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Emerging Role of Lipids in Metabolism and Disease – 3rd Edition

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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 (31 July 2022) | Viewed by 35636

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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

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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
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Dr. Antimo Cutone

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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,

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, attracted the interest of several researchers because of its involvement in human health. Lipid disorders are at the root of several diseases characterized by altered lipid metabolism in different tissues. Metabolic syndrome and cardiovascular disease, for instance, are closely related to these metabolic dysfunctions. Moreover, connections with misbalances of cholesterol homeostasis in neurodegenerative and neurodevelopmental disorders have also been demonstrated. Thus, the aim of this Special Issue is to gather 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

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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

Published Papers (14 papers)

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Editorial

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4 pages, 205 KiB

Open AccessEditorial

Fat Checking: Emerging Role of Lipids in Metabolism and Disease

by Marco Segatto, Antimo Cutone and Valentina Pallottini

Int. J. Mol. Sci. 2022, 23(22), 13842; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232213842 - 10 Nov 2022

Cited by 1 | Viewed by 931

Abstract

Lipids are hydrophobic molecules involved in a plethora of biological functions; for example, they are employed for the storage of energy, serve as essential constituents of cell membranes and participate in the assembly of bilayer configuration [...] Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 3rd Edition)

Research

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13 pages, 7833 KiB

Open AccessCommunication

Mechanism Underlying Naringenin Hypocholesterolemic Effects: Involvement of Estrogen Receptor α Subtype

by Valentina Pallottini, Marco Segatto, Filippo Acconcia, Marco Fiocchetti and Maria Marino

Int. J. Mol. Sci. 2022, 23(24), 15809; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415809 - 13 Dec 2022

Cited by 1 | Viewed by 1033

Abstract

Naringenin (Nar) is one of major citrus flavonoids predominantly found in grapefruit and orange. In vivo studies have demonstrated Nar potential as a normolipidemic agent capable to reduce circulating cholesterol in hypercholesterolemic rabbits, rats, and patients, suggesting a new role for this molecule in cardiovascular disease prevention. Although Nar cholesterol-lowering effects are known, the underlying mechanisms have not yet been elucidated. Interestingly, Nar binds to the estrogen receptors (ERs), modulating both transcriptional and membrane-initiating signals. Although estrogen and ERs are deeply involved in lipid metabolism, no data are available regarding a putative role of these nuclear receptors as mediators of the hypocholesterolemic effect exerted by Nar. Thus, the aim of this work was to study the involvement of ERs in Nar-induced modulation of cholesterol metabolism. Results obtained in HepG2 cell line demonstrate that Nar can modulate the molecular network of cholesterol homeostasis. However, these effects were only partially dependent on the activity of estrogen receptor α. As a whole, our data highlight new molecular mechanisms by which Nar influences cholesterol metabolism, opening a new scenery about dietary impact on human health. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 3rd Edition)

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15 pages, 2024 KiB

Open AccessArticle

Diversified Effects of COVID-19 as a Consequence of the Differential Metabolism of Phospholipids and Lipid Peroxidation Evaluated in the Plasma of Survivors and Deceased Patients upon Admission to the Hospital

by Neven Žarković, Wojciech Łuczaj, Iwona Jarocka-Karpowicz, Biserka Orehovec, Bruno Baršić, Marko Tarle, Marta Kmet, Ivica Lukšić, Michał Biernacki and Elżbieta Skrzydlewska

Int. J. Mol. Sci. 2022, 23(19), 11810; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911810 - 05 Oct 2022

Cited by 5 | Viewed by 1680

Abstract

As a result of SARS-CoV-2 infection, inflammation develops, which promotes oxidative stress, leading to modification of phospholipid metabolism. Therefore, the aim of this study is to compare the effects of COVID-19 on the levels of phospholipid and free polyunsaturated fatty acids (PUFAs) and their metabolites produced in response to reactions with reactive oxygen species (ROS) and enzymes (cyclooxygenases-(COXs) and lipoxygenase-(LOX)) in the plasma of patients who either recovered or passed away within a week of hospitalization. In the plasma of COVID-19 patients, especially of the survivors, the actions of ROS and phospholipase A2 (PLA2) cause a decrease in phospholipid fatty acids level and an increase in free fatty acids (especially arachidonic acid) despite increased COXs and LOX activity. This is accompanied by an increased level in lipid peroxidation products (malondialdehyde and 8-isoprostaglandin F2α) and lipid mediators generated by enzymes. There is also an increase in eicosanoids, both pro-inflammatory as follows: thromboxane B2 and prostaglandin E2, and anti-inflammatory as follows: 15-deoxy-Δ-12,14-prostaglandin J2 and 12-hydroxyeicosatetraenoic acid, as well as endocannabinoids (anandamide-(AEA) and 2-arachidonylglycerol-(2-AG)) observed in the plasma of patients who recovered. Moreover, the expression of tumor necrosis factor α and interleukins (IL-6 and IL-10) is increased in patients who recovered. However, in the group of patients who died, elevated levels of N-oleoylethanolamine and N-palmitoylethanolamine are found. Since lipid mediators may have different functions depending on the onset of pathophysiological processes, a stronger pro-inflammatory response in patients who have recovered may be the result of the defensive response to SARS-CoV-2 in survivors associated with specific changes in the phospholipid metabolism, which could also be considered a prognostic factor. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 3rd Edition)

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18 pages, 3580 KiB

Open AccessArticle

PLA2G2A Phospholipase Promotes Fatty Acid Synthesis and Energy Metabolism in Pancreatic Cancer Cells with K-ras Mutation

by Mingquan Zhang, Rong Xiang, Christophe Glorieux and Peng Huang

Int. J. Mol. Sci. 2022, 23(19), 11721; https://doi.org/10.3390/ijms231911721 - 03 Oct 2022

Cited by 9 | Viewed by 2193

Abstract

Oncogenic K-ras is often activated in pancreatic ductal adenocarcinoma (PDAC) due to frequent mutation (>90%), which drives multiple cellular processes, including alterations in lipid metabolism associated with a malignant phenotype. However, the role and mechanism of the altered lipid metabolism in K-ras-driven cancer remains poorly understood. In this study, using human pancreatic epithelial cells harboring inducible K-ras^G12D (HPNE/K-ras^G12D) and pancreatic cancer cell lines, we found that the expression of phospholipase A2 group IIA (PLA2G2A) was upregulated by oncogenic K-ras. The elevated expression of PLA2G2A was also observed in pancreatic cancer tissues and was correlated with poor survival of PDAC patients. Abrogation of PLA2G2A by siRNA or by pharmacological inhibition using tanshinone I significantly increased lipid peroxidation, reduced fatty acid synthase (FASN) expression, and impaired mitochondrial function manifested by a decrease in mitochondrial transmembrane potential and a reduction in ATP production, leading to the inhibition of cancer cell proliferation. Our study suggests that high expression of PLA2G2A induced by oncogenic K-ras promotes cancer cell survival, likely by reducing lipid peroxidation through its ability to facilitate the removal of polyunsaturated fatty acids from lipid membranes by enhancing the de novo fatty acid synthesis and energy metabolism to support cancer cell proliferation. As such, PLA2G2A might function as a downstream mediator of K-ras and could be a potential therapeutic target. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 3rd Edition)

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11 pages, 789 KiB

Open AccessArticle

Alteration of Fatty Acid Profile in Fragile X Syndrome

by Armita Abolghasemi, Maria Paulina Carullo, Ester Cisneros Aguilera, Asma Laroui, Rosalie Plantefeve, Daniela Rojas, Serine Benachenhou, María Victoria Ramírez, Mélodie Proteau-Lemieux, Jean-François Lepage, François Corbin, Mélanie Plourde, Mauricio Farez, Patricia Cogram and Artuela Çaku

Int. J. Mol. Sci. 2022, 23(18), 10815; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810815 - 16 Sep 2022

Cited by 3 | Viewed by 1572

Abstract

Fragile X Syndrome (FXS) is the most prevalent monogenic cause of Autism Spectrum Disorders (ASDs). Despite a common genetic etiology, the affected individuals display heterogenous metabolic abnormalities including hypocholesterolemia. Although changes in the metabolism of fatty acids (FAs) have been reported in various neuropsychiatric disorders, it has not been explored in humans with FXS. In this study, we investigated the FA profiles of two different groups: (1) an Argentinian group, including FXS individuals and age- and sex-matched controls, and (2) a French-Canadian group, including FXS individuals and their age- and sex-matched controls. Since phospholipid FAs are an indicator of medium-term diet and endogenous metabolism, we quantified the FA profile in plasma phospholipids using gas chromatography. Our results showed significantly lower levels in various plasma FAs including saturated, monosaturated, ω-6 polyunsaturated, and ω-3 polyunsaturated FAs in FXS individuals compared to the controls. A decrease in the EPA/ALA (eicosapentaenoic acid/alpha linoleic acid) ratio and an increase in the DPA/EPA (docosapentaenoic acid/eicosapentaenoic acid) ratio suggest an alteration associated with desaturase and elongase activity, respectively. We conclude that FXS individuals present an abnormal profile of FAs, specifically FAs belonging to the ω-3 family, that might open new avenues of treatment to improve core symptoms of the disorder. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 3rd Edition)

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20 pages, 17552 KiB

Open AccessArticle

TIAM2 Contributes to Osimertinib Resistance, Cell Motility, and Tumor-Associated Macrophage M2-like Polarization in Lung Adenocarcinoma

by Lu Liang, Hua He, Shiyao Jiang, Yueying Liu, Jingjing Huang, Xiaoyan Sun, Yi Li, Yiqun Jiang and Li Cong

Int. J. Mol. Sci. 2022, 23(18), 10415; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810415 - 08 Sep 2022

Cited by 12 | Viewed by 3215

Abstract

Background: Osimertinib-based therapy effectively improves the prognosis of lung adenocarcinoma (LUAD) patients with epidermal growth factor receptor mutations. However, patients will have cancer progression after approximately one year due to the occurrence of drug resistance. Extensive evidence has revealed that lipid metabolism and tumor-associated macrophage (TAM) are associated with drug resistance, which deserves further exploration. Methods: An osimertinib resistance index (ORi) was built to investigate the link between lipid metabolism and osimertinib resistance. The ORi was constructed and validated using TCGA and GEO data, and the relationship between ORi and immune infiltration was discussed. Weighted gene co-expression network analysis based on the M2/M1 macrophage ratio determined the hub gene TIAM2 and the biological function of TIAM2 in LUAD was verified in vitro. Results: ORi based on nine lipid metabolism-related genes was successfully constructed, which could accurately reflect the resistance of LUAD patients to osimertinib, predict the prognosis, and correlate with M2-like TAM. Additionally, TIAM2 was found to increase osimertinib tolerance, enhance cell motility, and promote M2-like TAM polarization in LUAD. Conclusions: The lipid metabolism gene is strongly connected with osimertinib resistance. TIAM2 contributes to osimertinib resistance, enhances cell motility, and induces M2-like TAM polarization in LUAD. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 3rd Edition)

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14 pages, 1398 KiB

Open AccessArticle

Brain Cholesterol Biosynthetic Pathway Is Altered in a Preclinical Model of Fragile X Syndrome

by Martina Parente, Claudia Tonini, Valeria Buzzelli, Emilia Carbone, Viviana Trezza and Valentina Pallottini

Int. J. Mol. Sci. 2022, 23(6), 3408; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063408 - 21 Mar 2022

Cited by 7 | Viewed by 2413

Abstract

Fragile X Syndrome (FXS) is the most frequent form of inherited X-linked pathology, associated with an intellectual and developmental disability, and currently considered the first monogenic cause of autism spectrum disorder (ASD). Low levels of total cholesterol reported in the serum of FXS patients, and evidence that FMRP targets a subset of mRNAs encoding proteins of lipid synthesis and transport suggests that the cholesterol metabolism impairments could be involved in FXS. Thus, the aim of the presented work was to investigate the modulations of the cholesterol biosynthetic pathway and its end-products in a recently developed Fmr1-Δexon 8 rat model of FXS. Here, we show that this experimental model mimics what is found in FXS patients, exhibiting a lower serum cholesterol content, accompanied by a reduction in food intake and body weight compared to WT animals. Moreover, alterations of proteins committed to cholesterol synthesis and uptake have been observed in the amygdala, prefrontal cortex and nucleus accumbens. Interestingly, the end-products show a brain region-dependent modulation in Fmr1-Δexon 8 rats. Overall, our results demonstrate that the cholesterol biosynthetic pathway is altered in some brain regions of this preclinical model of FXS. This finding has relevance for future studies to delve deeper into the involvement of this metabolic process in FXS, and thus its possible role as a therapeutic target. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 3rd Edition)

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Review

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27 pages, 1172 KiB

Open AccessReview

Emerging Roles of Endocannabinoids as Key Lipid Mediators for a Successful Pregnancy

by Alessandro Rava and Viviana Trezza

Int. J. Mol. Sci. 2023, 24(6), 5220; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065220 - 09 Mar 2023

Cited by 3 | Viewed by 2268

Abstract

In recent years, Cannabis use/misuse for treating pregnancy-related symptoms and other chronic conditions has increased among pregnant women, favored by decriminalization and/or legalization of its recreational uses in addition to its easy accessibility. However, there is evidence that prenatal Cannabis exposure might have adverse consequences on pregnancy progression and a deleterious impact on proper neurodevelopmental trajectories in the offspring. Maternal Cannabis use could interfere with the complex and finely controlled role performed by the endocannabinoid system in reproductive physiology, impairing multiple gestational processes from blastocyst implantation to parturition, with long-lasting intergenerational effects. In this review, we discuss current clinical and preclinical evidence regarding the role of endocannabinoids in development, function, and immunity of the maternal–fetal interface, focusing on the impact of Cannabis constituents on each of these gestational processes. We also discuss the intrinsic limitations of the available studies and the future perspectives in this challenging research field. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 3rd Edition)

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18 pages, 1820 KiB

Open AccessReview

Impact of ROS-Dependent Lipid Metabolism on Psoriasis Pathophysiology

by Adam Wroński and Piotr Wójcik

Int. J. Mol. Sci. 2022, 23(20), 12137; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012137 - 12 Oct 2022

Cited by 10 | Viewed by 2618

Abstract

Psoriasis is the most common autoimmune disease, yet its pathophysiology is not fully understood. It is now believed that psoriasis is caused by the increased activation of immune cells, especially Th1 lymphocytes. However, in psoriasis, immune cells interfere with the metabolism of keratinocytes, leading to their increased activation. Therefore, the pathophysiology of psoriasis is currently associated with the overproduction of ROS, which are involved in the activation of immune cells and keratinocytes as well as the modulation of various signaling pathways within them. Nevertheless, ROS modulate the immune system by also boosting the increasing generation of various lipid mediators, such as products of lipid peroxidation as well as endocannabinoids and prostaglandins. In psoriasis, the excessive generation of ROS and lipid mediators is observed in different immune cells, such as granulocytes, dendritic cells, and lymphocytes. All of the above may be activated by ROS and lipid mediators, which leads to inflammation. Nevertheless, ROS and lipid mediators regulate lymphocyte differentiation in favor of Th1 and may also interact directly with keratinocytes, which is also observed in psoriasis. Thus, the analysis of the influence of oxidative stress and its consequences for metabolic changes, including lipidomic ones, in psoriasis may be of diagnostic and therapeutic importance. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 3rd Edition)

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23 pages, 1935 KiB

Open AccessReview

High-Density Lipoproteins: A Role in Inflammation in COPD

by Stanislav Kotlyarov

Int. J. Mol. Sci. 2022, 23(15), 8128; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158128 - 23 Jul 2022

Cited by 8 | Viewed by 2455

Abstract

Chronic obstructive pulmonary disease (COPD) is a widespread disease associated with high rates of disability and mortality. COPD is characterized by chronic inflammation in the bronchi as well as systemic inflammation, which contributes significantly to the clinically heterogeneous course of the disease. Lipid metabolism disorders are common in COPD, being a part of its pathogenesis. High-density lipoproteins (HDLs) are not only involved in lipid metabolism, but are also part of the organism’s immune and antioxidant defense. In addition, HDL is a versatile transport system for endogenous regulatory agents and is also involved in the removal of exogenous substances such as lipopolysaccharide. These functions, as well as information about lipoprotein metabolism disorders in COPD, allow a broader assessment of their role in the pathogenesis of heterogeneous and comorbid course of the disease. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 3rd Edition)

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17 pages, 1667 KiB

Open AccessReview

Serine Hydrolases in Lipid Homeostasis of the Placenta-Targets for Placental Function?

by Natascha Berger, Hanna Allerkamp and Christian Wadsack

Int. J. Mol. Sci. 2022, 23(12), 6851; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126851 - 20 Jun 2022

Cited by 3 | Viewed by 2584

Abstract

The metabolic state of pregnant women and their unborn children changes throughout pregnancy and adapts to the specific needs of each gestational week. These adaptions are accomplished by the actions of enzymes, which regulate the occurrence of their endogenous substrates and products in all three compartments: mother, placenta and the unborn. These enzymes determine bioactive lipid signaling, supply, and storage through the generation or degradation of lipids and fatty acids, respectively. This review focuses on the role of lipid-metabolizing serine hydrolases during normal pregnancy and in pregnancy-associated pathologies, such as preeclampsia, gestational diabetes mellitus, or preterm birth. The biochemical properties of each class of lipid hydrolases are presented, with special emphasis on their role in placental function or dysfunction. While, during a normal pregnancy, an appropriate tonus of bioactive lipids prevails, dysregulation and aberrant signaling occur in diseased states. A better understanding of the dynamics of serine hydrolases across gestation and their involvement in placental lipid homeostasis under physiological and pathophysiological conditions will help to identify new targets for placental function in the future. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 3rd Edition)

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27 pages, 3133 KiB

Open AccessReview

Emerging Role of Phospholipids and Lysophospholipids for Improving Brain Docosahexaenoic Acid as Potential Preventive and Therapeutic Strategies for Neurological Diseases

by Mayssa Hachem and Houda Nacir

Int. J. Mol. Sci. 2022, 23(7), 3969; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073969 - 02 Apr 2022

Cited by 19 | Viewed by 5080

Abstract

Docosahexaenoic acid (DHA, 22:6n-3) is an omega-3 polyunsaturated fatty acid (PUFA) essential for neural development, learning, and vision. Although DHA can be provided to humans through nutrition and synthesized in vivo from its precursor alpha-linolenic acid (ALA, 18:3n-3), deficiencies in cerebral DHA level were associated with neurodegenerative diseases including Parkinson’s and Alzheimer’s diseases. The aim of this review was to develop a complete understanding of previous and current approaches and suggest future approaches to target the brain with DHA in different lipids’ forms for potential prevention and treatment of neurodegenerative diseases. Since glycerophospholipids (GPs) play a crucial role in DHA transport to the brain, we explored their biosynthesis and remodeling pathways with a focus on cerebral PUFA remodeling. Following this, we discussed the brain content and biological properties of phospholipids (PLs) and Lyso-PLs with omega-3 PUFA focusing on DHA’s beneficial effects in healthy conditions and brain disorders. We emphasized the cerebral accretion of DHA when esterified at sn-2 position of PLs and Lyso-PLs. Finally, we highlighted the importance of DHA-rich Lyso-PLs’ development for pharmaceutical applications since most commercially available DHA formulations are in the form of PLs or triglycerides, which are not the preferred transporter of DHA to the brain. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 3rd Edition)

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16 pages, 649 KiB

Open AccessReview

Adaptation of Lipid Profiling in Depression Disease and Treatment: A Critical Review

by Bruno Pinto, Tiago Conde, Inês Domingues and M. Rosário Domingues

Int. J. Mol. Sci. 2022, 23(4), 2032; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042032 - 12 Feb 2022

Cited by 13 | Viewed by 3318

Abstract

Major depressive disorder (MDD), also called depression, is a serious disease that impairs the quality of life of patients and has a high incidence, affecting approximately 3.8% of the world population. Its diagnosis is very subjective and is not supported by measurable biomarkers mainly due to the lack of biochemical markers. Recently, disturbance of lipid profiling has been recognized in MDD, in animal models of MDD or in depressed patients, which may contribute to unravel the etiology of the disease and find putative new biomarkers, for a diagnosis or for monitoring the disease and therapeutics outcomes. In this review, we provide an overview of current knowledge of lipidomics analysis, both in animal models of MDD (at the brain and plasma level) and in humans (in plasma and serum). Furthermore, studies of lipidomics analyses after antidepressant treatment in rodents (in brain, plasma, and serum), in primates (in the brain) and in humans (in plasma) were reviewed and give evidence that antidepressants seem to counteract the modification seen in lipids in MDD, giving some evidence that certain altered lipid profiles could be useful MDD biomarkers for future precision medicine. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 3rd Edition)

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26 pages, 2084 KiB

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Emerging Insights on the Diverse Roles of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Chronic Liver Diseases: Cholesterol Metabolism and Beyond

by Thomas Grewal and Christa Buechler

Int. J. Mol. Sci. 2022, 23(3), 1070; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031070 - 19 Jan 2022

Cited by 6 | Viewed by 2833

Abstract

Chronic liver diseases are commonly associated with dysregulated cholesterol metabolism. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease of the proprotein convertase family that is mainly synthetized and secreted by the liver, and represents one of the key regulators of circulating low-density lipoprotein (LDL) cholesterol levels. Its ability to bind and induce LDL-receptor degradation, in particular in the liver, increases circulating LDL-cholesterol levels in the blood. Hence, inhibition of PCSK9 has become a very potent tool for the treatment of hypercholesterolemia. Besides PCSK9 limiting entry of LDL-derived cholesterol, affecting multiple cholesterol-related functions in cells, more recent studies have associated PCSK9 with various other cellular processes, including inflammation, fatty acid metabolism, cancerogenesis and visceral adiposity. It is increasingly becoming evident that additional roles for PCSK9 beyond cholesterol homeostasis are crucial for liver physiology in health and disease, often contributing to pathophysiology. This review will summarize studies analyzing circulating and hepatic PCSK9 levels in patients with chronic liver diseases. The factors affecting PCSK9 levels in the circulation and in hepatocytes, clinically relevant studies and the pathophysiological role of PCSK9 in chronic liver injury are discussed. Full article

(This article belongs to the Special Issue Emerging Role of Lipids in Metabolism and Disease – 3rd Edition)

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