrates are essential to fuel-based metabolic reprogramming that supports [...] Read more.
Macrophages and lymphocytes demonstrate metabolic plasticity, which is dependent partly on their state of activation and partly on the availability of various energy yielding and biosynthetic substrates (fatty acids, glucose, and amino acids). These substrates are essential to fuel-based metabolic reprogramming that supports optimal immune function, including the inflammatory response. In this review, we will focus on metabolism in macrophages and lymphocytes and discuss the role of fatty acids in governing the phenotype, activation, and functional status of these important cells. We summarize the current understanding of the pathways of fatty acid metabolism and related mechanisms of action and also explore possible new perspectives in this exciting area of research. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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13 pages, 738 KiB  
Review
The Role of Fatty Acids in Non-Alcoholic Fatty Liver Disease Progression: An Update
by Aleksandra Hliwa, Bruno Ramos-Molina, Dariusz Laski, Adriana Mika and Tomasz Sledzinski
Int. J. Mol. Sci. 2021, 22(13), 6900; https://doi.org/10.3390/ijms22136900 - 27 Jun 2021
Cited by 31 | Viewed by 4062
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major public health problem worldwide. NAFLD (both simple steatosis and steatohepatitis) is characterized by alterations in hepatic lipid metabolism, which may lead to the development of severe liver complications including cirrhosis and hepatocellular carcinoma. Thus, an [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is a major public health problem worldwide. NAFLD (both simple steatosis and steatohepatitis) is characterized by alterations in hepatic lipid metabolism, which may lead to the development of severe liver complications including cirrhosis and hepatocellular carcinoma. Thus, an exhaustive examination of lipid disorders in the liver of NAFLD patients is much needed. Mass spectrometry-based lipidomics platforms allow for in-depth analysis of lipid alterations in a number of human diseases, including NAFLD. This review summarizes the current research on lipid alterations associated with NAFLD and related complications, with special emphasis on the changes in long-chain and short-chain fatty acids levels in both serum and liver tissue, as well as in the hepatic expression of genes encoding the enzymes catalyzing lipid interconversions. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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12 pages, 682 KiB  
Review
Potential Contribution of Short Chain Fatty Acids to Hepatic Apolipoprotein A-I Production
by Herman E. Popeijus, Willem Zwaan, Jehad Z. Tayyeb and Jogchum Plat
Int. J. Mol. Sci. 2021, 22(11), 5986; https://doi.org/10.3390/ijms22115986 - 01 Jun 2021
Cited by 11 | Viewed by 2917
Abstract
Apolipoprotein A-I (ApoA-I) is the major protein of high density lipoprotein (HDL) particles and has a crucial role in reverse cholesterol transport (RCT). It has been postulated that elevating production of de novo ApoA-I might translate into the formation of new functional HDL [...] Read more.
Apolipoprotein A-I (ApoA-I) is the major protein of high density lipoprotein (HDL) particles and has a crucial role in reverse cholesterol transport (RCT). It has been postulated that elevating production of de novo ApoA-I might translate into the formation of new functional HDL particles that could lower cardiovascular disease (CVD) risk via RCT. During inflammation, serum ApoA-I concentrations are reduced, which contributes to the development of dysfunctional HDL particles as Serum Amyloid A (SAA) overtakes the position of ApoA-I within the HDL particles. Therefore, instead of elevating serum HDL cholesterol concentrations, rescuing lower serum ApoA-I concentrations could be beneficial in both normal and inflamed conditions. Several nutritional compounds, amongst others short chain fatty acids (SCFAs), have shown their capacity to modulate hepatic lipoprotein metabolism. In this review we provide an overview of HDL and more specific ApoA-I metabolism, SCFAs physiology and the current knowledge regarding the influence of SCFAs on ApoA-I expression and synthesis in human liver cells. We conclude that the current evidence regarding the effect of SCFAs on ApoA-I transcription and secretion is promising, however there is a need to investigate which dietary fibres could lead to increased SCFAs formation and consequent elevated ApoA-I concentrations. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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34 pages, 1730 KiB  
Review
Multifaced Roles of HDL in Sepsis and SARS-CoV-2 Infection: Renal Implications
by Alessandra Stasi, Rossana Franzin, Marco Fiorentino, Enrico Squiccimarro, Giuseppe Castellano and Loreto Gesualdo
Int. J. Mol. Sci. 2021, 22(11), 5980; https://doi.org/10.3390/ijms22115980 - 01 Jun 2021
Cited by 21 | Viewed by 5084
Abstract
High-density lipoproteins (HDLs) are a class of blood particles, principally involved in mediating reverse cholesterol transport from peripheral tissue to liver. Omics approaches have identified crucial mediators in the HDL proteomic and lipidomic profile, which are involved in distinct pleiotropic functions. Besides their [...] Read more.
High-density lipoproteins (HDLs) are a class of blood particles, principally involved in mediating reverse cholesterol transport from peripheral tissue to liver. Omics approaches have identified crucial mediators in the HDL proteomic and lipidomic profile, which are involved in distinct pleiotropic functions. Besides their role as cholesterol transporter, HDLs display anti-inflammatory, anti-apoptotic, anti-thrombotic, and anti-infection properties. Experimental and clinical studies have unveiled significant changes in both HDL serum amount and composition that lead to dysregulated host immune response and endothelial dysfunction in the course of sepsis. Most SARS-Coronavirus-2-infected patients admitted to the intensive care unit showed common features of sepsis disease, such as the overwhelmed systemic inflammatory response and the alterations in serum lipid profile. Despite relevant advances, episodes of mild to moderate acute kidney injury (AKI), occurring during systemic inflammatory diseases, are associated with long-term complications, and high risk of mortality. The multi-faceted relationship of kidney dysfunction with dyslipidemia and inflammation encourages to deepen the clarification of the mechanisms connecting these elements. This review analyzes the multifaced roles of HDL in inflammatory diseases, the renal involvement in lipid metabolism, and the novel potential HDL-based therapies. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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22 pages, 3858 KiB  
Review
PCSK9 Biology and Its Role in Atherothrombosis
by Cristina Barale, Elena Melchionda, Alessandro Morotti and Isabella Russo
Int. J. Mol. Sci. 2021, 22(11), 5880; https://doi.org/10.3390/ijms22115880 - 30 May 2021
Cited by 76 | Viewed by 8921
Abstract
It is now about 20 years since the first case of a gain-of-function mutation involving the as-yet-unknown actor in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9), was described. It was soon clear that this protein would have been of huge scientific and [...] Read more.
It is now about 20 years since the first case of a gain-of-function mutation involving the as-yet-unknown actor in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9), was described. It was soon clear that this protein would have been of huge scientific and clinical value as a therapeutic strategy for dyslipidemia and atherosclerosis-associated cardiovascular disease (CVD) management. Indeed, PCSK9 is a serine protease belonging to the proprotein convertase family, mainly produced by the liver, and essential for metabolism of LDL particles by inhibiting LDL receptor (LDLR) recirculation to the cell surface with the consequent upregulation of LDLR-dependent LDL-C levels. Beyond its effects on LDL metabolism, several studies revealed the existence of additional roles of PCSK9 in different stages of atherosclerosis, also for its ability to target other members of the LDLR family. PCSK9 from plasma and vascular cells can contribute to the development of atherosclerotic plaque and thrombosis by promoting platelet activation, leukocyte recruitment and clot formation, also through mechanisms not related to systemic lipid changes. These results further supported the value for the potential cardiovascular benefits of therapies based on PCSK9 inhibition. Actually, the passive immunization with anti-PCSK9 antibodies, evolocumab and alirocumab, is shown to be effective in dramatically reducing the LDL-C levels and attenuating CVD. While monoclonal antibodies sequester circulating PCSK9, inclisiran, a small interfering RNA, is a new drug that inhibits PCSK9 synthesis with the important advantage, compared with PCSK9 mAbs, to preserve its pharmacodynamic effects when administrated every 6 months. Here, we will focus on the major understandings related to PCSK9, from its discovery to its role in lipoprotein metabolism, involvement in atherothrombosis and a brief excursus on approved current therapies used to inhibit its action. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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27 pages, 1679 KiB  
Review
Neurotrophins as Key Regulators of Cell Metabolism: Implications for Cholesterol Homeostasis
by Mayra Colardo, Noemi Martella, Daniele Pensabene, Silvia Siteni, Sabrina Di Bartolomeo, Valentina Pallottini and Marco Segatto
Int. J. Mol. Sci. 2021, 22(11), 5692; https://doi.org/10.3390/ijms22115692 - 26 May 2021
Cited by 22 | Viewed by 5660
Abstract
Neurotrophins constitute a family of growth factors initially characterized as predominant mediators of nervous system development, neuronal survival, regeneration and plasticity. Their biological activity is promoted by the binding of two different types of receptors, leading to the generation of multiple and variegated [...] Read more.
Neurotrophins constitute a family of growth factors initially characterized as predominant mediators of nervous system development, neuronal survival, regeneration and plasticity. Their biological activity is promoted by the binding of two different types of receptors, leading to the generation of multiple and variegated signaling cascades in the target cells. Increasing evidence indicates that neurotrophins are also emerging as crucial regulators of metabolic processes in both neuronal and non-neuronal cells. In this context, it has been reported that neurotrophins affect redox balance, autophagy, glucose homeostasis and energy expenditure. Additionally, the trophic support provided by these secreted factors may involve the regulation of cholesterol metabolism. In this review, we examine the neurotrophins’ signaling pathways and their effects on metabolism by critically discussing the most up-to-date information. In particular, we gather experimental evidence demonstrating the impact of these growth factors on cholesterol metabolism. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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11 pages, 1334 KiB  
Review
Motility Plays an Important Role in the Lifetime of Mammalian Lipid Droplets
by Yi Jin, Zhuqing Ren, Yanjie Tan, Pengxiang Zhao and Jian Wu
Int. J. Mol. Sci. 2021, 22(8), 3802; https://doi.org/10.3390/ijms22083802 - 07 Apr 2021
Cited by 8 | Viewed by 3152
Abstract
The lipid droplet is a kind of organelle that stores neutral lipids in cells. Recent studies have found that in addition to energy storage, lipid droplets also play an important role in biological processes such as resistance to stress, immunity, cell proliferation, apoptosis, [...] Read more.
The lipid droplet is a kind of organelle that stores neutral lipids in cells. Recent studies have found that in addition to energy storage, lipid droplets also play an important role in biological processes such as resistance to stress, immunity, cell proliferation, apoptosis, and signal transduction. Lipid droplets are formed at the endoplasmic reticulum, and mature lipid droplets participate in various cellular processes. Lipid droplets are decomposed by lipase and lysosomes. In the life of a lipid droplet, the most important thing is to interact with other organelles, including the endoplasmic reticulum, mitochondria, peroxisomes, and autophagic lysosomes. The interaction between lipid droplets and other organelles requires them to be close to each other, which inevitably involves the motility of lipid droplets. In fact, through many microscopic observation techniques, researchers have discovered that lipid droplets are highly dynamic organelles that move quickly. This paper reviews the process of lipid droplet motility, focusing on explaining the molecular basis of lipid droplet motility, the factors that regulate lipid droplet motility, and the influence of motility on the formation and decomposition of lipid droplets. In addition, this paper also proposes several unresolved problems for lipid droplet motility. Finally, this paper makes predictions about the future research of lipid droplet motility. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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20 pages, 1866 KiB  
Review
Oxidative Stress and Lipid Mediators Modulate Immune Cell Functions in Autoimmune Diseases
by Piotr Wójcik, Agnieszka Gęgotek, Neven Žarković and Elżbieta Skrzydlewska
Int. J. Mol. Sci. 2021, 22(2), 723; https://doi.org/10.3390/ijms22020723 - 13 Jan 2021
Cited by 52 | Viewed by 6105
Abstract
Autoimmune diseases, including psoriasis, systemic lupus erythematosus (SLE), and rheumatic arthritis (RA), are caused by a combination of environmental and genetic factors that lead to overactivation of immune cells and chronic inflammation. Since oxidative stress is a common feature of these diseases, which [...] Read more.
Autoimmune diseases, including psoriasis, systemic lupus erythematosus (SLE), and rheumatic arthritis (RA), are caused by a combination of environmental and genetic factors that lead to overactivation of immune cells and chronic inflammation. Since oxidative stress is a common feature of these diseases, which activates leukocytes to intensify inflammation, antioxidants could reduce the severity of these diseases. In addition to activating leukocytes, oxidative stress increases the production of lipid mediators, notably of endocannabinoids and eicosanoids, which are products of enzymatic lipid metabolism that act through specific receptors. Because the anti-inflammatory CB2 receptors are the predominant cannabinoid receptors in leukocytes, endocannabinoids are believed to act as anti-inflammatory factors that regulate compensatory mechanisms in autoimmune diseases. While administration of eicosanoids in vitro leads to the differentiation of lymphocytes into T helper 2 (Th2) cells, eicosanoids are also necessary for the different0iation of Th1 and Th17 cells. Therefore, their antagonists and/or the genetic deletion of their receptors abolish inflammation in animal models of psoriasis—RA and SLE. On the other hand, products of non-enzymatic lipid peroxidation, especially acrolein and 4-hydroxynonenal-protein adducts, mostly generated by an oxidative burst of granulocytes, may enhance inflammation and even acting as autoantigens and extracellular signaling molecules in the vicious circle of autoimmune diseases. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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Graphical abstract

27 pages, 1254 KiB  
Review
The Lipid Paradox as a Metabolic Checkpoint and Its Therapeutic Significance in Ameliorating the Associated Cardiovascular Risks in Rheumatoid Arthritis Patients
by Tapan Behl, Ishnoor Kaur, Aayush Sehgal, Gokhan Zengin, Ciprian Brisc, Mihaela Cristina Brisc, Mihai Alexandru Munteanu, Delia Carmen Nistor-Cseppento and Simona Bungau
Int. J. Mol. Sci. 2020, 21(24), 9505; https://doi.org/10.3390/ijms21249505 - 14 Dec 2020
Cited by 28 | Viewed by 5172
Abstract
While the most common manifestations associated with rheumatoid arthritis (RA) are synovial damage and inflammation, the systemic effects of this autoimmune disorder are life-threatening, and are prevalent in 0.5–1% of the population, mainly associated with cardiovascular disorders (CVDs). Such effects have been instigated [...] Read more.
While the most common manifestations associated with rheumatoid arthritis (RA) are synovial damage and inflammation, the systemic effects of this autoimmune disorder are life-threatening, and are prevalent in 0.5–1% of the population, mainly associated with cardiovascular disorders (CVDs). Such effects have been instigated by an altered lipid profile in RA patients, which has been reported to correlate with CV risks. Altered lipid paradox is related to inflammatory burden in RA patients. The review highlights general lipid pathways (exogenous and endogenous), along with the changes in different forms of lipids and lipoproteins in RA conditions, which further contribute to elevated risks of CVDs like ischemic heart disease, atherosclerosis, myocardial infarction etc. The authors provide a deep insight on altered levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) in RA patients and their consequence on the cardiovascular health of the patient. This is followed by a detailed description of the impact of anti-rheumatoid therapy on the lipid profile in RA patients, comprising DMARDs, corticosteroids, anti-TNF agents, anti-IL-6 agents, JAK inhibitors and statins. Furthermore, this review elaborates on the prospects to be considered to optimize future investigation on management of RA and treatment therapies targeting altered lipid paradigms in patients. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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20 pages, 2715 KiB  
Review
The Role of Metabolic Factors in Renal Cancers
by Jacek Rysz, Beata Franczyk, Janusz Ławiński, Robert Olszewski and Anna Gluba-Brzózka
Int. J. Mol. Sci. 2020, 21(19), 7246; https://doi.org/10.3390/ijms21197246 - 30 Sep 2020
Cited by 14 | Viewed by 2598
Abstract
An increasing number of evidence indicates that metabolic factors may play an important role in the development and progression of certain types of cancers, including renal cell carcinoma (RCC). This tumour is the most common kidney cancer which accounts for approximately 3–5% of [...] Read more.
An increasing number of evidence indicates that metabolic factors may play an important role in the development and progression of certain types of cancers, including renal cell carcinoma (RCC). This tumour is the most common kidney cancer which accounts for approximately 3–5% of malignant tumours in adults. Numerous studies indicated that concomitant diseases, including diabetes mellitus (DM) and hypertension, as well as obesity, insulin resistance, and lipid disorders, may also influence the prognosis and cancer-specific overall survival. However, the results of studies concerning the impact of metabolic factors on RCC are controversial. It appears that obesity increases the risk of RCC development; however, it may be a favourable factor in terms of prognosis. Obesity is closely related to insulin resistance and the development of diabetes mellitus type 2 (DM2T) since the adipocytes in visceral tissue secrete substances responsible for insulin resistance, e.g., free fatty acids. Interactions between insulin and insulin-like growth factor (IGF) system appear to be of key importance in the development and progression of RCC; however, the exact role of insulin and IGFs in RCC pathophysiology remains elusive. Studies indicated that diabetes increased the risk of RCC, but it might not alter cancer-related survival. The risk associated with a lipid profile is most mysterious, as numerous studies provided conflicting results. Even though large studies unravelling pathomechanisms involved in cancer growth are required to finally establish the impact of metabolic factors on the development, progression, and prognosis of renal cancers, it seems that the monitoring of health conditions, such as diabetes, low body mass index (BMI), and lipid disorders is of high importance in clear-cell RCC. Full article
(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 2nd Edition)
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