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Åström H, Takami Lageborn C, Hagström H. Psychosocial risks in metabolic dysfunction-associated steatotic liver disease. Expert Rev Gastroenterol Hepatol 2025:1-18. [PMID: 39953908 DOI: 10.1080/17474124.2025.2468297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/03/2025] [Accepted: 02/13/2025] [Indexed: 02/17/2025]
Abstract
INTRODUCTION Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly becoming more prevalent in the general population. MASLD is more common in persons with low socioeconomic status (SES), yet little is known about the psychosocial challenges associated with this disease, and clinical recommendations on how to approach psychosocial challenges are lacking. AREAS COVERED A PubMed search using the search terms MASLD, psychosocial risks, stigmatization, psychiatric comorbidities (i.e. depression, bipolar disorder, psychosis, attention deficit hyperactivity disorder, and substance abuse), SES, quality of life (QoL), over the past 20 years (2004-2024) was performed. EXPERT OPINION Persons with MASLD often experience psychosocial adversities that may be expressed as lower SES, high prevalence of depression, and reduced QoL. Knowledge gaps remain regarding the association between severe mental disorders (e.g. psychosis and bipolar disorders). Timely detection and treatment of MASLD in persons with psychosocial risks may require attention and cross-field collaboration. Studies on QoL in persons with MASLD differ in methodology which makes formal comparisons difficult. Psychosocial adversity may be a barrier to lifestyle modifications, which remain the cornerstone of MASLD management. Guidelines on how to address psychosocial adversities in a clinical setting are warranted to improve outcomes and decrease further multimorbidity.
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Affiliation(s)
- Hanne Åström
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | | | - Hannes Hagström
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
- Division of Hepatology, Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden
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2
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Park WJ, Oh E, Kim Y. Protaetia brevitarsis larvae extract protects against lipopolysaccharides-induced ferroptosis and inflammation by inhibiting acid sphingomyelinase. Nutr Res Pract 2024; 18:602-616. [PMID: 39398879 PMCID: PMC11464277 DOI: 10.4162/nrp.2024.18.5.602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/02/2024] [Accepted: 05/31/2024] [Indexed: 10/15/2024] Open
Abstract
BACKGROUND/OBJECTIVES Inflammation and ferroptosis are implicated in various diseases and lipopolysaccharides (LPS) have been linked with these disorders. Recently, many edible insects, such as Gryllus bimaculatus, Protaetia brevitarsis larvae (PB) and Tenebrio molitor larvae, have been recommended as alternative foods because they contain lots of nutritional sources. In this study, we explored the potential of PB extract in preventing LPS-induced inflammation and ferroptosis in Hep3B cells. MATERIALS/METHODS PB powder was extracted using 70% ethanol and applied to Hep3B cells. Co-treatment with LPS was conducted to induce ferroptosis and inflammation. The anti-inflammatory and anti-ferroptosis mechanisms of the PB extract were confirmed using Western blot, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction analysis. RESULTS PB extract effectively prevented LPS-induced cell death and restored LPS-induced inflammatory cytokine production, NF-κB signaling, endoplasmic reticulum (ER) stress and ferroptosis. Interestingly, PB extract reduced LPS-induced ceramide increase and acid sphingomyelinase (ASMase) expression. The use of the ASMase inhibitor, desipramine, also demonstrated a reduction in these pathways, highlighting the pivotal role of ASMase in inflammation and ferroptosis. Treatment with each inhibitor revealed that ferroptosis causes ER stress and that NF-κB and MAP kinase pathways are involved in inflammation. CONCLUSION PB emerges as a potential functional food with inhibitory effects on LPS-induced inflammation and ferroptosis, making it a promising candidate for nutritional interventions.
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Affiliation(s)
- Woo-Jae Park
- Department of Biochemistry, Chung-Ang University College of Medicine, Seoul 06974, Korea
| | - Eunyoung Oh
- Interdisciplinary Program in Sustainable Living System, Graduate School, Korea University, Seoul 02841, Korea
- Department of Human Ecology, Graduate School, Korea University, Seoul 02841, Korea
| | - Yookyung Kim
- Department of Human Ecology, Graduate School, Korea University, Seoul 02841, Korea
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3
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Ruiz-Blázquez P, Fernández-Fernández M, Pistorio V, Martinez-Sanchez C, Costanzo M, Iruzubieta P, Zhuravleva E, Cacho-Pujol J, Ariño S, Del Castillo-Cruz A, Núñez S, Andersen JB, Ruoppolo M, Crespo J, García-Ruiz C, Pavone LM, Reinheckel T, Sancho-Bru P, Coll M, Fernández-Checa JC, Moles A. Cathepsin D is essential for the degradomic shift of macrophages required to resolve liver fibrosis. Mol Metab 2024; 87:101989. [PMID: 39019115 PMCID: PMC11327474 DOI: 10.1016/j.molmet.2024.101989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 07/03/2024] [Accepted: 07/08/2024] [Indexed: 07/19/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Fibrosis contributes to 45% of deaths in industrialized nations and is characterized by an abnormal accumulation of extracellular matrix (ECM). There are no specific anti-fibrotic treatments for liver fibrosis, and previous unsuccessful attempts at drug development have focused on preventing ECM deposition. Because liver fibrosis is largely acknowledged to be reversible, regulating fibrosis resolution could offer novel therapeutical options. However, little is known about the mechanisms controlling ECM remodeling during resolution. Changes in proteolytic activity are essential for ECM homeostasis and macrophages are an important source of proteases. Herein, in this study we evaluate the role of macrophage-derived cathepsin D (CtsD) during liver fibrosis. METHODS CtsD expression and associated pathways were characterized in single-cell RNA sequencing and transcriptomic datasets in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD and hepatocyte-CtsD knock-out mice. RESULTS Analysis of single-cell RNA sequencing datasets demonstrated CtsD was expressed in macrophages and hepatocytes in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD (CtsDΔMyel) and hepatocyte-CtsD knock-out mice. CtsD deletion in macrophages, but not in hepatocytes, resulted in enhanced liver fibrosis. Both inflammatory and matrisome proteomic signatures were enriched in fibrotic CtsDΔMyel livers. Besides, CtsDΔMyel liver macrophages displayed functional, phenotypical and secretomic changes, which resulted in a degradomic phenotypical shift, responsible for the defective proteolytic processing of collagen I in vitro and impaired collagen remodeling during fibrosis resolution in vivo. Finally, CtsD-expressing mononuclear phagocytes of cirrhotic human livers were enriched in lysosomal and ECM degradative signaling pathways. CONCLUSIONS Our work describes for the first-time CtsD-driven lysosomal activity as a central hub for restorative macrophage function during fibrosis resolution and opens new avenues to explore their degradome landscape to inform drug development.
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Affiliation(s)
- Paloma Ruiz-Blázquez
- Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain; CiberEHD, Spain; University of Barcelona, Barcelona, Spain; IDIBAPS, Barcelona, Spain
| | - María Fernández-Fernández
- Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain; CiberEHD, Spain; University of Barcelona, Barcelona, Spain; IDIBAPS, Barcelona, Spain
| | - Valeria Pistorio
- Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy; Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Paris, France
| | | | - Michele Costanzo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy; CEINGE-Biotecnologie Avanzate Franco Salvatore s.c.ar.l., Naples, Italy
| | - Paula Iruzubieta
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Ekaterina Zhuravleva
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; LEO Foundation Skin Immunology Research Center (SIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Júlia Cacho-Pujol
- Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain; University of Barcelona, Barcelona, Spain; IDIBAPS, Barcelona, Spain
| | - Silvia Ariño
- CiberEHD, Spain; University of Barcelona, Barcelona, Spain; IDIBAPS, Barcelona, Spain
| | | | | | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Margherita Ruoppolo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy; CEINGE-Biotecnologie Avanzate Franco Salvatore s.c.ar.l., Naples, Italy
| | - Javier Crespo
- Department of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Carmen García-Ruiz
- Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain; CiberEHD, Spain; IDIBAPS, Barcelona, Spain; USC Research Center for ALPD, Los Angeles, United States; Associated Unit IIBB-IMIM, Barcelona, Spain
| | - Luigi Michele Pavone
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Thomas Reinheckel
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany; German Cancer Consortium (DKTK), DKFZ Partner Site Freiburg, Germany; Center for Biological Signaling Studies BIOSS, University of Freiburg, Germany
| | - Pau Sancho-Bru
- CiberEHD, Spain; University of Barcelona, Barcelona, Spain; IDIBAPS, Barcelona, Spain
| | - Mar Coll
- CiberEHD, Spain; University of Barcelona, Barcelona, Spain; IDIBAPS, Barcelona, Spain; Medicine Department, Faculty of Medicine, University of Barcelona, Spain
| | - José C Fernández-Checa
- Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain; CiberEHD, Spain; IDIBAPS, Barcelona, Spain; USC Research Center for ALPD, Los Angeles, United States; Associated Unit IIBB-IMIM, Barcelona, Spain
| | - Anna Moles
- Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain; CiberEHD, Spain; IDIBAPS, Barcelona, Spain; Associated Unit IIBB-IMIM, Barcelona, Spain.
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Zhou S, Li J, Liu J, Dong S, Chen N, Ran Y, Liu H, Wang X, Yang H, Liu M, Chu H, Wang B, Li Y, Guo L, Zhou L. Depressive symptom as a risk factor for cirrhosis in patients with primary biliary cholangitis: Analysis based on Lasso-logistic regression and decision tree models. Brain Behav 2024; 14:e3639. [PMID: 39099389 PMCID: PMC11298689 DOI: 10.1002/brb3.3639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 05/06/2024] [Accepted: 07/09/2024] [Indexed: 08/06/2024] Open
Abstract
BACKGROUND Depressive symptoms are frequently observed in patients with primary biliary cholangitis (PBC). The role of depressive symptoms on cirrhosis has not been fully noticed in PBC. We aimed to establish a risk model for cirrhosis that took depressive symptoms into account. METHODS Depressive symptoms were assessed by the 17-item Hamilton Depression Rating Scale (HAMD-17). HAMD-17 score was analyzed in relation to clinical parameters. Least absolute shrinkage and selection operator (Lasso)-logistic regression and decision tree models were used to explore the effect of depressive symptoms on cirrhosis. RESULTS The rate of depressive symptom in patients with PBC (n = 162) was higher than in healthy controls (n = 180) (52.5% vs. 16.1%; p < .001). HAMD-17 score was negatively associated with C4 levels and positively associated with levels of alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), total bilirubin (TB), Immunoglobulin (Ig) G, and IgM (r = -0.162, 0.197, 0.355, 0.203, 0.182, 0.314, p < .05). In Lasso-logistic regression analysis, HAMD-17 score, human leukocyte antigen (HLA)-DRB1*03:01 allele, age, ALP levels, and IgM levels (odds ratio [OR] = 1.087, 7.353, 1.075, 1.009, 1.005; p < 0.05) were independent risk factors for cirrhosis. Elevated HAMD-17 score was also a discriminating factor for high risk of cirrhosis in patients with PBC in decision tree model. CONCLUSIONS Depressive symptoms were associated with disease severity. Elevated HAMD-17 score was a risk factor for cirrhosis in patients with PBC.
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Affiliation(s)
- Simin Zhou
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Jiwen Li
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Jiangpeng Liu
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Shijing Dong
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Nian Chen
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Ying Ran
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Haifeng Liu
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Xiaoyi Wang
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Hui Yang
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Man Liu
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Hongyu Chu
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Yanni Li
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Liping Guo
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical UniversityTianjinChina
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Mir IH, Thirunavukkarasu C. The relevance of acid sphingomyelinase as a potential target for therapeutic intervention in hepatic disorders: current scenario and anticipated trends. Arch Toxicol 2023; 97:2069-2087. [PMID: 37248308 PMCID: PMC10226719 DOI: 10.1007/s00204-023-03529-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 05/22/2023] [Indexed: 05/31/2023]
Abstract
Acid sphingomyelinase (ASMase) serves as one of the most remarkable enzymes in sphingolipid biology. ASMase facilitates the hydrolysis of sphingomyelin, yielding ceramide and phosphorylcholine via the phospholipase C signal transduction pathway. Owing to its prominent intervention in apoptosis, ASMase, and its product ceramide is now at the bleeding edge of lipid research due to the coalesced efforts of several research institutions over the past 40 years. ASMase-catalyzed ceramide synthesis profoundly alters the physiological properties of membrane structure in response to a broad range of stimulations, orchestrating signaling cascades for endoplasmic reticulum stress, autophagy, and lysosomal membrane permeabilization, which influences the development of hepatic disorders, such as steatohepatitis, hepatic fibrosis, drug-induced liver injury, and hepatocellular carcinoma. As a result, the potential to modulate the ASMase action with appropriate pharmaceutical antagonists has sparked a lot of curiosity. This article emphasizes the fundamental mechanisms of the systems that govern ASMase aberrations in various hepatic pathologies. Furthermore, we present an insight into the potential therapeutic agents used to mitigate ASMase irregularities and the paramountcy of such inhibitors in drug repurposing.
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Affiliation(s)
- Ishfaq Hassan Mir
- Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, 605 014, India
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Musso G, Saba F, Cassader M, Gambino R. Lipidomics in pathogenesis, progression and treatment of nonalcoholic steatohepatitis (NASH): Recent advances. Prog Lipid Res 2023; 91:101238. [PMID: 37244504 DOI: 10.1016/j.plipres.2023.101238] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/20/2023] [Accepted: 05/21/2023] [Indexed: 05/29/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting up to 30% of the general adult population. NAFLD encompasses a histological spectrum ranging from pure steatosis to non-alcoholic steatohepatitis (NASH). NASH can progress to cirrhosis and is becoming the most common indication for liver transplantation, as a result of increasing disease prevalence and of the absence of approved treatments. Lipidomic readouts of liver blood and urine samples from experimental models and from NASH patients disclosed an abnormal lipid composition and metabolism. Collectively, these changes impair organelle function and promote cell damage, necro-inflammation and fibrosis, a condition termed lipotoxicity. We will discuss the lipid species and metabolic pathways leading to NASH development and progression to cirrhosis, as well as and those species that can contribute to inflammation resolution and fibrosis regression. We will also focus on emerging lipid-based therapeutic opportunities, including specialized proresolving lipid molecules and macrovesicles contributing to cell-to-cell communication and NASH pathophysiology.
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Affiliation(s)
- Giovanni Musso
- Dept of Emergency Medicine, San Luigi Gonzaga University Hospital, Orbassano, Turin, Italy.
| | - Francesca Saba
- Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
| | - Maurizio Cassader
- Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
| | - Roberto Gambino
- Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
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7
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Pfrieger FW. The Niemann-Pick type diseases – A synopsis of inborn errors in sphingolipid and cholesterol metabolism. Prog Lipid Res 2023; 90:101225. [PMID: 37003582 DOI: 10.1016/j.plipres.2023.101225] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/27/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023]
Abstract
Disturbances of lipid homeostasis in cells provoke human diseases. The elucidation of the underlying mechanisms and the development of efficient therapies represent formidable challenges for biomedical research. Exemplary cases are two rare, autosomal recessive, and ultimately fatal lysosomal diseases historically named "Niemann-Pick" honoring the physicians, whose pioneering observations led to their discovery. Acid sphingomyelinase deficiency (ASMD) and Niemann-Pick type C disease (NPCD) are caused by specific variants of the sphingomyelin phosphodiesterase 1 (SMPD1) and NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2) genes that perturb homeostasis of two key membrane components, sphingomyelin and cholesterol, respectively. Patients with severe forms of these diseases present visceral and neurologic symptoms and succumb to premature death. This synopsis traces the tortuous discovery of the Niemann-Pick diseases, highlights important advances with respect to genetic culprits and cellular mechanisms, and exposes efforts to improve diagnosis and to explore new therapeutic approaches.
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8
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Alarcón-Vila C, Insausti-Urkia N, Torres S, Segalés-Rovira P, Conde de la Rosa L, Nuñez S, Fucho R, Fernández-Checa JC, García-Ruiz C. Dietary and genetic disruption of hepatic methionine metabolism induce acid sphingomyelinase to promote steatohepatitis. Redox Biol 2023; 59:102596. [PMID: 36610223 PMCID: PMC9827379 DOI: 10.1016/j.redox.2022.102596] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 12/28/2022] [Indexed: 01/03/2023] Open
Abstract
Alcoholic (ASH) and nonalcoholic. (NASH).steatohepatitis are advanced.stages.of.fatty.liver.disease.Methionine adenosyltransferase 1A (MAT1A) plays a key role in hepatic methionine metabolism and germline Mat1a deletion in mice promotes NASH. Acid sphingomyelinase (ASMase) triggers hepatocellular apoptosis and liver fibrosis and has been shown to downregulate MAT1A expression in the context of fulminant liver failure. Given the role of ASMase in steatohepatitis development, we investigated the status of ASMase in Mat1a-/- mice and the regulation of ASMase by SAM/SAH. Consistent with its role in NASH, Mat1a-/- mice fed a choline-deficient (CD) diet exhibited macrosteatosis, inflammation, fibrosis and liver injury as well as reduced total and mitochondrial GSH levels. Our data uncovered an increased basal expression and activity of ASMase but not neutral SMase in Mat1a-/- mice, which further increased upon CD feeding. Interestingly, adenovirus-mediated shRNA expression targeting ASMase reduced ASMase activity and protected Mat1a-/- mice against CD diet-induced NASH. Similar results were observed in CD fed Mat1a-/- mice by pharmacological inhibition of ASMase with amitriptyline. Moreover, Mat1a/ASMase double knockout mice were resistant to CD-induced NASH. ASMase knockdown protected wild type mice against NASH induced by feeding a diet deficient in methionine and choline. Furthermore, Mat1a-/- mice developed acute-on-chronic ASH and this outcome was ameliorated by amitriptyline treatment. In vitro data in primary mouse hepatocytes revealed that decreased SAM/SAH ratio increased ASMase mRNA level and activity. MAT1A and ASMase mRNA levels exhibited an inverse correlation in liver samples from patients with ASH and NASH. Thus, disruption of methionine metabolism sensitizes to steatohepatitis by ASMase activation via decreased SAM/SAH. These findings imply that MAT1A deletion and ASMase activation engage in a self-sustained loop of relevance for steatohepatitis.
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Affiliation(s)
- Cristina Alarcón-Vila
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
| | - Naroa Insausti-Urkia
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
| | - Sandra Torres
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
| | - Paula Segalés-Rovira
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
| | - Laura Conde de la Rosa
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
| | - Susana Nuñez
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
| | - Raquel Fucho
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
| | - Jose C Fernández-Checa
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain; University of Southern California Research Center for Liver Diseases, Keck School of Medicine, USC, Los Angeles, CA, USA.
| | - Carmen García-Ruiz
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain; University of Southern California Research Center for Liver Diseases, Keck School of Medicine, USC, Los Angeles, CA, USA.
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9
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Zhu C, Huai Q, Zhang X, Dai H, Li X, Wang H. Insights into the roles and pathomechanisms of ceramide and sphigosine-1-phosphate in nonalcoholic fatty liver disease. Int J Biol Sci 2023; 19:311-330. [PMID: 36594091 PMCID: PMC9760443 DOI: 10.7150/ijbs.78525] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/12/2022] [Indexed: 11/24/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), as one of the main causes of chronic liver disease worldwide, encompasses a spectrum of liver conditions that are not caused by other etiology, such as overt alcohol consumption, from simple steatosis to more aggressive non-alcoholic steatohepatitis (NASH) that involves liver inflammation and fibrosis, and to the lethal cirrhosis that may result in liver cancer and liver failure. The molecular mechanisms governing the transition from steatosis to NASH remain not fully understood, but the hepatic lipidome is extensively altered in the setting of steatosis and steatohepatitis, which also correlate with disease progression. With the tremendous advancement in the field of lipidomics in last two decades, a better understanding of the specific role of sphingolipids in fatty liver disease has taken shape. Among the numerous lipid subtypes that accumulate, ceramides are particularly impactful. On the one hand, excessive ceramides deposition in the liver cause hepatic steatosis. On the other hand, ceramides as lipotoxic lipid have significant effects on hepatic inflammation, apoptosis and insulin resistance that contribute to NAFLD. In this review, we summarize and evaluate current understanding of the multiple roles of ceramides in the onset of fatty liver disease and the pathogenic mechanisms underlying their effects, and we also discuss recent advances and challenges in pharmacological interventions targeting ceramide metabolism for the treatment of NAFLD.
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Affiliation(s)
- Cheng Zhu
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Qian Huai
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xu Zhang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Hanren Dai
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xiaolei Li
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
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10
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Yu XD, Wang JW. Ceramide de novo synthesis in non-alcoholic fatty liver disease: Pathogenic mechanisms and therapeutic perspectives. Biochem Pharmacol 2022; 202:115157. [PMID: 35777449 DOI: 10.1016/j.bcp.2022.115157] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/23/2022] [Accepted: 06/24/2022] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and its advanced form non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma. Ceramides have been shown to exacerbate NAFLD development through enhancing insulin resistance, reactive oxygen species production, liver steatosis, lipotoxicity and hepatocyte apoptosis, and eventually causing hepatic inflammation and fibrosis. Emerging evidence indicates that ceramide production in NAFLD is predominantly attributed to activation of the de novo synthesis pathway of ceramides in hepatocytes. More importantly, pharmacological modulation of ceramide de novo synthesis in preclinical studies seems efficacious for the treatment of NAFLD. In this review, we provide an overview of the pathogenic mechanisms of ceramides in NAFLD, discuss recent advances and challenges in pharmacological interventions targeting ceramide de novo synthesis, and propose some research directions in the field.
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Affiliation(s)
- Xiao-Dong Yu
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Nanomedicine Translational Research Programme, Centre for NanoMedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jiong-Wei Wang
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Nanomedicine Translational Research Programme, Centre for NanoMedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Cardiovascular Research Institute (CVRI), National University Heart Centre Singapore (NUHCS), Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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11
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Riccio S, Melone R, Vitulano C, Guida P, Maddaluno I, Guarino S, Marzuillo P, Miraglia del Giudice E, Di Sessa A. Advances in pediatric non-alcoholic fatty liver disease: From genetics to lipidomics. World J Clin Pediatr 2022; 11:221-238. [PMID: 35663007 PMCID: PMC9134151 DOI: 10.5409/wjcp.v11.i3.221] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/05/2021] [Accepted: 04/02/2022] [Indexed: 02/06/2023] Open
Abstract
As a result of the obesity epidemic, non-alcoholic fatty liver disease (NAFLD) represents a global medical concern in childhood with a closely related increased cardiometabolic risk. Knowledge on NAFLD pathophysiology has been largely expanded over the last decades. Besides the well-known key NAFLD genes (including the I148M variant of the PNPLA3 gene, the E167K allele of the TM6SF2, the GCKR gene, the MBOAT7-TMC4 rs641738 variant, and the rs72613567:TA variant in the HSD17B13 gene), an intriguing pathogenic role has also been demonstrated for the gut microbiota. More interestingly, evidence has added new factors involved in the "multiple hits" theory. In particular, omics determinants have been highlighted as potential innovative markers for NAFLD diagnosis and treatment. In fact, different branches of omics including metabolomics, lipidomics (in particular sphingolipids and ceramides), transcriptomics (including micro RNAs), epigenomics (such as DNA methylation), proteomics, and glycomics represent the most attractive pathogenic elements in NAFLD development, by providing insightful perspectives in this field. In this perspective, we aimed to provide a comprehensive overview of NAFLD pathophysiology in children, from the oldest pathogenic elements (including genetics) to the newest intriguing perspectives (such as omics branches).
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Affiliation(s)
- Simona Riccio
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Rosa Melone
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Caterina Vitulano
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Pierfrancesco Guida
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Ivan Maddaluno
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Stefano Guarino
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Pierluigi Marzuillo
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Emanuele Miraglia del Giudice
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Anna Di Sessa
- Department of Woman, Child, General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
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12
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Characterization and Roles of Membrane Lipids in Fatty Liver Disease. MEMBRANES 2022; 12:membranes12040410. [PMID: 35448380 PMCID: PMC9025760 DOI: 10.3390/membranes12040410] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/05/2022] [Accepted: 04/07/2022] [Indexed: 12/12/2022]
Abstract
Obesity has reached global epidemic proportions and it affects the development of insulin resistance, type 2 diabetes, fatty liver disease and other metabolic diseases. Membrane lipids are important structural and signaling components of the cell membrane. Recent studies highlight their importance in lipid homeostasis and are implicated in the pathogenesis of fatty liver disease. Here, we discuss the numerous membrane lipid species and their metabolites including, phospholipids, sphingolipids and cholesterol, and how dysregulation of their composition and physiology contribute to the development of fatty liver disease. The development of new genetic and pharmacological mouse models has shed light on the role of lipid species on various mechanisms/pathways; these lipids impact many aspects of the pathophysiology of fatty liver disease and could potentially be targeted for the treatment of fatty liver disease.
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13
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Abstract
The relationship between sphingolipid levels and NAFLD pathology has been recognized for some time. Numerous studies using pharmacological and genetic approaches in vitro and in animal models of NAFLD have demonstrated that modifications to sphingolipid metabolism can attenuate various facets of NAFLD pathology. However, a more precise understanding of the role of sphingolipids and NAFLD pathology is essential to creating therapeutics that target this pathway. This chapter touches on the scale and variety of sphingolipid metabolites at play in NAFLD, which vary widely in their chemical structures and biological functions. With advances in liquid chromatography and tandem mass spectrometry approaches, each of thousands of individual sphingolipid species and sphingolipid metabolites can be identified and precisely quantified. These approaches are beginning to reveal specific sub-classes and species of sphingolipids that change in NAFLD, and as such, enzymes that generate them can be identified and potentially serve as therapeutic targets. Advances in lipidomics technology have been, and will continue to be, critical to these gains in our understanding of NAFLD.
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Affiliation(s)
- David Montefusco
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA.
| | - Johana Lambert
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA
| | - Andrea Anderson
- Department of Biology, Virginia Commonwealth University, Richmond, VA, USA
| | - Jeremy Allegood
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA
| | - L Ashley Cowart
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA
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14
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Ruiz-Blázquez P, Pistorio V, Fernández-Fernández M, Moles A. The multifaceted role of cathepsins in liver disease. J Hepatol 2021; 75:1192-1202. [PMID: 34242696 DOI: 10.1016/j.jhep.2021.06.031] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 06/16/2021] [Accepted: 06/21/2021] [Indexed: 12/15/2022]
Abstract
Proteases are the most abundant enzyme gene family in vertebrates and they execute essential functions in all living organisms. Their main role is to hydrolase the peptide bond within proteins, a process also called proteolysis. Contrary to the conventional paradigm, proteases are not only random catalytic devices, but can perform highly selective and targeted cleavage of specific substrates, finely modulating multiple essential cellular processes. Lysosomal protease cathepsins comprise 3 families of proteases that preferentially act within acidic cellular compartments, but they can also be found in other cellular locations. They can operate alone or as part of signalling cascades and regulatory circuits, playing important roles in apoptosis, extracellular matrix remodelling, hepatic stellate cell activation, autophagy and metastasis, contributing to the initiation, development and progression of liver disease. In this review, we comprehensively summarise current knowledge on the role of lysosomal cathepsins in liver disease, with a particular emphasis on liver fibrosis, non-alcoholic fatty liver disease and hepatocellular carcinoma.
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Affiliation(s)
- Paloma Ruiz-Blázquez
- Institute of Biomedical Research of Barcelona, Spanish National Research Council (IIBB-CSIC), Barcelona, Spain
| | - Valeria Pistorio
- Institute of Biomedical Research of Barcelona, Spanish National Research Council (IIBB-CSIC), Barcelona, Spain; University of Naples Federico II, Naples, Italy
| | - María Fernández-Fernández
- Institute of Biomedical Research of Barcelona, Spanish National Research Council (IIBB-CSIC), Barcelona, Spain
| | - Anna Moles
- Institute of Biomedical Research of Barcelona, Spanish National Research Council (IIBB-CSIC), Barcelona, Spain; IDIBAPS, Barcelona, Spain; CiberEHD, Spain.
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15
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Xiang H, Jin S, Tan F, Xu Y, Lu Y, Wu T. Physiological functions and therapeutic applications of neutral sphingomyelinase and acid sphingomyelinase. Biomed Pharmacother 2021; 139:111610. [PMID: 33957567 DOI: 10.1016/j.biopha.2021.111610] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 04/05/2021] [Accepted: 04/12/2021] [Indexed: 11/15/2022] Open
Abstract
Sphingomyelin (SM) can be converted into ceramide (Cer) by neutral sphingomyelinase (NSM) and acid sphingomyelinase (ASM). Cer is a second messenger of lipids and can regulate cell growth and apoptosis. Increasing evidence shows that NSM and ASM play key roles in many processes, such as apoptosis, immune function and inflammation. Therefore, NSM and ASM have broad prospects in clinical treatments, especially in cancer, cardiovascular diseases (such as atherosclerosis), nervous system diseases (such as Alzheimer's disease), respiratory diseases (such as chronic obstructive pulmonary disease) and the phenotype of dwarfisms in adolescents, playing a complex regulatory role. This review focuses on the physiological functions of NSM and ASM and summarizes their roles in certain diseases and their potential applications in therapy.
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Affiliation(s)
- Hongjiao Xiang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shengjie Jin
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fenglang Tan
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yifan Xu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yifei Lu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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16
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Naggie S, Lusk S, Thompson JW, Mock M, Moylan C, Lucas JE, Dubois L, St John-Williams L, Moseley MA, Patel K. Metabolomic Signature as a Predictor of Liver Disease Events in Patients With HIV/HCV Coinfection. J Infect Dis 2021; 222:2012-2020. [PMID: 32502252 DOI: 10.1093/infdis/jiaa316] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 06/02/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Advanced liver disease due to hepatitis C virus (HCV) is a leading cause of human immunodeficiency virus (HIV)-related morbidity and mortality. There remains a need to develop noninvasive predictors of clinical outcomes in persons with HIV/HCV coinfection. METHODS We conducted a nested case-control study in 126 patients with HIV/HCV and utilized multiple quantitative metabolomic assays to identify a prognostic profile that predicts end-stage liver disease (ESLD) events including ascites, hepatic encephalopathy, hepatocellular carcinoma, esophageal variceal bleed, and spontaneous bacterial peritonitis. Each analyte class was included in predictive modeling, and area under the receiver operator characteristic curves (AUC) and accuracy were determined. RESULTS The baseline model including demographic and clinical data had an AUC of 0.79. Three models (baseline plus amino acids, lipid metabolites, or all combined metabolites) had very good accuracy (AUC, 0.84-0.89) in differentiating patients at risk of developing an ESLD complication up to 2 years in advance. The all combined metabolites model had sensitivity 0.70, specificity 0.85, positive likelihood ratio 4.78, and negative likelihood ratio 0.35. CONCLUSIONS We report that quantification of a novel set of metabolites may allow earlier identification of patients with HIV/HCV who have the greatest risk of developing ESLD clinical events.
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Affiliation(s)
- Susanna Naggie
- Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA.,Duke University School of Medicine, Durham, North Carolina, USA
| | - Sam Lusk
- Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA
| | - J Will Thompson
- Duke Center for Genomic and Computational Biology, Duke University, Durham, North Carolina, USA.,Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA
| | - Meredith Mock
- Duke University School of Medicine, Durham, North Carolina, USA
| | - Cynthia Moylan
- Duke University School of Medicine, Durham, North Carolina, USA
| | | | - Laura Dubois
- Duke Center for Genomic and Computational Biology, Duke University, Durham, North Carolina, USA
| | - Lisa St John-Williams
- Duke Center for Genomic and Computational Biology, Duke University, Durham, North Carolina, USA
| | - M Arthur Moseley
- Duke Center for Genomic and Computational Biology, Duke University, Durham, North Carolina, USA
| | - Keyur Patel
- Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA.,University of Toronto, Toronto, Ontario, Canada
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17
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Hajduch E, Lachkar F, Ferré P, Foufelle F. Roles of Ceramides in Non-Alcoholic Fatty Liver Disease. J Clin Med 2021; 10:jcm10040792. [PMID: 33669443 PMCID: PMC7920467 DOI: 10.3390/jcm10040792] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/10/2021] [Accepted: 02/12/2021] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease is one of the most common chronic liver diseases, ranging from simple steatosis to steatohepatitis, fibrosis, and cirrhosis. Its prevalence is rapidly increasing and presently affects around 25% of the general population of Western countries, due to the obesity epidemic. Liver fat accumulation induces the synthesis of specific lipid species and particularly ceramides, a sphingolipid. In turn, ceramides have deleterious effects on hepatic metabolism, a phenomenon called lipotoxicity. We review here the evidence showing the role of ceramides in non-alcoholic fatty liver disease and the mechanisms underlying their effects.
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Affiliation(s)
- Eric Hajduch
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, 75006 Paris, France; (E.H.); (F.L.); (P.F.)
- Institute of Cardiometabolism and Nutrition (ICAN), Hôpital Pitié-Salpêtrière, AP-HP, 75013 Paris, France
| | - Floriane Lachkar
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, 75006 Paris, France; (E.H.); (F.L.); (P.F.)
- Institute of Cardiometabolism and Nutrition (ICAN), Hôpital Pitié-Salpêtrière, AP-HP, 75013 Paris, France
| | - Pascal Ferré
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, 75006 Paris, France; (E.H.); (F.L.); (P.F.)
- Institute of Cardiometabolism and Nutrition (ICAN), Hôpital Pitié-Salpêtrière, AP-HP, 75013 Paris, France
| | - Fabienne Foufelle
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, 75006 Paris, France; (E.H.); (F.L.); (P.F.)
- Institute of Cardiometabolism and Nutrition (ICAN), Hôpital Pitié-Salpêtrière, AP-HP, 75013 Paris, France
- Correspondence: ; Tel.: +33-1-44-27-24-25
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18
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Sphingomyelinases and Liver Diseases. Biomolecules 2020; 10:biom10111497. [PMID: 33143193 PMCID: PMC7692672 DOI: 10.3390/biom10111497] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 10/27/2020] [Accepted: 10/28/2020] [Indexed: 02/06/2023] Open
Abstract
Sphingolipids (SLs) are critical components of membrane bilayers that play a crucial role in their physico-chemical properties. Ceramide is the prototype and most studied SL due to its role as a second messenger in the regulation of multiple signaling pathways and cellular processes. Ceramide is a heterogeneous lipid entity determined by the length of the fatty acyl chain linked to its carbon backbone sphingosine, which can be generated either by de novo synthesis from serine and palmitoyl-CoA in the endoplasmic reticulum or via sphingomyelin (SM) hydrolysis by sphingomyelinases (SMases). Unlike de novo synthesis, SMase-induced SM hydrolysis represents a rapid and transient mechanism of ceramide generation in specific intracellular sites that accounts for the diverse biological effects of ceramide. Several SMases have been described at the molecular level, which exhibit different pH requirements for activity: neutral, acid or alkaline. Among the SMases, the neutral (NSMase) and acid (ASMase) are the best characterized for their contribution to signaling pathways and role in diverse pathologies, including liver diseases. As part of a Special Issue (Phospholipases: From Structure to Biological Function), the present invited review summarizes the physiological functions of NSMase and ASMase and their role in chronic and metabolic liver diseases, of which the most relevant is nonalcoholic steatohepatitis and its progression to hepatocellular carcinoma, due to the association with the obesity and type 2 diabetes epidemic. A better understanding of the regulation and role of SMases in liver pathology may offer the opportunity for novel treatments of liver diseases.
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19
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Perakakis N, Stefanakis K, Mantzoros CS. The role of omics in the pathophysiology, diagnosis and treatment of non-alcoholic fatty liver disease. Metabolism 2020; 111S:154320. [PMID: 32712221 PMCID: PMC7377759 DOI: 10.1016/j.metabol.2020.154320] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/15/2020] [Accepted: 07/18/2020] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multifaceted metabolic disorder, whose spectrum covers clinical, histological and pathophysiological developments ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and liver fibrosis, potentially evolving into cirrhosis, hepatocellular carcinoma and liver failure. Liver biopsy remains the gold standard for diagnosing NAFLD, while there are no specific treatments. An ever-increasing number of high-throughput Omics investigations on the molecular pathobiology of NAFLD at the cellular, tissue and system levels produce comprehensive biochemical patient snapshots. In the clinical setting, these applications are considerably enhancing our efforts towards obtaining a holistic insight on NAFLD pathophysiology. Omics are also generating non-invasive diagnostic modalities for the distinct stages of NAFLD, that remain though to be validated in multiple, large, heterogenous and independent cohorts, both cross-sectionally as well as prospectively. Finally, they aid in developing novel therapies. By tracing the flow of information from genomics to epigenomics, transcriptomics, proteomics, metabolomics, lipidomics and glycomics, the chief contributions of these techniques in understanding, diagnosing and treating NAFLD are summarized herein.
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Affiliation(s)
- Nikolaos Perakakis
- Department of Internal Medicine, Boston VA Healthcare system and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA..
| | - Konstantinos Stefanakis
- Department of Internal Medicine, Boston VA Healthcare system and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Christos S Mantzoros
- Department of Internal Medicine, Boston VA Healthcare system and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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20
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An Overview of Lipid Metabolism and Nonalcoholic Fatty Liver Disease. BIOMED RESEARCH INTERNATIONAL 2020; 2020:4020249. [PMID: 32733940 PMCID: PMC7383338 DOI: 10.1155/2020/4020249] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 06/14/2020] [Accepted: 06/25/2020] [Indexed: 12/11/2022]
Abstract
The occurrence of nonalcoholic fatty liver disease (NAFLD) is associated with major abnormalities of hepatic lipid metabolism. We propose that lipid abnormalities directly or indirectly contribute to NAFLD, especially fatty acid accumulation, arachidonic acid metabolic disturbance, and ceramide overload. The effects of lipid intake and accumulation on NAFLD and NAFLD treatment are explained with theoretical and experimental details. Overall, these findings provide further understanding of lipid metabolism in NAFLD and may lead to novel therapies.
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21
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Park WJ, Song JH, Kim GT, Park TS. Ceramide and Sphingosine 1-Phosphate in Liver Diseases. Mol Cells 2020; 43:419-430. [PMID: 32392908 PMCID: PMC7264474 DOI: 10.14348/molcells.2020.0054] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 04/06/2020] [Accepted: 04/19/2020] [Indexed: 12/12/2022] Open
Abstract
The liver is an important organ in the regulation of glucose and lipid metabolism. It is responsible for systemic energy homeostasis. When energy need exceeds the storage capacity in the liver, fatty acids are shunted into nonoxidative sphingolipid biosynthesis, which increases the level of cellular ceramides. Accumulation of ceramides alters substrate utilization from glucose to lipids, activates triglyceride storage, and results in the development of both insulin resistance and hepatosteatosis, increasing the likelihood of major metabolic diseases. Another sphingolipid metabolite, sphingosine 1-phosphate (S1P) is a bioactive signaling molecule that acts via S1P-specific G protein coupled receptors. It regulates many cellular and physiological events. Since an increase in plasma S1P is associated with obesity, it seems reasonable that recent studies have provided evidence that S1P is linked to lipid pathophysiology, including hepatosteatosis and fibrosis. Herein, we review recent findings on ceramides and S1P in obesity-mediated liver diseases and the therapeutic potential of these sphingolipid metabolites.
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Affiliation(s)
- Woo-Jae Park
- Department of Biochemistry, College of Medicine, Gachon University, Incheon 2999, Korea
| | - Jae-Hwi Song
- Department of Life Science, Gachon University, Seongnam 1310, Korea
| | - Goon-Tae Kim
- Department of Life Science, Gachon University, Seongnam 1310, Korea
| | - Tae-Sik Park
- Department of Life Science, Gachon University, Seongnam 1310, Korea
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22
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de Gregorio E, Colell A, Morales A, Marí M. Relevance of SIRT1-NF-κB Axis as Therapeutic Target to Ameliorate Inflammation in Liver Disease. Int J Mol Sci 2020; 21:E3858. [PMID: 32485811 PMCID: PMC7312021 DOI: 10.3390/ijms21113858] [Citation(s) in RCA: 129] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/26/2020] [Accepted: 05/27/2020] [Indexed: 12/12/2022] Open
Abstract
Inflammation is an adaptive response in pursuit of homeostasis reestablishment triggered by harmful conditions or stimuli, such as an infection or tissue damage. Liver diseases cause approximately 2 million deaths per year worldwide and hepatic inflammation is a common factor to all of them, being the main driver of hepatic tissue damage and causing progression from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH), cirrhosis and, ultimately, hepatocellular carcinoma (HCC). The metabolic sensor SIRT1, a class III histone deacetylase with strong expression in metabolic tissues such as the liver, and transcription factor NF-κB, a master regulator of inflammatory response, show an antagonistic relationship in controlling inflammation. For this reason, SIRT1 targeting is emerging as a potential strategy to improve different metabolic and/or inflammatory pathologies. In this review, we explore diverse upstream regulators and some natural/synthetic activators of SIRT1 as possible therapeutic treatment for liver diseases.
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Affiliation(s)
- Estefanía de Gregorio
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain;
| | - Anna Colell
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 08036 Barcelona, Spain;
| | - Albert Morales
- Department of Cell Death and Proliferation, IIBB-CSIC, Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic of Barcelona, University of Barcelona, CIBEREHD, 08036 Barcelona, Spain;
| | - Montserrat Marí
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain;
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23
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Simon J, Ouro A, Ala-Ibanibo L, Presa N, Delgado TC, Martínez-Chantar ML. Sphingolipids in Non-Alcoholic Fatty Liver Disease and Hepatocellular Carcinoma: Ceramide Turnover. Int J Mol Sci 2019; 21:40. [PMID: 31861664 PMCID: PMC6982102 DOI: 10.3390/ijms21010040] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 12/12/2019] [Accepted: 12/17/2019] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the main causes of chronic liver disease worldwide. NAFLD comprises a group of conditions characterized by the accumulation of hepatic lipids that can eventually lead to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), the fifth most common cancer type with a poor survival rate. In this context, several works have pointed out perturbations in lipid metabolism and, particularly, changes in bioactive sphingolipids, as a hallmark of NAFLD and derived HCC. In the present work, we have reviewed existing literature about sphingolipids and the development of NAFLD and NAFLD-derived HCC. During metabolic syndrome, considered a risk factor for steatosis development, an increase in ceramide and sphigosine-1-phosphate (S1P) have been reported. Likewise, other reports have highlighted that increased sphingomyelin and ceramide content is observed during steatosis and NASH. Ceramide also plays a role in liver fibrosis and cirrhosis, acting synergistically with S1P. Finally, during HCC, metabolic fluxes are redirected to reduce cellular ceramide levels whilst increasing S1P to support tumor growth.
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Affiliation(s)
- Jorge Simon
- Liver Disease and Liver Metabolism Lab, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, Spain; (L.A.-I.); (T.C.D.); (M.L.M.-C.)
| | - Alberto Ouro
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48980 Leioa, Bizkaia, Spain; (A.O.); (N.P.)
- Instituto Biofisika (UPV/EHU, CSIC), University of the Basque Country, 48940 Leioa, Spain
| | - Lolia Ala-Ibanibo
- Liver Disease and Liver Metabolism Lab, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, Spain; (L.A.-I.); (T.C.D.); (M.L.M.-C.)
| | - Natalia Presa
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48980 Leioa, Bizkaia, Spain; (A.O.); (N.P.)
| | - Teresa Cardoso Delgado
- Liver Disease and Liver Metabolism Lab, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, Spain; (L.A.-I.); (T.C.D.); (M.L.M.-C.)
| | - María Luz Martínez-Chantar
- Liver Disease and Liver Metabolism Lab, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, Spain; (L.A.-I.); (T.C.D.); (M.L.M.-C.)
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Meng X, Gu Z, Xie X, Su Y, Zhang X, Ma H, Guo Y, Liu X, Cheng Y, Chang Y, Bao J. Acid sphingomyelinase mediates the noise-induced liver disorder in mice. Clin Exp Pharmacol Physiol 2019; 46:556-566. [PMID: 30854677 DOI: 10.1111/1440-1681.13083] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 02/27/2019] [Accepted: 03/06/2019] [Indexed: 12/19/2022]
Abstract
Noise-induced structural and functional disorder of the liver has been realized, but the underlying mechanism remains to be characterized, which has limited the introduction of precautious measures. Over-activation of acid sphingomyelinase (ASM)/ceramide (Cer) pathway takes centre stage in hepatocyte injury entailed by various stimulus. We aimed to investigate whether it mediated the noise elicited liver disorder on infrastructure, lipid metabolism, apoptosis, and oxidative stress. Mice were exposed to broad band noise (20-20k Hz, 90-110 dB) for 1, 3, 5 or 7 days by 3 hr/d. Doxepin hydrochloride (DOX), an ASM inhibitor was given by 5 mg/kg/d gavage. We showed that 5 or 7 days intense, broad band noise exposure caused significant infrastructure derangement and lipid droplets storage in hepatocytes. The content of cholesterol, free fatty acids or triglyceride was increased significantly in liver tissue upon noise stimulation. Moreover, the noise promoted apoptosis and superoxide generation in hepatocytes significantly, enhancing activity of aspartate aminotransferase (AST) or alanine amino transferase (ALT) in serum. Acid sphingomyelinase activity and Cer generation in liver tissue were elevated by noise exposure, which was normalized with DOX administrated. Accordingly, DOX alleviated steatosis, apoptosis, oxidative stress and enzymatic change in hepatocytes or serum of noise exposed mice substantially. In summary, our results suggest the ASM/Cer pathway contributes to the broad band noise elicited liver damage in mice.
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Affiliation(s)
- Xingxing Meng
- Department of Aerospace Hygiene, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Zhenghui Gu
- Department of Aerospace Hygiene, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xiaoping Xie
- Department of Aerospace Hygiene, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yuting Su
- Department of Aerospace Hygiene, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xi Zhang
- Department of Aerospace Hygiene, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Hongzhe Ma
- Department of Aerospace Hygiene, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yibin Guo
- Department of Aerospace Hygiene, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xincheng Liu
- Department of Aerospace Hygiene, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yaoping Cheng
- Department of Aerospace Hygiene, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yaoming Chang
- Department of Aerospace Hygiene, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Junxiang Bao
- Department of Aerospace Hygiene, Fourth Military Medical University, Xi'an, Shaanxi, China
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25
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Shmarakov IO, Jiang H, Liu J, Fernandez EJ, Blaner WS. Hepatic stellate cell activation: A source for bioactive lipids. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:629-642. [PMID: 30735856 DOI: 10.1016/j.bbalip.2019.02.004] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 01/30/2019] [Accepted: 02/03/2019] [Indexed: 02/06/2023]
Abstract
Hepatic stellate cells (HSCs) are non-parenchymal liver cells that characteristically contain multiple retinoid (vitamin A)-containing lipid droplets. In this study, we addressed the metabolic fate of non-retinoid lipids originating from lipid droplet loss during HSCs activation. UPLC/MS/MS and qRT-PCR were used to monitor the lipid composition and mRNA expression of selected genes regulating lipid metabolism in freshly isolated, overnight-, 3- and 7-day cultures or primary mouse HSCs. A preferential accumulation of specific C20-C24 fatty acid species, especially arachidonic (C20:4) and docosahexaenoic acids (C22:6), was revealed in culture-activated HSCs along with an upregulation of transcription of fatty acid desaturases (Scd1, Scd2) and elongases (Elovl5, Elovl6). This was accompanied with an enrichment of activated HSCs with 36:4 and 38:4 phosphatidylcholine species containing polyunsaturated fatty acids and associated accumulation of selective lipid mediators, including endocannabinoids and related N-acylethanolamides, as well as ceramides. An increase in 2-arachidonoylglycerol and N-arachydonoylethanolamide concentrations was observed along with an upregulation of Daglα mRNA expression in HSCs during culture activation. N-palmitoylethanolamide was identified as the most abundant endocannabinoid-like species in activated HSCs. An increase in total ceramide levels and enrichment with N-palmitoyl (C16:0), N-tetracosenoyl (C24:1), N-tetracosanoyl (C24:0) and N-docosanoyl (C22:0) ceramides was detected in activated HSC cultures and was preceded by increased mRNA expression of ceramide synthesizing enzymes (CerS2, CerS5 and Smpd1). Our data suggest an active redistribution of non-retinoid lipids in HSCs underlying the formation of low abundance, highly bioactive lipid species that may affect signaling during HSC activation, as well as extracellularly within the liver.
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Affiliation(s)
- Igor O Shmarakov
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, 630 West 168(th) Street, New York, NY 10032, USA.
| | - Hongfeng Jiang
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, 630 West 168(th) Street, New York, NY 10032, USA
| | - Jing Liu
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, 630 West 168(th) Street, New York, NY 10032, USA
| | - Elias J Fernandez
- Department of Biochemistry and Cellular & Molecular Biology, University of Tennessee, Knoxville, TN 37916, USA
| | - William S Blaner
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, 630 West 168(th) Street, New York, NY 10032, USA
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26
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Nikolova-Karakashian M. Alcoholic and non-alcoholic fatty liver disease: Focus on ceramide. Adv Biol Regul 2018; 70:40-50. [PMID: 30455063 DOI: 10.1016/j.jbior.2018.11.004] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 11/13/2018] [Accepted: 11/13/2018] [Indexed: 12/24/2022]
Abstract
Sphingolipids are class of metabolically distinct lipids that play structural and signaling functions in all organisms. Sphingolipid metabolism is deregulated during various diseases such as cancer, neurological and immune disorders, and metabolic syndrome. With the advancement of sphingo-lipidomics and sphingo-genomics, an understanding of the specific roles of ceramide, the quintessential bioactive sphingolipid, in fatty liver disease has taken shape. Two major pathways for ceramide generation, the de novo pathway and the sphingomyelinase pathway are activated in the course of both, the non-alcoholic and the alcoholic, forms of fatty liver disease. The mechanisms of activation of these two pathways are distinct and reflect the different disease etiology in each case; at the same time, common processes impacted by the resulting ceramide overproduction involve lipotoxocity, ER/mitochondrial stress, inflammation, and de-regulation of hepatic lipid metabolism. Studies in human patients and animal models have delineated specific enzymes and ceramide species that are involved at the different stages of the disease, and represent novel pharmaceutical targets for successful management of fatty liver disease.
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Affiliation(s)
- Mariana Nikolova-Karakashian
- Department of Physiology, University of Kentucky College of Medicine, 800 Rose Str., MS 508, Lexington, KY, 40536, United States.
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27
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Acid Sphingomyelinase Inhibition Stabilizes Hepatic Ceramide Content and Improves Hepatic Biotransformation Capacity in a Murine Model of Polymicrobial Sepsis. Int J Mol Sci 2018; 19:ijms19103163. [PMID: 30326559 PMCID: PMC6214114 DOI: 10.3390/ijms19103163] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 10/07/2018] [Accepted: 10/10/2018] [Indexed: 12/14/2022] Open
Abstract
Liver dysfunction during sepsis is an independent risk factor leading to increased mortality rates. Specifically, dysregulation of hepatic biotransformation capacity, especially of the cytochrome P450 (CYP) system, represents an important distress factor during host response. The activity of the conserved stress enzyme sphingomyelin phosphodiesterase 1 (SMPD1) has been shown to be elevated in sepsis patients, allowing for risk stratification. Therefore, the aim of the present study was to investigate whether SMPD1 activity has an impact on expression and activity of different hepatic CYP enzymes using an animal model of polymicrobial sepsis. Polymicrobial sepsis was induced in SMPD1 wild-type and heterozygous mice and hepatic ceramide content as well as CYP mRNA, protein expression and enzyme activities were assessed at two different time points, at 24 h, representing the acute phase, and at 28 days, representing the post-acute phase of host response. In the acute phase of sepsis, SMPD1+/+ mice showed an increased hepatic C16- as well as C18-ceramide content. In addition, a downregulation of CYP expression and activities was detected. In SMPD1+/- mice, however, no noticeable changes of ceramide content and CYP expression and activities during sepsis could be observed. After 28 days, CYP expression and activities were normalized again in all study groups, whereas mRNA expression remained downregulated in SMPD+/+ animals. In conclusion, partial genetic inhibition of SMPD1 stabilizes hepatic ceramide content and improves hepatic monooxygenase function in the acute phase of polymicrobial sepsis. Since we were also able to show that the functional inhibitor of SMPD1, desipramine, ameliorates downregulation of CYP mRNA expression and activities in the acute phase of sepsis in wild-type mice, SMPD1 might be an interesting pharmacological target, which should be further investigated.
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28
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Musso G, Cassader M, Paschetta E, Gambino R. Bioactive Lipid Species and Metabolic Pathways in Progression and Resolution of Nonalcoholic Steatohepatitis. Gastroenterology 2018; 155:282-302.e8. [PMID: 29906416 DOI: 10.1053/j.gastro.2018.06.031] [Citation(s) in RCA: 241] [Impact Index Per Article: 34.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 05/30/2018] [Accepted: 06/01/2018] [Indexed: 02/06/2023]
Abstract
The prevalence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, yet there are no effective treatments. A decade has passed since the initial lipidomics analyses of liver tissues from patients with nonalcoholic fatty liver disease. We have learned that liver cells from patients with NASH have an abnormal lipid composition and that the accumulation of lipids leads to organelle dysfunction, cell injury and death, and chronic inflammation, called lipotoxicity. We review the lipid species and metabolic pathways that contribute to the pathogenesis of NASH and potential therapeutic targets, including enzymes involved in fatty acid and triglyceride synthesis, bioactive sphingolipids and polyunsaturated-derived eicosanoids, and specialized pro-resolving lipid mediators. We discuss the concept that NASH is a disease that can resolve and the roles of lipid molecules in the resolution of inflammation and regression of fibrosis.
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Affiliation(s)
| | - Maurizio Cassader
- Department of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
| | | | - Roberto Gambino
- Department of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
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29
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Chen JY, Ren Y, Yan P, Belina ME, Chung RT, Butt AA. Tricyclic antidepressant use and the risk of fibrosis progression in hepatitis C-infected persons: Results from ERCHIVES. J Viral Hepat 2018; 25:825-833. [PMID: 29478294 PMCID: PMC6019114 DOI: 10.1111/jvh.12884] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 01/15/2018] [Indexed: 12/19/2022]
Abstract
Recent preclinical studies have suggested an antifibrotic role for tricyclic antidepressants (TCA). Using the Electronically Retrieved Cohort of hepatitis C virus (HCV) Infected Veterans, we aimed to evaluate the impact of TCA use on fibrosis progression and development of hepatocellular carcinoma (HCC) among HCV-infected persons. Subjects were categorized according to use of TCAs, selective serotonin reuptake inhibitors (SSRI) or no antidepressants. TCAs or selective serotonin uptake inhibitors use was defined according to cumulative defined daily dose (cDDD), and categories were mutually exclusive. Subjects with HIV coinfection, hepatitis B surface antigen (HbsAg) positivity, cirrhosis or HCC at baseline were excluded. Outcomes were liver fibrosis progression measured by APRI scores and incident HCC. We utilized Cox proportional hazards regression to determine predictors of cirrhosis, defined as APRI > 2, and incident hepatocellular carcinoma (iHCC). Among 128 201 eligible HCV+ persons, 4% received TCAs, 43% received selective serotonin uptake inhibitors, and 53% received no antidepressants. Fewer TCAs users had drug abuse (34% and 43%) and alcohol abuse (32% vs 42%) compared to selective serotonin uptake inhibitor users. After adjusting for age, baseline APRI score, diabetes, hypertension, alcohol use, drug abuse and HCV RNA levels, TCAs use was associated with decreased risk of cirrhosis (hazard ratio [HR] = 0.77, 95% CI = 0.60, 0.99) and delayed time to development of cirrhosis, but not with decreased iHCC. In conclusion among a large cohort of HCV-positive Veterans, TCAs use was associated with decreased fibrosis progression and lower risk of developing cirrhosis. These data provide supportive evidence for the beneficial effects of TCAs on progression of liver fibrosis in patients with chronic HCV infection.
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Affiliation(s)
- Jennifer Y. Chen
- Department of Medicine, University of California, San Francisco, California USA,The Liver Center, University of California, San Francisco, California USA
| | - Yanjie Ren
- Veterans Research Foundation, Pittsburgh, PA USA
| | - Peng Yan
- Veterans Research Foundation, Pittsburgh, PA USA
| | - Morgan E. Belina
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA
| | - Raymond T. Chung
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA
| | - Adeel A. Butt
- VA Pittsburgh Healthcare System, Pittsburgh, PA USA,Weill Cornell Medical College, Doha, Qatar and New York, NY USA,Hamad Healthcare Quality Institute and Hamad Medical Corporation, Doha, Qatar
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30
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Soufan O, Ba-Alawi W, Magana-Mora A, Essack M, Bajic VB. DPubChem: a web tool for QSAR modeling and high-throughput virtual screening. Sci Rep 2018; 8:9110. [PMID: 29904147 PMCID: PMC6002400 DOI: 10.1038/s41598-018-27495-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 05/31/2018] [Indexed: 01/01/2023] Open
Abstract
High-throughput screening (HTS) performs the experimental testing of a large number of chemical compounds aiming to identify those active in the considered assay. Alternatively, faster and cheaper methods of large-scale virtual screening are performed computationally through quantitative structure-activity relationship (QSAR) models. However, the vast amount of available HTS heterogeneous data and the imbalanced ratio of active to inactive compounds in an assay make this a challenging problem. Although different QSAR models have been proposed, they have certain limitations, e.g., high false positive rates, complicated user interface, and limited utilization options. Therefore, we developed DPubChem, a novel web tool for deriving QSAR models that implement the state-of-the-art machine-learning techniques to enhance the precision of the models and enable efficient analyses of experiments from PubChem BioAssay database. DPubChem also has a simple interface that provides various options to users. DPubChem predicted active compounds for 300 datasets with an average geometric mean and F1 score of 76.68% and 76.53%, respectively. Furthermore, DPubChem builds interaction networks that highlight novel predicted links between chemical compounds and biological assays. Using such a network, DPubChem successfully suggested a novel drug for the Niemann-Pick type C disease. DPubChem is freely available at www.cbrc.kaust.edu.sa/dpubchem .
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Affiliation(s)
- Othman Soufan
- Institute of Parasitology, McGill University, Montreal, QC, H9X 3V9, Canada
| | - Wail Ba-Alawi
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada
| | - Arturo Magana-Mora
- Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, 135-0064, Japan
| | - Magbubah Essack
- Computational Bioscience Research Center, King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
| | - Vladimir B Bajic
- Computational Bioscience Research Center, King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
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31
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is a group of liver disorders encompassing simple hepatic steatosis and its more aggressive forms of nonalcoholic steatohepatitis and cirrhosis. It is a rapidly growing health concern and the major cause for the increasing incidence of primary liver tumors. Unequivocal evidence shows that sphingolipid metabolism is altered in the course of the disease and these changes might contribute to NAFLD progression. Recent data provide solid support to the notion that deregulated ceramide and sphingosine-1-phosphate metabolism are present at all stages of NAFLD, i.e., steatosis, nonalcoholic steatohepatitis, advanced fibrosis, and hepatocellular carcinoma (HCC). Insulin sensitivity, de novo lipogenesis, and the resulting lipotoxicity, fibrosis, and angiogenesis are all seemingly regulated in a manner that involves either ceramide and/or sphingosine-1-phosphate. Sphingolipids might also participate in the onset of hepatocellular senescence. The latter has been shown to contribute to the advancement of cirrhosis to HCC in the classical cases of end-stage liver disease, i.e., viral- or alcohol-induced; however, emerging evidence suggests that senescence is also involved in the pathogenicity of NAFLD possibly via changes in ceramide metabolism.
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32
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The role of sphingolipids in psychoactive drug use and addiction. J Neural Transm (Vienna) 2018; 125:651-672. [DOI: 10.1007/s00702-018-1840-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 01/03/2018] [Indexed: 12/14/2022]
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33
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Chung HY, Witt CJ, Jbeily N, Hurtado-Oliveros J, Giszas B, Lupp A, Gräler MH, Bruns T, Stallmach A, Gonnert FA, Claus RA. Acid Sphingomyelinase Inhibition Prevents Development of Sepsis Sequelae in the Murine Liver. Sci Rep 2017; 7:12348. [PMID: 28955042 PMCID: PMC5617833 DOI: 10.1038/s41598-017-11837-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 08/25/2017] [Indexed: 12/16/2022] Open
Abstract
The molecular mechanisms of maladaptive response in liver tissue with respect to the acute and post-acute phase of sepsis are not yet fully understood. Long-term sepsis survivors might develop hepatocellular/hepatobiliary injury and fibrosis. Here, we demonstrate that acid sphingomyelinase, an important regulator of hepatocyte apoptosis and hepatic stellate cell (HSC) activation, is linked to the promotion of liver dysfunction in the acute phase of sepsis as well as to fibrogenesis in the long-term. In both phases, we observed a beneficial effect of partial genetic sphingomyelinase deficiency in heterozygous animals (smpd1+/−) on oxidative stress levels, hepatobiliary function, macrophage infiltration and on HSC activation. Strikingly, similar to heterozygote expression of SMPD1, either preventative (p-smpd1+/+) or therapeutic (t-smpd1+/+) pharmacological treatment strategies with desipramine – a functional inhibitor of acid sphingomyelinase (FIASMA) – significantly improved liver function and survival. The inhibition of sphingomyelinase exhibited a protective effect on liver function in the acute-phase, and the reduction of HSC activation diminished development of sepsis-associated liver fibrosis in the post-acute phase of sepsis. In summary, targeting sphingomyelinase with FDA-approved drugs is a novel promising strategy to overcome sepsis-induced liver dysfunction.
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Affiliation(s)
- Ha-Yeun Chung
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07747, Germany.,Department of Anesthesiology and Intensive Care, Jena University Hospital, Am Klinikum 1, Jena, 07747, Germany.,Hans-Berger Department of Neurology, Jena University Hospital, Jena, 07747, Germany
| | - C Julius Witt
- Department of Anesthesiology and Intensive Care, Jena University Hospital, Am Klinikum 1, Jena, 07747, Germany
| | - Nayla Jbeily
- Department of Anesthesiology and Intensive Care, Jena University Hospital, Am Klinikum 1, Jena, 07747, Germany
| | | | - Benjamin Giszas
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07747, Germany
| | - Amelie Lupp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, 07747, Germany
| | - Markus H Gräler
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07747, Germany.,Department of Anesthesiology and Intensive Care, Jena University Hospital, Am Klinikum 1, Jena, 07747, Germany
| | - Tony Bruns
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07747, Germany.,Department of Internal Medicine IV (Gastroenterology, Hepatology and Infectious Diseases), Jena University Hospital, Jena, 07747, Germany
| | - Andreas Stallmach
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07747, Germany.,Department of Internal Medicine IV (Gastroenterology, Hepatology and Infectious Diseases), Jena University Hospital, Jena, 07747, Germany
| | - Falk A Gonnert
- Department of Anesthesiology and Intensive Care, Jena University Hospital, Am Klinikum 1, Jena, 07747, Germany
| | - Ralf A Claus
- Center for Sepsis Control and Care, Jena University Hospital, Jena, 07747, Germany. .,Department of Anesthesiology and Intensive Care, Jena University Hospital, Am Klinikum 1, Jena, 07747, Germany.
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34
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Biswas R, Trout KL, Jessop F, Harkema JR, Holian A. Imipramine blocks acute silicosis in a mouse model. Part Fibre Toxicol 2017; 14:36. [PMID: 28893276 PMCID: PMC5594487 DOI: 10.1186/s12989-017-0217-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Accepted: 08/31/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Inhalation of crystalline silica is associated with pulmonary inflammation and silicosis. Although silicosis remains a prevalent health problem throughout the world, effective treatment choices are limited. Imipramine (IMP) is a FDA approved tricyclic antidepressant drug with lysosomotropic characteristics. The aim of this study was to evaluate the potential for IMP to reduce silicosis and block phagolysosome membrane permeabilization. METHODS C57BL/6 alveolar macrophages (AM) exposed to crystalline silica ± IMP in vitro were assessed for IL-1β release, cytotoxicity, particle uptake, lysosomal stability, and acid sphingomyelinase activity. Short term (24 h) in vivo studies in mice instilled with silica (± IMP) evaluated inflammation and cytokine release, in addition to cytokine release from ex vivo cultured AM. Long term (six to ten weeks) in vivo studies in mice instilled with silica (± IMP) evaluated histopathology, lung damage, and hydroxyproline content as an indicator of collagen accumulation. RESULTS IMP significantly attenuated silica-induced cytotoxicity and release of mature IL-1β from AM in vitro. IMP treatment in vivo reduced silica-induced inflammation in a short-term model. Furthermore, IMP was effective in blocking silica-induced lung damage and collagen deposition in a long-term model. The mechanism by which IMP reduces inflammation was explored by assessing cellular processes such as particle uptake and acid sphingomyelinase activity. CONCLUSIONS Taken together, IMP was anti-inflammatory against silica exposure in vitro and in vivo. The results were consistent with IMP blocking silica-induced phagolysosomal lysis, thereby preventing cell death and IL-1β release. Thus, IMP could be therapeutic for silica-induced inflammation and subsequent disease progression as well as other diseases involving phagolysosomal lysis.
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Affiliation(s)
- Rupa Biswas
- Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, 59812, USA
| | - Kevin L Trout
- Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, 59812, USA
| | - Forrest Jessop
- Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, 59812, USA
| | - Jack R Harkema
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI, 48824, USA
| | - Andrij Holian
- Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, 59812, USA.
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35
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Cano A, Mariño Z, Millet O, Martínez-Arranz I, Navasa M, Falcón-Pérez JM, Pérez-Cormenzana M, Caballería J, Embade N, Forns X, Bosch J, Castro A, Mato JM. A Metabolomics Signature Linked To Liver Fibrosis In The Serum Of Transplanted Hepatitis C Patients. Sci Rep 2017; 7:10497. [PMID: 28874799 PMCID: PMC5585246 DOI: 10.1038/s41598-017-10807-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 08/11/2017] [Indexed: 12/17/2022] Open
Abstract
Liver fibrosis must be evaluated in patients with hepatitis C virus (HCV) after liver transplantation because its severity affects their prognosis and the recurrence of HCV. Since invasive biopsy is still the gold standard to identify patients at risk of graft loss from rapid fibrosis progression, it becomes crucial the development of new accurate, non-invasive methods that allow repetitive examination of the patients. Therefore, we have developed a non-invasive, accurate model to distinguish those patients with different liver fibrosis stages. Two hundred and three patients with HCV were histologically classified (METAVIR) into five categories of fibrosis one year after liver transplantation. In this cross-sectional study, patients at fibrosis stages F0-F1 (n = 134) were categorised as “slow fibrosers” and F2-F4 (n = 69) as “rapid fibrosers”. Chloroform/methanol serum extracts were analysed by reverse ultra-high performance liquid chromatography coupled to mass spectrometry. A diagnostic model was built through linear discriminant analyses. An algorithm consisting of two sphingomyelins and two phosphatidylcholines accurately classifies rapid and slow fibrosers after transplantation. The proposed model yielded an AUROC of 0.92, 71% sensitivity, 85% specificity, and 84% accuracy. Moreover, specific bile acids and sphingomyelins increased notably along with liver fibrosis severity, differentiating between rapid and slow fibrosers.
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Affiliation(s)
- Ainara Cano
- OWL, Parque Tecnológico de Bizkaia, Derio, 48160, Bizkaia, Spain.
| | - Zoe Mariño
- Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd); Institut d'Investigacions Biomediques August Pi Sunyer (IDIBAPS), Barcelona, Spain
| | - Oscar Millet
- Metabolomic Unit, CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, 48160, Spain.,Ikerbasque, Basque Foundation for Science, Bilbao, Bizkaia, Spain
| | | | - Miquel Navasa
- Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd); Institut d'Investigacions Biomediques August Pi Sunyer (IDIBAPS), Barcelona, Spain
| | - Juan Manuel Falcón-Pérez
- Metabolomic Unit, CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, 48160, Spain.,Ikerbasque, Basque Foundation for Science, Bilbao, Bizkaia, Spain
| | | | - Joan Caballería
- Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd); Institut d'Investigacions Biomediques August Pi Sunyer (IDIBAPS), Barcelona, Spain
| | - Nieves Embade
- Metabolomic Unit, CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, 48160, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd); Institut d'Investigacions Biomediques August Pi Sunyer (IDIBAPS), Barcelona, Spain
| | - Jaume Bosch
- Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd); Institut d'Investigacions Biomediques August Pi Sunyer (IDIBAPS), Barcelona, Spain
| | - Azucena Castro
- OWL, Parque Tecnológico de Bizkaia, Derio, 48160, Bizkaia, Spain
| | - José María Mato
- Metabolomic Unit, CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, 48160, Spain
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36
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Manchanda M, Das P, Gahlot GPS, Singh R, Roeb E, Roderfeld M, Datta Gupta S, Saraya A, Pandey RM, Chauhan SS. Cathepsin L and B as Potential Markers for Liver Fibrosis: Insights From Patients and Experimental Models. Clin Transl Gastroenterol 2017; 8:e99. [PMID: 28617446 PMCID: PMC5518948 DOI: 10.1038/ctg.2017.25] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 04/27/2017] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Cathepsin L (CTSL) and B (CTSB) have a crucial role in extracellular matrix (ECM) degradation and tissue remodeling, which is a prominent feature of fibrogenesis. The aim of this study was to determine the role and clinical significance of these cathepsins in liver fibrosis. METHODS Hepatic histological CTSL and CTSB expression were assessed in experimental models of liver fibrosis, patients with liver cirrhosis, chronic viral hepatitis, and controls by real-time PCR and immunohistochemistry. Plasma levels of CTSL and CTSB were analyzed in 51 liver cirrhosis patients (Child-Pugh stages A, B and C) and 15 controls. RESULTS Significantly enhanced CTSL mRNA (P=0.02) and protein (P=0.01) levels were observed in the liver of carbon tetrachloride-treated mice compared with controls. Similarly, hepatic CTSL and CTSB mRNA levels (P=0.02) were markedly increased in Abcb4-/- (ATP-binding cassette transporter knockout) mice compared with wild-type littermates. Elevated levels of CTSL and CTSB were also found in the liver (P=0.001) and plasma (P<0.0001) of patients with hepatic cirrhosis compared with healthy controls. Furthermore, CTSL and CTSB levels correlated well with the hepatic collagen (r=0.5, P=0.007; r=0.64, P=0.0001). CTSL and CTSB levels increased with the Child-Pugh stage of liver cirrhosis and correlated with total bilirubin content (r=0.4/0.2; P≤0.05). CTSL, CTSB, and their combination had a high diagnostic accuracy (area under the curve: 0.91, 0.89 and 0.96, respectively) for distinguishing patients from controls. CONCLUSIONS Our data demonstrate the overexpression of CTSL and CTSB in patients and experimental mouse models, suggesting their potential as diagnostic biomarkers for chronic liver diseases.
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Affiliation(s)
- Mansi Manchanda
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Gaurav P S Gahlot
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Ratnakar Singh
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Elke Roeb
- Department of Gastroenterology, Justus-Liebig-University, Giessen, Germany
| | - Martin Roderfeld
- Department of Gastroenterology, Justus-Liebig-University, Giessen, Germany
| | | | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - R M Pandey
- Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
| | - Shyam S Chauhan
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
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Adjustment of Dysregulated Ceramide Metabolism in a Murine Model of Sepsis-Induced Cardiac Dysfunction. Int J Mol Sci 2017; 18:ijms18040839. [PMID: 28420138 PMCID: PMC5412423 DOI: 10.3390/ijms18040839] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Revised: 04/02/2017] [Accepted: 04/10/2017] [Indexed: 12/24/2022] Open
Abstract
Cardiac dysfunction, in particular of the left ventricle, is a common and early event in sepsis, and is strongly associated with an increase in patients’ mortality. Acid sphingomyelinase (SMPD1)—the principal regulator for rapid and transient generation of the lipid mediator ceramide—is involved in both the regulation of host response in sepsis as well as in the pathogenesis of chronic heart failure. This study determined the degree and the potential role to which SMPD1 and its modulation affect sepsis-induced cardiomyopathy using both genetically deficient and pharmacologically-treated animals in a polymicrobial sepsis model. As surrogate parameters of sepsis-induced cardiomyopathy, cardiac function, markers of oxidative stress as well as troponin I levels were found to be improved in desipramine-treated animals, desipramine being an inhibitor of ceramide formation. Additionally, ceramide formation in cardiac tissue was dysregulated in SMPD1+/+ as well as SMPD1−/− animals, whereas desipramine pretreatment resulted in stable, but increased ceramide content during host response. This was a result of elevated de novo synthesis. Strikingly, desipramine treatment led to significantly improved levels of surrogate markers. Furthermore, similar results in desipramine-pretreated SMPD1−/− littermates suggest an SMPD1-independent pathway. Finally, a pattern of differentially expressed transcripts important for regulation of apoptosis as well as antioxidative and cytokine response supports the concept that desipramine modulates ceramide formation, resulting in beneficial myocardial effects. We describe a novel, protective role of desipramine during sepsis-induced cardiac dysfunction that controls ceramide content. In addition, it may be possible to modulate cardiac function during host response by pre-conditioning with the Food and Drug Administration (FDA)-approved drug desipramine.
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38
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Chen JY, Newcomb B, Zhou C, Pondick JV, Ghoshal S, York SR, Motola DL, Coant N, Yi JK, Mao C, Tanabe KK, Bronova I, Berdyshev EV, Fuchs BC, Hannun Y, Chung RT, Mullen AC. Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells. Sci Rep 2017; 7:44867. [PMID: 28322247 PMCID: PMC5359599 DOI: 10.1038/srep44867] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 02/15/2017] [Indexed: 12/21/2022] Open
Abstract
Activation of hepatic stellate cells (HSCs) in response to injury is a key step in hepatic fibrosis, and is characterized by trans-differentiation of quiescent HSCs to HSC myofibroblasts, which secrete extracellular matrix proteins responsible for the fibrotic scar. There are currently no therapies to directly inhibit hepatic fibrosis. We developed a small molecule screen to identify compounds that inactivate human HSC myofibroblasts through the quantification of lipid droplets. We screened 1600 compounds and identified 21 small molecules that induce HSC inactivation. Four hits were tricyclic antidepressants (TCAs), and they repressed expression of pro-fibrotic factors Alpha-Actin-2 (ACTA2) and Alpha-1 Type I Collagen (COL1A1) in HSCs. RNA sequencing implicated the sphingolipid pathway as a target of the TCAs. Indeed, TCA treatment of HSCs promoted accumulation of ceramide through inhibition of acid ceramidase (aCDase). Depletion of aCDase also promoted accumulation of ceramide and was associated with reduced COL1A1 expression. Treatment with B13, an inhibitor of aCDase, reproduced the antifibrotic phenotype as did the addition of exogenous ceramide. Our results show that detection of lipid droplets provides a robust readout to screen for regulators of hepatic fibrosis and have identified a novel antifibrotic role for ceramide.
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Affiliation(s)
- Jennifer Y Chen
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA
| | - Benjamin Newcomb
- Health Science Center, Stony Brook University, Stony Brook, NY USA
| | - Chan Zhou
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA
| | - Joshua V Pondick
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA
| | - Sarani Ghoshal
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA USA
| | - Samuel R York
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA
| | - Daniel L Motola
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA
| | - Nicolas Coant
- Health Science Center, Stony Brook University, Stony Brook, NY USA
| | - Jae Kyo Yi
- Health Science Center, Stony Brook University, Stony Brook, NY USA
| | - Cungui Mao
- Health Science Center, Stony Brook University, Stony Brook, NY USA
| | - Kenneth K Tanabe
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA USA
| | | | | | - Bryan C Fuchs
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA USA
| | - Yusuf Hannun
- Health Science Center, Stony Brook University, Stony Brook, NY USA
| | - Raymond T Chung
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA
| | - Alan C Mullen
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA.,Harvard Stem Cell Institute, Cambridge, MA 02138 USA
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Sydor S, Sowa JP, Megger DA, Schlattjan M, Jafoui S, Wingerter L, Carpinteiro A, Baba HA, Bechmann LP, Sitek B, Gerken G, Gulbins E, Canbay A. Acid sphingomyelinase deficiency in Western diet-fed mice protects against adipocyte hypertrophy and diet-induced liver steatosis. Mol Metab 2017; 6:416-427. [PMID: 28462076 PMCID: PMC5404101 DOI: 10.1016/j.molmet.2017.03.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 03/02/2017] [Accepted: 03/07/2017] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Alterations in sphingolipid and ceramide metabolism have been associated with various diseases, including nonalcoholic fatty liver disease (NAFLD). Acid sphingomyelinase (ASM) converts the membrane lipid sphingomyelin to ceramide, thereby affecting membrane composition and domain formation. We investigated the ways in which the Asm knockout (Smpd1-/-) genotype affects diet-induced NAFLD. METHODS Smpd1-/- mice and wild type controls were fed either a standard or Western diet (WD) for 6 weeks. Liver and adipose tissue morphology and mRNA expression were assessed. Quantitative proteome analysis of liver tissue was performed. Expression of selected genes was quantified in adipose and liver tissue of obese NAFLD patients. RESULTS Although Smpd1-/- mice exhibited basal steatosis with normal chow, no aggravation of NAFLD-type injury was observed with a Western diet. This protective effect was associated with the absence of adipocyte hypertrophy and the increased expression of genes associated with brown adipocyte differentiation. In white adipose tissue from obese patients with NAFLD, no expression of these genes was detectable. To further elucidate which pathways in liver tissue may be affected by Smpd1-/-, we performed an unbiased proteome analysis. Protein expression in WD-fed Smpd1-/- mice indicated a reduction in Rictor (mTORC2) activity; this reduction was confirmed by diminished Akt phosphorylation and altered mRNA expression of Rictor target genes. CONCLUSION These findings indicate that the protective effect of Asm deficiency on diet-induced steatosis is conferred by alterations in adipocyte morphology and lipid metabolism and by reductions in Rictor activation.
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Affiliation(s)
- Svenja Sydor
- Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Hufelandstr. 55, 45120 Essen, Germany.
| | - Jan-Peter Sowa
- Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Hufelandstr. 55, 45120 Essen, Germany.
| | - Dominik A Megger
- Medizinisches Proteom-Center, Ruhr-Universität Bochum, Universitätsstraße 150, 44801 Bochum, Germany; Institute of Virology, University Hospital, University Duisburg-Essen, Hufelandstr. 55, 45120 Essen, Germany.
| | - Martin Schlattjan
- Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Hufelandstr. 55, 45120 Essen, Germany.
| | - Sami Jafoui
- Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Hufelandstr. 55, 45120 Essen, Germany.
| | - Lena Wingerter
- Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Hufelandstr. 55, 45120 Essen, Germany.
| | - Alexander Carpinteiro
- Department of Molecular Biology, University Duisburg-Essen, Hufelandstr. 55, 45120 Essen, Germany.
| | - Hideo A Baba
- Institute of Pathology, University Hospital, University Duisburg-Essen, Hufelandstr. 55, 45120 Essen, Germany.
| | - Lars P Bechmann
- Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Hufelandstr. 55, 45120 Essen, Germany.
| | - Barbara Sitek
- Medizinisches Proteom-Center, Ruhr-Universität Bochum, Universitätsstraße 150, 44801 Bochum, Germany.
| | - Guido Gerken
- Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Hufelandstr. 55, 45120 Essen, Germany.
| | - Erich Gulbins
- Department of Molecular Biology, University Duisburg-Essen, Hufelandstr. 55, 45120 Essen, Germany.
| | - Ali Canbay
- Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Hufelandstr. 55, 45120 Essen, Germany; Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany.
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González-Fernández B, Sánchez DI, Crespo I, San-Miguel B, Álvarez M, Tuñón MJ, González-Gallego J. Inhibition of the SphK1/S1P signaling pathway by melatonin in mice with liver fibrosis and human hepatic stellate cells. Biofactors 2017; 43:272-282. [PMID: 27801960 DOI: 10.1002/biof.1342] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Revised: 09/07/2016] [Accepted: 10/03/2016] [Indexed: 01/02/2023]
Abstract
The sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) system is involved in different pathological processes, including fibrogenesis. Melatonin abrogates activation of hepatic stellate cells (HSCs) and attenuates different profibrogenic pathways in animal models of fibrosis, but it is unknown if protection associates with its inhibitory effect on the SphK1/S1P axis. Mice in treatment groups received carbon tetrachloride (CCl4 ) 5 μL g-1 body wt i.p. twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg kg-1 day-1 i.p, beginning 2 weeks after the start of CCl4 administration. At both 4 and 6 weeks following CCl4 treatment, liver mRNA levels, protein concentration and immunohistochemical labelling for SphK1 increased significantly. S1P production, and expression of S1P receptor (S1PR)1, S1PR3 and acid sphingomyelinase (ASMase) were significantly elevated. However, there was a decreased expression of S1PR2 and S1P lyase (S1PL). Melatonin attenuated liver fibrosis, as shown by a significant inhibition of the expression of α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β and collagen (Col) Ι. Furthermore, melatonin inhibited S1P production, lowered expression of SphK1, S1PR1, SP1R3, and ASMase, and increased expression of S1PL. Melatonin induced a reversal of activated human HSCs cell line LX2, as evidenced by a reduction in α-SMA, TGF-β, and Col I expression. Melatonin-treated cells also exhibited an inhibition of the SphK1/S1P axis. Antifibrogenic effect of SphK1 inhibition was confirmed by treatment of LX2 cells with PF543. Abrogation of the lipid signaling pathway by the indole reveals novel molecular pathways that may account for the protective effect of melatonin in liver fibrogenesis. © 2016 BioFactors, 43(2):272-282, 2017.
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Affiliation(s)
| | - Diana I Sánchez
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
| | - Irene Crespo
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | | | | | - María J Tuñón
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | - Javier González-Gallego
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
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Wu T, Zheng X, Yang M, Zhao A, Li M, Chen T, Panee J, Jia W, Ji G. Serum lipid alterations identified in chronic hepatitis B, hepatitis B virus-associated cirrhosis and carcinoma patients. Sci Rep 2017; 7:42710. [PMID: 28198443 PMCID: PMC5309878 DOI: 10.1038/srep42710] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 01/12/2017] [Indexed: 01/03/2023] Open
Abstract
The incidences of chronic hepatitis B (CHB), Hepatitis B virus (HBV)-associated cirrhosis and HBV-associated carcinoma are high and increasing. This study was designed to evaluate serum lipid metabolite changes that are associated with the progression from CHB to HBV-associated cirrhosis and ultimately to HBV-associated HCC. A targeted metabolomic assay was performed in fasting sera from 136 CHB patients, 104 HBV-associated cirrhosis, and 95 HBV-associated HCC using ultra-performance liquid chromatography triple quadrupole mass spectrometry. A total of 140 metabolites were identified. Clear separations between each two groups were obtained using the partial least squares discriminate analysis of 9 lipid metabolites. Progressively lower levels of long-chain lysophosphatidylcholines (lysoPC a C18:2, lysoPC a C20:3, lysoPC a C20:4) were observed from CHB to cirrhosis to carcinoma; lower levels of lysoPC a C20:4 were found in patients with higher model for end-stage liver disease in the same disease group; and lysoPC a C20:3 levels were lower in Child-Pugh Class C than in Class A and Class B in HBV-associated cirrhosis and HBV-associated HCC groups. The octadecadienyl carnitine level was higher in HBV-associated cirrhosis group than in other two groups. Serum levels of selected long-chain lysoPCs are promising markers for the progression of HBV-associated liver diseases.
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Affiliation(s)
- Tao Wu
- Center of Chinese Medical Therapy and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Xiaojiao Zheng
- Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
| | - Ming Yang
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Aihua Zhao
- Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
| | - Meng Li
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Tianlu Chen
- Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
| | - Jun Panee
- Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Monoa, Honolulu, Hawaii 96813, United States
| | - Wei Jia
- Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
- University of Hawaii Cancer Center, Honolulu, Hawaii 96813, United States
| | - Guang Ji
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- E-institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Hubel E, Saroha A, Park WJ, Pewzner-Jung Y, Lavoie EG, Futerman AH, Bruck R, Fishman S, Dranoff JA, Shibolet O, Zvibel I. Sortilin Deficiency Reduces Ductular Reaction, Hepatocyte Apoptosis, and Liver Fibrosis in Cholestatic-Induced Liver Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:122-133. [DOI: 10.1016/j.ajpath.2016.09.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 08/04/2016] [Accepted: 09/01/2016] [Indexed: 01/14/2023]
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43
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Cao W, Li Y, Li M, Zhang X, Liao M. Txn1, Ctsd and Cdk4 are key proteins of combination therapy with taurine, epigallocatechin gallate and genistein against liver fibrosis in rats. Biomed Pharmacother 2016; 85:611-619. [PMID: 27894668 DOI: 10.1016/j.biopha.2016.11.071] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 11/11/2016] [Accepted: 11/16/2016] [Indexed: 01/14/2023] Open
Abstract
The anti-fibrotic mechanism of combination therapy with taurine, epigallocatechin gallate and genistein was studied from the perspective of serum proteomics in our previous work. In order to further investigate and systematically analyse other possible therapeutic mechanism of combination therapy against liver fibrosis, isobaric tags for relative and absolute quantification (iTRAQ) proteomic analysis was applied to study the protein profile changes in liver tissue of carbon tetrachloride-induced liver fibrosis rats after combination therapy. A total of 115 differentially expressed proteins containing 84 up-regulated and 31 down-regulated proteins in response to combination therapy were identified. Three differentially expressed proteins (Txn1, Ctsd and Cdk4) involved in antioxidant defense system and the activation and proliferation of hepatic stellate cell were selected for further validation by western blot and real-time PCR analysis. Our study highlight the importance of differentially expressed proteins Txn1, Ctsd and Cdk4 against liver fibrosis, which may provide a more precise and comprehensive perspective for clarifying the roles of combination therapy as a potential agent for treatment of liver fibrosis.
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Affiliation(s)
- Wen Cao
- Department of Pharmacology, Guangxi Medical University, Nanning, China
| | - Yan Li
- Guangxi University Library, Guangxi University, Nanning, China
| | - Min Li
- Medical Scientific Research Centre, Guangxi Medical University, Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, China
| | - Xuerong Zhang
- Medical Scientific Research Centre, Guangxi Medical University, Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, China
| | - Ming Liao
- Medical Scientific Research Centre, Guangxi Medical University, Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, China.
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de Mingo Á, de Gregorio E, Moles A, Tarrats N, Tutusaus A, Colell A, Fernandez-Checa JC, Morales A, Marí M. Cysteine cathepsins control hepatic NF-κB-dependent inflammation via sirtuin-1 regulation. Cell Death Dis 2016; 7:e2464. [PMID: 27831566 PMCID: PMC5260902 DOI: 10.1038/cddis.2016.368] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 10/11/2016] [Accepted: 10/12/2016] [Indexed: 12/18/2022]
Abstract
Sirtuin-1 (SIRT1) regulates hepatic metabolism but its contribution to NF-κB-dependent inflammation has been overlooked. Cysteine cathepsins (Cathepsin B or S, CTSB/S) execute specific functions in physiological processes, such as protein degradation, having SIRT1 as a substrate. We investigated the roles of CTSB/S and SIRT1 in the regulation of hepatic inflammation using primary parenchymal and non-parenchymal hepatic cell types and cell lines. In all cells analyzed, CTSB/S inhibition reduces nuclear p65-NF-κB and κB-dependent gene expression after LPS or TNF through enhanced SIRT1 expression. Accordingly, SIRT1 silencing was sufficient to enhance inflammatory gene expression. Importantly, in a dietary mouse model of non-alcoholic steatohepatitis, or in healthy and fibrotic mice after LPS challenge, cathepsins as well as NF-κB-dependent gene expression are activated. Consistent with the prominent role of cathepsin/SIRT1, cysteine cathepsin inhibition limits NF-κB-dependent hepatic inflammation through the regulation of SIRT1 in all in vivo settings, providing a novel anti-inflammatory therapeutic target in liver disease.
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Affiliation(s)
- Álvaro de Mingo
- Department of Cell Death and Proliferation, IIBB-CSIC/IDIBAPS, Barcelona, Catalonia, Spain
| | - Estefanía de Gregorio
- Department of Cell Death and Proliferation, IIBB-CSIC/IDIBAPS, Barcelona, Catalonia, Spain
| | - Anna Moles
- Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK
| | - Núria Tarrats
- Department of Cell Death and Proliferation, IIBB-CSIC/IDIBAPS, Barcelona, Catalonia, Spain
| | - Anna Tutusaus
- Department of Cell Death and Proliferation, IIBB-CSIC/IDIBAPS, Barcelona, Catalonia, Spain
| | - Anna Colell
- Department of Cell Death and Proliferation, IIBB-CSIC/IDIBAPS, Barcelona, Catalonia, Spain
| | - Jose C Fernandez-Checa
- Department of Cell Death and Proliferation, IIBB-CSIC/IDIBAPS, Barcelona, Catalonia, Spain.,Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Albert Morales
- Department of Cell Death and Proliferation, IIBB-CSIC/IDIBAPS, Barcelona, Catalonia, Spain
| | - Montserrat Marí
- Department of Cell Death and Proliferation, IIBB-CSIC/IDIBAPS, Barcelona, Catalonia, Spain
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Citrate functionalized Mn 3O 4 in nanotherapy of hepatic fibrosis by oral administration. Future Sci OA 2016; 2:FSO146. [PMID: 28116129 PMCID: PMC5242211 DOI: 10.4155/fsoa-2016-0029] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2016] [Accepted: 08/26/2016] [Indexed: 12/13/2022] Open
Abstract
Aim: To test the potential of orally administered citrate functionalized Mn3O4 nanoparticles (C-Mn3O4 NPs) as a therapeutic agent against hepatic fibrosis and associated chronic liver diseases. Materials & methods: C-Mn3O4 NPs were synthesized and the pH dependent antioxidant mechanism was characterized by in vitro studies. CCl4 intoxicated mice were orally treated with C-Mn3O4 NPs to test its in vivo antioxidant and antifibrotic ability. Results: We demonstrated ultrahigh efficacy of the C-Mn3O4 NPs in treatment of chronic liver diseases such as hepatic fibrosis and cirrhosis in mice compared with conventional medicine silymarin without any toxicological implications. Conclusion: These findings may pave the way for practical clinical use of the NPs as safe medication of chronic liver diseases associated with fibrosis and cirrhosis in human subjects. Hepatic fibrosis is a common response to chronic liver injury from a number of causes including alcohol, toxin, and persistent viral and helminthic infections, which may ultimately lead to hepatic carcinoma. Although billions of people are affected throughout the world, there is no drug available for treatment of this chronic disease. Here, in a preclinical study, we have shown that oral administration of citrate functionalized Mn3O4 nanoparticles can effectively reduce the extent of liver fibrosis in mice. We have also predicted the underlying therapeutic mechanism that involves mitochondria and antioxidant systems of the body.
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Sato M, Ikeda H, Uranbileg B, Kurano M, Saigusa D, Aoki J, Maki H, Kudo H, Hasegawa K, Kokudo N, Yatomi Y. Sphingosine kinase-1, S1P transporter spinster homolog 2 and S1P2 mRNA expressions are increased in liver with advanced fibrosis in human. Sci Rep 2016; 6:32119. [PMID: 27562371 PMCID: PMC4999825 DOI: 10.1038/srep32119] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 08/02/2016] [Indexed: 12/12/2022] Open
Abstract
The role of sphingosine 1-phosphate (S1P) in liver fibrosis or inflammation was not fully examined in human. Controversy exists which S1P receptors, S1P1 and S1P3 vs S1P2, would be importantly involved in its mechanism. To clarify these matters, 80 patients who received liver resection for hepatocellular carcinoma and 9 patients for metastatic liver tumor were enrolled. S1P metabolism was analyzed in background, non-tumorous liver tissue. mRNA levels of sphingosine kinase 1 (SK1) but not SK2 were increased in livers with fibrosis stages 3-4 compared to those with 0-2 and to normal liver. However, S1P was not increased in advanced fibrotic liver, where mRNA levels of S1P transporter spinster homolog 2 (SPNS2) but not S1P-degrading enzymes were enhanced. Furthermore, mRNA levels of S1P2 but not S1P1 or S1P3 were increased in advanced fibrotic liver. These increased mRNA levels of SK1, SPNS2 and S1P2 in fibrotic liver were correlated with α-smooth muscle actin mRNA levels in liver, and with serum ALT levels. In conclusion, S1P may be actively generated, transported to outside the cells, and bind to its specific receptor in human liver to play a role in fibrosis or inflammation. Altered S1P metabolism in fibrotic liver may be their therapeutic target.
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Affiliation(s)
- Masaya Sato
- Department of Clinical Laboratory Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo Japan
| | - Hitoshi Ikeda
- Department of Clinical Laboratory Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo Japan.,CREST, JST, Japan
| | - Baasanjav Uranbileg
- Department of Clinical Laboratory Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo Japan
| | - Makoto Kurano
- Department of Clinical Laboratory Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo Japan.,CREST, JST, Japan
| | - Daisuke Saigusa
- CREST, JST, Japan.,Department of Integrative Genomics, Tohoku Medical Megabank Organization, 2-1 Seiryo machi, Aobaku Sendai, Miyagi, Japan
| | - Junken Aoki
- CREST, JST, Japan.,Graduate School of Pharmaceutical Science, Tohoku University, 6-3, Ara-makiazaaoba, Aobaku, Sendai, Miyagi, Japan
| | - Harufumi Maki
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Hiroki Kudo
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Yutaka Yatomi
- Department of Clinical Laboratory Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo Japan.,CREST, JST, Japan
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47
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Gu YJ, Sun WY, Zhang S, Li XR, Wei W. Targeted blockade of JAK/STAT3 signaling inhibits proliferation, migration and collagen production as well as inducing the apoptosis of hepatic stellate cells. Int J Mol Med 2016; 38:903-11. [PMID: 27460897 DOI: 10.3892/ijmm.2016.2692] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 07/08/2016] [Indexed: 11/06/2022] Open
Abstract
Protein tyrosine kinases belonging to the Janus kinase (JAK) family are associated with many cytokine receptors, which, on ligand binding, regulate important cellular functions such as proliferation, apoptosis and differentiation. The protective effects of JAK inhibitors on fibrotic diseases such as myelofibrosis and bone marrow fibrosis have been demonstrated in previous studies. The JAK inhibitor SHR0302 is a synthetic molecule that potently inhibits all members of the JAK family, particularly JAK1. However, its effect on hepatic fibrosis has not been investigated to date, to the best of our knowledge. In the present study, the effects of SHR0302 on the activation, proliferation, migration and apoptosis of hepatic stellate cells (HSCs) as well as HSC collagen production were investigated. Our data demonstrated that treatment with SHR0302 (10-9-10-5 mol/l) exerted an inhibitory effect on the activation, proliferation and migration of HSCs. In addition, the expression of collagen I and collagen III were significantly decreased following treatment with SHR0302. Furthermore, SHR0302 induced the apoptosis of HSCs, which was demonstrated by Annexin V/PI staining. SHR0302 significantly increased the activation of caspase-3 and Bax in HSCs whereas it decreased the expression of Bcl-2. SHR0302 also inhibited the activation of Akt signaling pathway. The pharmacological inhibition of the JAK1/signal transducer and activator of transcription (STAT)3 pathway led to the disruption of functions essential for HSC growth. Taken together, these findings provide evidence that SHR0302 may have the potential to alleviate hepatic fibrosis by targeting HSC functions.
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Affiliation(s)
- Yuan-Jing Gu
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui 230032, P.R. China
| | - Wu-Yi Sun
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui 230032, P.R. China
| | - Sen Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui 230032, P.R. China
| | - Xin-Ran Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui 230032, P.R. China
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui 230032, P.R. China
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48
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Mansy SS, Nosseir MM, Othman MM, Zoheiry MA, Guda MF, Yehia HA, Hassanein MH. Spotlight on the three main hepatic fibrogenic cells in HCV-infected patients: Multiple immunofluorescence and ultrastructure study. Ultrastruct Pathol 2016; 40:276-87. [DOI: 10.1080/01913123.2016.1194507] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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49
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Chung HY, Hupe DC, Otto GP, Sprenger M, Bunck AC, Dorer MJ, Bockmeyer CL, Deigner HP, Gräler MH, Claus RA. Acid Sphingomyelinase Promotes Endothelial Stress Response in Systemic Inflammation and Sepsis. Mol Med 2016; 22:412-423. [PMID: 27341515 DOI: 10.2119/molmed.2016.00140] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 06/02/2016] [Indexed: 01/08/2023] Open
Abstract
The pathophysiology of sepsis involves activation of acid sphingomyelinase (SMPD1) with subsequent generation of the bioactive mediator ceramide. We herein evaluated the hypothesis that the enzyme exerts biological effects in endothelial stress response. Plasma-secreted sphingomyelinase activity, ceramide generation and lipid raft formation were measured in human microcirculatory endothelial cells (HMEC-1) stimulated with serum obtained from sepsis patients. Clustering of receptors relevant for signal transduction was studied by immuno staining. The role of SMPD1 for macrodomain formation was tested by pharmacological inhibition. To confirm the involvement of the stress enzyme, direct inhibitors (amino bisphosphonates) and specific downregulation of the gene was tested with respect to ADAMTS13 expression and cytotoxicity. Plasma activity and amount of SMPD1 were increased in septic patients dependent on clinical severity. Increased breakdown of sphingomyelin to ceramide in HMECs was observed following stimulation with serum from sepsis patients in vitro. Hydrolysis of sphingomyelin, clustering of receptor complexes, such as the CD95L/Fas-receptor, as well as formation of ceramide enriched macrodomains was abrogated using functional inhibitors (desipramine and NB6). Strikingly, the stimulation of HMECs with serum obtained from sepsis patients or mixture of proinflammatory cytokines resulted in cytotoxicity and ADAMTS13 downregulation which was abrogated using desipramine, amino bisphosphonates and genetic inhibitors. SMPD1 is involved in the dysregulation of ceramide metabolism in endothelial cells leading to macrodomain formation, cytotoxicity and downregulation of ADAMTS13 expression. Functional inhibitors, such as desipramine, are capable to improve endothelial stress response during sepsis and might be considered as a pharmacological treatment strategy to favor the outcome.
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Affiliation(s)
- Ha-Yeun Chung
- Center for Sepsis Control & Care (CSCC), Jena University Hospital, Germany.,Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Germany
| | - Daniel C Hupe
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Germany
| | - Gordon P Otto
- Center for Sepsis Control & Care (CSCC), Jena University Hospital, Germany.,Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Germany
| | - Marcel Sprenger
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Germany
| | - Alexander C Bunck
- Department of Radiology, University Hospital Cologne, Cologne, Germany
| | - Michael J Dorer
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Germany
| | - Clemens L Bockmeyer
- Department of Nephropathology, University Hospital Erlangen, Erlangen, Germany
| | - Hans-Peter Deigner
- Hochschule Furtwangen University, Faculty Medical and Life Sciences, Villingen-Schwenningen, Germany.,Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany
| | - Markus H Gräler
- Center for Sepsis Control & Care (CSCC), Jena University Hospital, Germany.,Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Germany
| | - Ralf A Claus
- Center for Sepsis Control & Care (CSCC), Jena University Hospital, Germany.,Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Germany
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50
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Ilan Y. Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance. Am J Physiol Gastrointest Liver Physiol 2016; 310:G1102-17. [PMID: 27173510 DOI: 10.1152/ajpgi.00095.2016] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 05/04/2016] [Indexed: 01/31/2023]
Abstract
The compounds of sphingomyelin-ceramide-glycosphingolipid pathways have been studied as potential secondary messenger molecules in various systems, along with liver function and insulin resistance. Secondary messenger molecules act directly or indirectly to affect cell organelles and intercellular interactions. Their potential role in the pathogenesis of steatohepatitis and diabetes has been suggested. Data samples collected from patients with Gaucher's disease, who had high levels of glucocerebroside, support a role for compounds from these pathways as a messenger molecules in the pathogenesis of fatty liver disease and diabetes. The present review summarizes some of the recent data on the role of glycosphingolipid molecules as messenger molecules in various physiological and pathological conditions, more specifically including insulin resistance and fatty liver disease.
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Affiliation(s)
- Yaron Ilan
- Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel
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