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Gruevska A, Leslie J, Perpiñán E, Maude H, Collins AL, Johnson S, Evangelista L, Sabey E, French J, White S, Moir J, Robinson SM, Alrawashdeh W, Thakkar R, Forlano R, Manousou P, Goldin R, Carling D, Hoare M, Thursz M, Mann DA, Cebola I, Posma JM, Safinia N, Oakley F, Hall Z. Spatial lipidomics reveals sphingolipid metabolism as anti-fibrotic target in the liver. Metabolism 2025; 168:156237. [PMID: 40127860 DOI: 10.1016/j.metabol.2025.156237] [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: 01/13/2025] [Revised: 03/18/2025] [Accepted: 03/20/2025] [Indexed: 03/26/2025]
Abstract
BACKGROUND AND AIMS Steatotic liver disease (SLD), which encompasses various causes of fat accumulation in the liver, is a major cause of liver fibrosis. Understanding the specific mechanisms of lipotoxicity, dysregulated lipid metabolism, and the role of different hepatic cell types involved in fibrogenesis is crucial for therapy development. METHODS We analysed liver tissue from SLD patients and 3 mouse models. We combined bulk/spatial lipidomics, transcriptomics, imaging mass cytometry (IMC) and analysis of published spatial and single-cell RNA sequencing (scRNA-seq) data to explore the metabolic microenvironment in fibrosis. Pharmacological inhibition of sphingolipid metabolism with myriocin, fumonisin B1, miglustat and D-PDMP was carried out in hepatic stellate cells (HSCs) and human precision cut liver slices (hPCLSs). RESULTS Bulk lipidomics revealed increased glycosphingolipids, ether lipids and saturated phosphatidylcholines in fibrotic samples. Spatial lipidomics detected >40 lipid species enriched within fibrotic regions, notably sphingomyelin (SM) 34:1. Using bulk transcriptomics (mouse) and analysis of published spatial transcriptomics data (human) we found that sphingolipid metabolism was also dysregulated in fibrosis at transcriptome level, with increased gene expression for ceramide and glycosphingolipid synthesis. Analysis of human scRNA-seq data showed that sphingolipid-related genes were widely expressed in non-parenchymal cells. By integrating spatial lipidomics with IMC of hepatic cell markers, we found excellent spatial correlation between sphingolipids, such as SM(34:1), and myofibroblasts. Inhibiting sphingolipid metabolism resulted in anti-fibrotic effects in HSCs and hPCLSs. CONCLUSIONS Our spatial multi-omics approach suggests cell type-specific mechanisms of fibrogenesis involving sphingolipid metabolism. Importantly, sphingolipid metabolic pathways are modifiable targets, which may have potential as an anti-fibrotic therapeutic strategy.
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Affiliation(s)
- Aleksandra Gruevska
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, University of Newcastle, Newcastle-upon-Tyne, United Kingdom
| | - Elena Perpiñán
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, United Kingdom
| | - Hannah Maude
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Amy L Collins
- Newcastle Fibrosis Research Group, Biosciences Institute, University of Newcastle, Newcastle-upon-Tyne, United Kingdom
| | - Sophia Johnson
- Newcastle Fibrosis Research Group, Biosciences Institute, University of Newcastle, Newcastle-upon-Tyne, United Kingdom
| | - Laila Evangelista
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Eleanor Sabey
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Jeremy French
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom
| | - Steven White
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom
| | - John Moir
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom
| | - Stuart M Robinson
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom
| | - Wasfi Alrawashdeh
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom
| | - Rohan Thakkar
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom
| | - Roberta Forlano
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Pinelopi Manousou
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Robert Goldin
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - David Carling
- MRC Laboratory of Medical Sciences, London, United Kingdom; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Matthew Hoare
- Early Cancer Institute, University of Cambridge, Cambridge, United Kingdom
| | - Mark Thursz
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, University of Newcastle, Newcastle-upon-Tyne, United Kingdom
| | - Inês Cebola
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Joram M Posma
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Niloufar Safinia
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, United Kingdom
| | - Fiona Oakley
- Newcastle Fibrosis Research Group, Biosciences Institute, University of Newcastle, Newcastle-upon-Tyne, United Kingdom; FibroFind, Unit 26/27, Baker's Yard, Christon Road, Newcastle upon Tyne, United Kingdom
| | - Zoe Hall
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom.
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Ceja-Galicia ZA, Cespedes-Acuña CLA, El-Hafidi M. Protection Strategies Against Palmitic Acid-Induced Lipotoxicity in Metabolic Syndrome and Related Diseases. Int J Mol Sci 2025; 26:788. [PMID: 39859502 PMCID: PMC11765695 DOI: 10.3390/ijms26020788] [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: 11/26/2024] [Revised: 12/26/2024] [Accepted: 01/03/2025] [Indexed: 01/27/2025] Open
Abstract
Diets rich in carbohydrate and saturated fat contents, when combined with a sedentary lifestyle, contribute to the development of obesity and metabolic syndrome (MetS), which subsequently increase palmitic acid (PA) levels. At high concentrations, PA induces lipotoxicity through several mechanisms involving endoplasmic reticulum (ER) stress, mitochondrial dysfunction, inflammation and cell death. Nevertheless, there are endogenous strategies to mitigate PA-induced lipotoxicity through its unsaturation and elongation and its channeling and storage in lipid droplets (LDs), which plays a crucial role in sequestering oxidized lipids, thereby reducing oxidative damage to lipid membranes. While extended exposure to PA promotes mitochondrial reactive oxygen species (ROS) generation leading to cell damage, acute exposure of ß-cells to PA increases glucose-stimulated insulin secretion (GSIS), through the activation of free fatty acid receptors (FFARs). Subsequently, the activation of FFARs by exogenous agonists has been suggested as a potential therapeutic strategy to prevent PA-induced lipotoxicity in ß cells. Moreover, some saturated fatty acids, including oleic acid, can counteract the negative impact of PA on cellular health, suggesting a complex interaction between different dietary fats and cellular outcomes. Therefore, the challenge is to prevent the lipid peroxidation of dietary unsaturated fatty acids through the utilization of natural antioxidants. This complexity indicates the necessity for further research into the function of palmitic acid in diverse pathological conditions and to find the main therapeutic target against its lipotoxicity. The aim of this review is, therefore, to examine recent data regarding the mechanism underlying PA-induced lipotoxicity in order to identify strategies that can promote protection mechanisms against lipotoxicity, dysfunction and apoptosis in MetS and obesity.
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Affiliation(s)
- Zeltzin Alejandra Ceja-Galicia
- Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico;
| | | | - Mohammed El-Hafidi
- Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico;
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Arghavani H, Bilodeau JF, Rudkowska I. Association Between Circulating Fatty Acids and Blood Pressure: A Review. Curr Nutr Rep 2025; 14:15. [PMID: 39775363 DOI: 10.1007/s13668-024-00602-3] [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] [Accepted: 12/10/2024] [Indexed: 01/11/2025]
Abstract
PURPOSE OF REVIEW High blood pressure (BP) or hypertension (HTN) remains key risk factors for cardiovascular disease (CVD). Circulating fatty acids (FAs) in the blood can affect directly cardiovascular hemodynamics and serves as building blocks for endocrine mediators modifying inflammatory processes and vascular function. This review aims to describe optimal circulating FA profiles for BP to adjust dietary recommendations for HTN prevention. RECENT FINDINGS Recent research highlights the critical role of FAs in regulating inflammation and vascular function. Different FAs have varying effects on oxidative stress, insulin resistance, inflammation, and vascular dysfunction, all contributing to HTN. These findings emphasize the importance of FAs in managing BP and preventing CVD. Up-to-now, findings suggest that eicosapentaenoic acid (20:5n3), docosahexaenoic acid (22:6n3), arachidic acid (20:0), behenic acid (22:0) and lignoceric acid (24:0) were promising candidates in reducing BP and thus, dietary intake could be recommended. Conversely, dietary intake of myristic acid (14:0), palmitic acid (16:0), and industrial trans FAs (iTFAs) should be restricted due to their association with elevated BP. Further research is warranted for pentadecanoic acid (15:0), heptadecanoic acid (17:0), stearic acid (18:0), alpha-linolenic acid (18:3n3), docosapentaenoic acid (22:5n3), linoleic acid (18:2n6), dihomo-gamma-linolenic acid (20:3n6), arachidonic acid (20:4n6), palmitoleic acid (16:1n7), and ruminant TFAs since their associations with BP present inconsistencies in the literature. Lifestyle factors such as dietary intake, physical activity, alcohol consumption and smoking should be considered when examining the relationship between FAs and BP. Overall, the FAs profile may contribute to BP level management; therefore, dietary recommendations are important.
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Affiliation(s)
- Hana Arghavani
- Endocrinology and Nephrology Research Axis, CHU de Québec Research Center, CHU of Quebec-Laval University, CHUL - 2705, Boulevard. Laurier, Quebec, G1V 4G2, Canada
| | - Jean-François Bilodeau
- Endocrinology and Nephrology Research Axis, CHU de Québec Research Center, CHU of Quebec-Laval University, CHUL - 2705, Boulevard. Laurier, Quebec, G1V 4G2, Canada
- Department of Medicine, Faculty of Medicine, Laval University, Quebec, QC, G1V 0A6, Canada
| | - Iwona Rudkowska
- Endocrinology and Nephrology Research Axis, CHU de Québec Research Center, CHU of Quebec-Laval University, CHUL - 2705, Boulevard. Laurier, Quebec, G1V 4G2, Canada.
- Department of Kinesiology, Faculty of Medicine, Laval University, Quebec, QC, G1V 0A6, Canada.
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Doll CL, Snider AJ. The diverse roles of sphingolipids in inflammatory bowel disease. FASEB J 2024; 38:e23777. [PMID: 38934445 PMCID: PMC467036 DOI: 10.1096/fj.202400830r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 05/28/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024]
Abstract
The incidence of inflammatory bowel disease (IBD) has increased over the last 20 years. A variety of causes, both physiological and environmental, contribute to the initiation and progression of IBD, making disease management challenging. Current treatment options target various aspects of the immune response to dampen intestinal inflammation; however, their effectiveness at retaining remission, their side effects, and loss of response from patients over time warrant further investigation. Finding a common thread within the multitude causes of IBD is critical in developing robust treatment options. Sphingolipids are evolutionary conserved bioactive lipids universally generated in all cell types. This diverse lipid family is involved in a variety of fundamental, yet sometimes opposing, processes such as proliferation and apoptosis. Implicated as regulators in intestinal diseases, sphingolipids are a potential cornerstone in understanding IBD. Herein we will describe the role of host- and microbial-derived sphingolipids as they relate to the many factors of intestinal health and IBD.
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Affiliation(s)
- Chelsea L. Doll
- School of Nutritional Sciences and Wellness, University of Arizona, Tucson, AZ 85721, USA
| | - Ashley J. Snider
- School of Nutritional Sciences and Wellness, University of Arizona, Tucson, AZ 85721, USA
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85721, USA
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Khan MM, Khan ZA, Khan MA. Metabolic complications of psychotropic medications in psychiatric disorders: Emerging role of de novo lipogenesis and therapeutic consideration. World J Psychiatry 2024; 14:767-783. [PMID: 38984346 PMCID: PMC11230099 DOI: 10.5498/wjp.v14.i6.767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 05/05/2024] [Accepted: 05/23/2024] [Indexed: 06/19/2024] Open
Abstract
Although significant advances have been made in understanding the patho-physiology of psychiatric disorders (PDs), therapeutic advances have not been very convincing. While psychotropic medications can reduce classical symptoms in patients with PDs, their long-term use has been reported to induce or exaggerate various pre-existing metabolic abnormalities including diabetes, obesity and non-alcoholic fatty liver disease (NAFLD). The mechanism(s) underlying these metabolic abnormalities is not clear; however, lipid/fatty acid accumulation due to enhanced de novo lipogenesis (DNL) has been shown to reduce membrane fluidity, increase oxidative stress and inflammation leading to the development of the aforementioned metabolic abnormalities. Intriguingly, emerging evidence suggest that DNL dysregulation and fatty acid accumulation could be the major mechanisms associated with the development of obesity, diabetes and NAFLD after long-term treatment with psychotropic medications in patients with PDs. In support of this, several adjunctive drugs comprising of anti-oxidants and anti-inflammatory agents, that are used in treating PDs in combination with psychotropic medications, have been shown to reduce insulin resistance and development of NAFLD. In conclusion, the above evidence suggests that DNL could be a potential pathological factor associated with various metabolic abnormalities, and a new avenue for translational research and therapeutic drug designing in PDs.
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Affiliation(s)
- Mohammad M Khan
- Laboratory of Translational Neurology and Molecular Psychiatry, Department of Biotechnology, Era’s Lucknow Medical College and Hospital, and Faculty of Science, Era University, Lucknow 226003, India
| | - Zaw Ali Khan
- Era’s Lucknow Medical College and Hospital, Era University, Lucknow 226003, India
| | - Mohsin Ali Khan
- Era’s Lucknow Medical College and Hospital, Era University, Lucknow 226003, India
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Portincasa P, Khalil M, Mahdi L, Perniola V, Idone V, Graziani A, Baffy G, Di Ciaula A. Metabolic Dysfunction-Associated Steatotic Liver Disease: From Pathogenesis to Current Therapeutic Options. Int J Mol Sci 2024; 25:5640. [PMID: 38891828 PMCID: PMC11172019 DOI: 10.3390/ijms25115640] [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: 04/02/2024] [Revised: 05/17/2024] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
The epidemiological burden of liver steatosis associated with metabolic diseases is continuously growing worldwide and in all age classes. This condition generates possible progression of liver damage (i.e., inflammation, fibrosis, cirrhosis, hepatocellular carcinoma) but also independently increases the risk of cardio-metabolic diseases and cancer. In recent years, the terminological evolution from "nonalcoholic fatty liver disease" (NAFLD) to "metabolic dysfunction-associated fatty liver disease" (MAFLD) and, finally, "metabolic dysfunction-associated steatotic liver disease" (MASLD) has been paralleled by increased knowledge of mechanisms linking local (i.e., hepatic) and systemic pathogenic pathways. As a consequence, the need for an appropriate classification of individual phenotypes has been oriented to the investigation of innovative therapeutic tools. Besides the well-known role for lifestyle change, a number of pharmacological approaches have been explored, ranging from antidiabetic drugs to agonists acting on the gut-liver axis and at a systemic level (mainly farnesoid X receptor (FXR) agonists, PPAR agonists, thyroid hormone receptor agonists), anti-fibrotic and anti-inflammatory agents. The intrinsically complex pathophysiological history of MASLD makes the selection of a single effective treatment a major challenge, so far. In this evolving scenario, the cooperation between different stakeholders (including subjects at risk, health professionals, and pharmaceutical industries) could significantly improve the management of disease and the implementation of primary and secondary prevention measures. The high healthcare burden associated with MASLD makes the search for new, effective, and safe drugs a major pressing need, together with an accurate characterization of individual phenotypes. Recent and promising advances indicate that we may soon enter the era of precise and personalized therapy for MASLD/MASH.
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Affiliation(s)
- Piero Portincasa
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.K.); (L.M.); (V.P.); (V.I.); (A.D.C.)
| | - Mohamad Khalil
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.K.); (L.M.); (V.P.); (V.I.); (A.D.C.)
| | - Laura Mahdi
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.K.); (L.M.); (V.P.); (V.I.); (A.D.C.)
| | - Valeria Perniola
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.K.); (L.M.); (V.P.); (V.I.); (A.D.C.)
| | - Valeria Idone
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.K.); (L.M.); (V.P.); (V.I.); (A.D.C.)
- Aboca S.p.a. Società Agricola, 52037 Sansepolcro, Italy
| | - Annarita Graziani
- Institut AllergoSan Pharmazeutische Produkte Forschungs- und Vertriebs GmbH, 8055 Graz, Austria;
| | - Gyorgy Baffy
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;
- Section of Gastroenterology, Department of Medicine, VA Boston Healthcare System, Boston, MA 02132, USA
| | - Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.K.); (L.M.); (V.P.); (V.I.); (A.D.C.)
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Gumpper-Fedus K, Crowe O, Hart PA, Pita-Grisanti V, Velez-Bonet E, Belury MA, L Ramsey M, Cole RM, Badi N, Culp S, Hinton A, F Lara L, Krishna SG, Conwell DL, Cruz-Monserrate Z. Differences in Plasma Fatty Acid Composition Related to Chronic Pancreatitis: A Pilot Study. Pancreas 2024; 53:e416-e423. [PMID: 38530954 PMCID: PMC11087201 DOI: 10.1097/mpa.0000000000002318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/28/2024]
Abstract
OBJECTIVES Chronic pancreatitis (CP) is an inflammatory disease affecting the absorption of fat-soluble nutrients. Signaling in pancreatic cells that lead to inflammation may be influenced by fatty acids (FAs) through diet and de novo lipogenesis. Here, we investigated the relationship between plasma FA composition in CP with heterogeneity of etiology and complications of CP. MATERIALS AND METHODS Blood and clinical parameters were collected from subjects with CP (n = 47) and controls (n = 22). Plasma was analyzed for FA composition using gas chromatography and compared between controls and CP and within CP. RESULTS Palmitic acid increased, and linoleic acid decreased in CP compared with controls. Correlations between age or body mass index and FAs are altered in CP compared with controls. Diabetes, pancreatic calcifications, and substance usage, but not exocrine pancreatic dysfunction, were associated with differences in oleic acid and linoleic acid relative abundance in CP. De novo lipogenesis index was increased in the plasma of subjects with CP compared with controls and in calcific CP compared with noncalcific CP. CONCLUSIONS Fatty acids that are markers of de novo lipogenesis and linoleic acid are dysregulated in CP depending on the etiology or complication. These results enhance our understanding of CP and highlight potential pathways targeting FAs for treating CP.
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Affiliation(s)
| | | | | | | | | | - Martha A Belury
- Department of Food Science and Technology, College of Food, Agriculture, and Environmental Sciences, The Ohio State University
| | - Mitchell L Ramsey
- From the Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine
| | - Rachel M Cole
- Department of Food Science and Technology, College of Food, Agriculture, and Environmental Sciences, The Ohio State University
| | | | | | - Alice Hinton
- Division of Biostatistics, College of Public Heath, The Ohio State University Wexner Medical Center, Columbus
| | - Luis F Lara
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH
| | | | - Darwin L Conwell
- Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, KY
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Zheng C, Lv S, Ye J, Zou L, Zhu K, Li H, Dong Y, Li L. Metabolomic Insights into the Mechanisms of Ganoderic Acid: Protection against α-Amanitin-Induced Liver Injury. Metabolites 2023; 13:1164. [PMID: 37999259 PMCID: PMC10672867 DOI: 10.3390/metabo13111164] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 11/16/2023] [Accepted: 11/18/2023] [Indexed: 11/25/2023] Open
Abstract
α-Amanitin is a representative toxin found in the Amanita genus of mushrooms, and the consumption of mushrooms containing α-Amanitin can lead to severe liver damage. In this study, we conduct toxicological experiments to validate the protective effects of Ganoderic acid A against α-amanitin-induced liver damage. By establishing animal models with different durations of Ganoderic acid A treatment and conducting a metabolomic analysis of the serum samples, we further confirmed the differences in serum metabolites between the AMA+GA and AMA groups. The analysis of differential serum metabolites after the Ganoderic acid A intervention suggests that Ganoderic acid A may intervene in α-amanitin-induced liver damage by participating in the regulation of retinol metabolism, tyrosine and tryptophan biosynthesis, fatty acid biosynthesis, sphingosine biosynthesis, spermidine and spermine biosynthesis, and branched-chain amino acid metabolism. This provides initial insights into the protective intervention mechanisms of GA against α-amanitin-induced liver damage and offers new avenues for the development of therapeutic drugs for α-Amanitin poisoning.
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Affiliation(s)
- Chong Zheng
- Guizhou Provincial Center for Disease Control and Prevention, Guiyang 550004, China; (C.Z.)
| | - Shaofang Lv
- School of Pharmacy, Guizhou Medical University, Guiyang 550025, China
| | - Jianfang Ye
- Guizhou Provincial Center for Disease Control and Prevention, Guiyang 550004, China; (C.Z.)
| | - Lu Zou
- Guizhou Provincial Center for Disease Control and Prevention, Guiyang 550004, China; (C.Z.)
| | - Kai Zhu
- Guizhou Provincial Center for Disease Control and Prevention, Guiyang 550004, China; (C.Z.)
| | - Haichang Li
- Guiyang Provincial Center for Disease Control and Prevention, Guiyang 550002, China
| | - Yongxi Dong
- School of Pharmacy, Guizhou Medical University, Guiyang 550025, China
| | - Lei Li
- Guizhou Provincial Center for Disease Control and Prevention, Guiyang 550004, China; (C.Z.)
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Arora M, Pavlíková Z, Kučera T, Kozlík P, Šopin T, Vacík T, Ľupták M, Duda M, Slanař O, Kutinová Canová N. Pharmacological effects of mTORC1/C2 inhibitor in a preclinical model of NASH progression. Biomed Pharmacother 2023; 167:115447. [PMID: 37683589 DOI: 10.1016/j.biopha.2023.115447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/29/2023] [Accepted: 09/04/2023] [Indexed: 09/10/2023] Open
Abstract
Knowledge of the benefits of mTOR inhibition concerning adipogenesis and inflammation has recently encouraged the investigation of a new generation of mTOR inhibitors for non-alcoholic steatohepatitis (NASH). We investigated whether treatment with a specific mTORC1/C2 inhibitor (Ku-0063794; KU) exerted any beneficial impacts on experimentally-induced NASH in vitro and in vivo. The results indicated that KU decreases palmitic acid-induced lipotoxicity in cultivated primary hepatocytes, thus emerging as a successful candidate for testing in an in vivo NASH dietary model, which adopted the intraperitoneal KU dosing route rather than oral application due to its significantly greater bioavailability in mice. The pharmacodynamics experiments commenced with the feeding of male C57BL/6 mice with a high-fat atherogenic western-type diet (WD) for differing intervals over several weeks aimed at inducing various phases of NASH. In addition to the WD, the mice were treated with KU for 3 weeks or 4 months. Acute and chronic KU treatments were observed to be safe at the given concentrations with no toxicity indications in the mice. KU was found to alleviate NASH-related hepatotoxicity, mitochondrial and oxidative stress, and decrease the liver triglyceride content and TNF-α mRNA in at least one set of in vivo experiments. The KU modulated liver expression of selected metabolic and oxidative stress-related genes depended upon the length and severity of the disease. Although KU failed to completely reverse the histological progression of NASH in the mice, we demonstrated the complexity of mTORC1/C2 signaling regulation and suggest a stratified therapeutic management approach throughout the disease course.
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Affiliation(s)
- Mahak Arora
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Zuzana Pavlíková
- Institute of Histology and Embryology, First Faculty of Medicine, Charles University, Prague, Czech Republic; Department of Anthropology and Human Genetics, Faculty of Science, Charles University, Prague, Czech Republic
| | - Tomáš Kučera
- Institute of Histology and Embryology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Petr Kozlík
- Department of Analytical Chemistry, Faculty of Science, Charles University, Prague, Czech Republic
| | - Tijana Šopin
- Institute of Biology and Medical Genetics of the First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Tomáš Vacík
- Institute of Biology and Medical Genetics of the First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Matej Ľupták
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Matthias Duda
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Ondřej Slanař
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Nikolina Kutinová Canová
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
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Shao Y, Chen S, Han L, Liu J. Pharmacotherapies of NAFLD: updated opportunities based on metabolic intervention. Nutr Metab (Lond) 2023; 20:30. [PMID: 37415199 DOI: 10.1186/s12986-023-00748-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 04/22/2023] [Indexed: 07/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that is becoming increasingly prevalent, and it ranges from simple steatosis to cirrhosis. However, there is still a lack of pharmacotherapeutic strategies approved by the Food and Drug Administration, which results in a higher risk of death related to carcinoma and cardiovascular complications. Of note, it is well established that the pathogenesis of NAFLD is tightly associated with whole metabolic dysfunction. Thus, targeting interconnected metabolic conditions could present promising benefits to NAFLD, according to a number of clinical studies. Here, we summarize the metabolic characteristics of the development of NAFLD, including glucose metabolism, lipid metabolism and intestinal metabolism, and provide insight into pharmacological targets. In addition, we present updates on the progresses in the development of pharmacotherapeutic strategies based on metabolic intervention globally, which could lead to new opportunities for NAFLD drug development.
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Affiliation(s)
- Yaodi Shao
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Suzhen Chen
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Liu Han
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| | - Junli Liu
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
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11
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Ortiz M, Sánchez F, Álvarez D, Flores C, Salas-Pérez F, Valenzuela R, Cantin C, Leiva A, Crisosto N, Maliqueo M. Association between maternal obesity, essential fatty acids and biomarkers of fetal liver function. Prostaglandins Leukot Essent Fatty Acids 2023; 190:102541. [PMID: 36736061 DOI: 10.1016/j.plefa.2023.102541] [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: 10/10/2022] [Revised: 01/13/2023] [Accepted: 01/15/2023] [Indexed: 01/18/2023]
Abstract
Maternal obesity and the imbalance in linoleic acid (C18:2 n-6, LA) and alpha-linolenic acid (C18:3 n-3, ALA) levels are related with hepatic disturbances in the offspring. However, whether these alterations are present during fetal life is not well understood. Obese and normal weight pregnant women were recruited to determine fatty acids (FAs) consumption, FAs profile (in maternal erythrocytes, placenta and neonatal very low-density lipoproteins VLDL) and biomarkers of fetal liver function, such as gamma-glutamyl transferase (GGT), alpha-fetoprotein (AFP) and albumin, in umbilical cord blood. Stearic acid (C18:0, ST) was lower, and total n-3 FAs tended to be lower in umbilical cord VLDLs of obese women compared to controls. Independently of maternal obesity, GGT levels in umbilical cord blood was positively correlated with the LA content and negatively correlated with the ALA content in maternal erythrocytes. We conclude that maternal obesity and its imbalance of LA and ALA are associated with changes in biomarkers of fetal liver function.
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Affiliation(s)
- Macarena Ortiz
- Laboratory of Endocrinology and Metabolism, Department of Medicine West Division, Universidad de Chile, Santiago, Chile
| | - Francisca Sánchez
- Laboratory of Endocrinology and Metabolism, Department of Medicine West Division, Universidad de Chile, Santiago, Chile
| | - Daniela Álvarez
- Laboratory of Endocrinology and Metabolism, Department of Medicine West Division, Universidad de Chile, Santiago, Chile
| | - Cristian Flores
- Laboratory of Endocrinology and Metabolism, Department of Medicine West Division, Universidad de Chile, Santiago, Chile
| | | | - Rodrigo Valenzuela
- Nutrition Department, School of Medicine, Universidad de Chile, Santiago, Chile
| | - Claudette Cantin
- School of Medical Technology, Faculty of Medicine and Science, Universidad San Sebastián, Santiago, Chile
| | - Andrea Leiva
- School of Medical Technology, Faculty of Medicine and Science, Universidad San Sebastián, Santiago, Chile
| | - Nicolás Crisosto
- Laboratory of Endocrinology and Metabolism, Department of Medicine West Division, Universidad de Chile, Santiago, Chile; Endocrinology Unit, Department of Medicine, Clínica Alemana de Santiago, Faculty of Medicine, Universidad del Desarrollo, Santiago, Chile
| | - Manuel Maliqueo
- Laboratory of Endocrinology and Metabolism, Department of Medicine West Division, Universidad de Chile, Santiago, Chile.
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12
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López-Acosta O, Ruiz-Ramírez A, Barrios-Maya MÁ, Alarcon-Aguilar J, Alarcon-Enos J, Céspedes Acuña CL, El-Hafidi M. Lipotoxicity, glucotoxicity and some strategies to protect vascular smooth muscle cell against proliferative phenotype in metabolic syndrome. Food Chem Toxicol 2023; 172:113546. [PMID: 36513245 DOI: 10.1016/j.fct.2022.113546] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 11/16/2022] [Accepted: 11/29/2022] [Indexed: 12/14/2022]
Abstract
Metabolic syndrome (MetS) is a risk factor for the development of cardiovascular disease (CVD) and atherosclerosis through a mechanism that involves vascular smooth muscle cell (VSMC) proliferation, lipotoxicity and glucotoxicity. Several molecules found to be increased in MetS, including free fatty acids, fatty acid binding protein 4, leptin, resistin, oxidized lipoprotein particles, and advanced glycation end products, influence VSMC proliferation. Most of these molecules act through their receptors on VSMCs by activating several signaling pathways associated with ROS generation in various cellular compartments. ROS from NADPH-oxidase and mitochondria have been found to promote VSMC proliferation and cell cycle progression. In addition, most of the natural or synthetic substances described in this review, including pharmaceuticals with hypoglycemic and hypolipidemic properties, attenuate VSMC proliferation by their simultaneous modulation of cell signaling and their scavenging property due to the presence of a phenolic ring in their structure. This review discusses recent data in the literature on the role that several MetS-related molecules and ROS play in the change from contractile to proliferative phenotype of VSMCs. Hence the importance of proposing an appropriate strategy to prevent uncontrolled VSMC proliferation using antioxidants, hypoglycemic and hypolipidemic agents.
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Affiliation(s)
- Ocarol López-Acosta
- Depto de Biomedicina Cardiovascular, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No 1, Colonia Sección XVI, Tlalpan, 14080, México D.F., Mexico
| | - Angélica Ruiz-Ramírez
- Depto de Biomedicina Cardiovascular, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No 1, Colonia Sección XVI, Tlalpan, 14080, México D.F., Mexico
| | - Miguel-Ángel Barrios-Maya
- Depto de Biomedicina Cardiovascular, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No 1, Colonia Sección XVI, Tlalpan, 14080, México D.F., Mexico
| | - Javier Alarcon-Aguilar
- Laboratorio de Farmacología, Depto. de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana Unidad Iztapalapa, Iztapalapa, Mexico
| | - Julio Alarcon-Enos
- Departamento de Ciencias Básicas, Facultad de Ciencias, Universidad del Bio Bio, Av. Andres Bello 720, Chillan, Chile
| | - Carlos L Céspedes Acuña
- Departamento de Ciencias Básicas, Facultad de Ciencias, Universidad del Bio Bio, Av. Andres Bello 720, Chillan, Chile.
| | - Mohammed El-Hafidi
- Depto de Biomedicina Cardiovascular, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No 1, Colonia Sección XVI, Tlalpan, 14080, México D.F., Mexico.
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13
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Gumpper-Fedus K, Crowe O, Hart PA, Pita-Grisanti V, Velez-Bonet E, Belury MA, Ramsey M, Cole RM, Badi N, Culp S, Hinton A, Lara L, Krishna SG, Conwell DL, Cruz-Monserrate Z. Changes in Plasma Fatty Acid Abundance Related to Chronic Pancreatitis: A Pilot Study. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.05.522899. [PMID: 36711757 PMCID: PMC9881940 DOI: 10.1101/2023.01.05.522899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Objectives Chronic pancreatitis (CP) is an inflammatory disease that affects the absorption of nutrients like fats. Molecular signaling in pancreatic cells can be influenced by fatty acids (FAs) and changes in FA abundance could impact CP-associated complications. Here, we investigated FA abundance in CP compared to controls and explored how CP-associated complications and risk factors affect FA abundance. Methods Blood and clinical parameters were collected from subjects with (n=47) and without CP (n=22). Plasma was analyzed for relative FA abundance using gas chromatography and compared between controls and CP. Changes in FA abundance due to clinical parameters were also assessed in both groups. Results Decreased relative abundance of polyunsaturated fatty acids (PUFAs) and increased monounsaturated fatty acids (MUFAs) were observed in subjects with CP in a sex-dependent manner. The relative abundance of linoleic acid increased, and oleic acid decreased in CP subjects with exocrine pancreatic dysfunction and a history of substance abuse. Conclusions Plasma FAs like linoleic acid are dysregulated in CP in a sex-dependent manner. Additionally, risk factors and metabolic dysfunction further dysregulate FA abundance in CP. These results enhance our understanding of CP and highlight potential novel targets and metabolism-related pathways for treating CP.
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Martinez-Gili L, Pechlivanis A, McDonald JA, Begum S, Badrock J, Dyson JK, Jones R, Hirschfield G, Ryder SD, Sandford R, Rushbrook S, Thorburn D, Taylor-Robinson SD, Crossey MM, Marchesi JR, Mells G, Holmes E, Jones D. Bacterial and metabolic phenotypes associated with inadequate response to ursodeoxycholic acid treatment in primary biliary cholangitis. Gut Microbes 2023; 15:2208501. [PMID: 37191344 PMCID: PMC10190197 DOI: 10.1080/19490976.2023.2208501] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 04/06/2023] [Accepted: 04/21/2023] [Indexed: 05/17/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. Poor response to UDCA is associated with a higher risk of progressing to cirrhosis, but the underlying mechanisms are unclear. UDCA modulates the composition of primary and bacterial-derived bile acids (BAs). We characterized the phenotypic response to UDCA based on BA and bacterial profiles of PBC patients treated with UDCA. Patients from the UK-PBC cohort (n = 419) treated with UDCA for a minimum of 12-months were assessed using the Barcelona dynamic response criteria. BAs from serum, urine, and feces were analyzed using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry and fecal bacterial composition measured using 16S rRNA gene sequencing. We identified 191 non-responders, 212 responders, and a subgroup of responders with persistently elevated liver biomarkers (n = 16). Responders had higher fecal secondary and tertiary BAs than non-responders and lower urinary bile acid abundances, with the exception of 12-dehydrocholic acid, which was higher in responders. The sub-group of responders with poor liver function showed lower alpha-diversity evenness, lower abundance of fecal secondary and tertiary BAs than the other groups and lower levels of phyla with BA-deconjugation capacity (Actinobacteriota/Actinomycetota, Desulfobacterota, Verrucomicrobiota) compared to responders. UDCA dynamic response was associated with an increased capacity to generate oxo-/epimerized secondary BAs. 12-dehydrocholic acid is a potential biomarker of treatment response. Lower alpha-diversity and lower abundance of bacteria with BA deconjugation capacity might be associated with an incomplete response to treatment in some patients.
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Affiliation(s)
- Laura Martinez-Gili
- Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Alexandros Pechlivanis
- Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Biomic_Auth, Bioanalysis and Omics Laboratory, Center for Interdisciplinary Research and Innovation (CIRI-AUTH), Balkan Centre, Thessaloniki, Greece
| | - Julie A.K. McDonald
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Sofina Begum
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Jonathan Badrock
- Academic Department of Medical Genetics, Cambridge University, Cambridge, UK
| | - Jessica K. Dyson
- Liver Unit, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Institute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne, UK
| | - Rebecca Jones
- Leeds Liver Unit, St James’s University Hospital, Leeds, UK
| | - Gideon Hirschfield
- Center for Liver and Gastroenterology Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK
| | - Stephen D. Ryder
- NIHR Biomedical Research Centre at Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, UK
| | - Richard Sandford
- Academic Department of Medical Genetics, Cambridge University, Cambridge, UK
| | - Simon Rushbrook
- Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, UK
| | - Douglas Thorburn
- UCL Royal Free Campus, Royal Free Hospital, University College London Institute of Liver and Digestive Health, London, UK
| | | | - Mary M.E. Crossey
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Julian R. Marchesi
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - George Mells
- Academic Department of Medical Genetics, Cambridge University, Cambridge, UK
- Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Elaine Holmes
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Center for Computational & Systems Medicine, Murdoch University, Perth, Australia
| | - David Jones
- Liver Unit, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Institute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne, UK
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15
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Taya N, Katakami N, Omori K, Hosoe S, Watanabe H, Takahara M, Miyashita K, Nishizawa H, Konya Y, Obara S, Hidaka A, Nakao M, Takahashi M, Izumi Y, Shimomura I, Bamba T. Change in fatty acid composition of plasma triglyceride caused by a 2 week comprehensive risk management for diabetes: A prospective observational study of type 2 diabetes patients with supercritical fluid chromatography/mass spectrometry-based semi-target lipidomic analysis. J Diabetes Investig 2022; 14:102-110. [PMID: 36208067 PMCID: PMC9807157 DOI: 10.1111/jdi.13924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 09/02/2022] [Accepted: 09/26/2022] [Indexed: 01/07/2023] Open
Abstract
AIMS/INTRODUCTION Hypertriglyceridemia is common in patients with diabetes. Although the fatty acid (FA) composition of triglycerides (TGs) is suggested to be related to the pathology of diabetes and its complications, changes in the fatty acid composition caused by diabetes treatment remain unclear. This study aimed to identify short-term changes in the fatty acid composition of plasma triglycerides after diabetes treatment. MATERIALS AND METHODS This study was a sub-analysis of a prospective observational study of patients with type 2 diabetes aged between 20 and 75 years who were hospitalized to improve glycemic control (n = 31). A lipidomic analysis of plasma samples on the 2nd and 16th hospital days was conducted by supercritical fluid chromatography coupled with mass spectrometry. RESULTS In total, 104 types of triglycerides with different compositions were identified. Most of them tended to decrease after treatment. In particular, triglycerides with a lower carbon number and fewer double bonds showed a relatively larger reduction. The inclusion of FA 14:0 (myristic acid), as a constituent of triglyceride, was significantly associated with a more than 50%, and statistically significant, reduction (odds ratio 39.0; P < 0.001). The total amount of FA 14:0 as a constituent of triglycerides also decreased significantly, and its rate of decrease was the greatest of all the fatty acid constituents. CONCLUSIONS A 2 week comprehensive risk management for diabetes resulted in decreased levels of plasma triglycerides and a change in the fatty acid composition of triglycerides, characterized by a relatively large reduction in FA 14:0 as a constituent of triglycerides.
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Affiliation(s)
- Naohiro Taya
- Department of Metabolic MedicineOsaka University Graduate School of MedicineOsakaJapan
| | - Naoto Katakami
- Department of Metabolic MedicineOsaka University Graduate School of MedicineOsakaJapan
| | - Kazuo Omori
- Department of Metabolic MedicineOsaka University Graduate School of MedicineOsakaJapan
| | - Shigero Hosoe
- Department of Metabolic MedicineOsaka University Graduate School of MedicineOsakaJapan
| | - Hirotaka Watanabe
- Department of Metabolic MedicineOsaka University Graduate School of MedicineOsakaJapan
| | - Mitsuyoshi Takahara
- Department of Metabolic MedicineOsaka University Graduate School of MedicineOsakaJapan,Department of Diabetes Care Medicine, Graduate School of MedicineOsaka UniversityOsakaJapan
| | - Kazuyuki Miyashita
- Department of Metabolic MedicineOsaka University Graduate School of MedicineOsakaJapan
| | - Hitoshi Nishizawa
- Department of Metabolic MedicineOsaka University Graduate School of MedicineOsakaJapan
| | - Yutaka Konya
- Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of BioregulationKyushu UniversityFukuokaJapan
| | - Sachiko Obara
- Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of BioregulationKyushu UniversityFukuokaJapan
| | - Ayako Hidaka
- Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of BioregulationKyushu UniversityFukuokaJapan
| | - Motonao Nakao
- Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of BioregulationKyushu UniversityFukuokaJapan
| | - Masatomo Takahashi
- Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of BioregulationKyushu UniversityFukuokaJapan
| | - Yoshihiro Izumi
- Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of BioregulationKyushu UniversityFukuokaJapan
| | - Iichiro Shimomura
- Department of Metabolic MedicineOsaka University Graduate School of MedicineOsakaJapan
| | - Takeshi Bamba
- Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of BioregulationKyushu UniversityFukuokaJapan
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16
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Yu A, Cable C, Sharma S, Shihan MH, Mattis AN, Mileva I, Hannun YA, Duwaerts CC, Chen JY. Targeting acid ceramidase ameliorates fibrosis in mouse models of non-alcoholic steatohepatitis. Front Med (Lausanne) 2022; 9:881848. [PMID: 36275798 PMCID: PMC9582277 DOI: 10.3389/fmed.2022.881848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 09/15/2022] [Indexed: 11/26/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common cause of liver disease worldwide, and is characterized by the accumulation of fat in the liver. Non-alcoholic steatohepatitis (NASH), an advanced form of NAFLD, is a leading cause of liver transplantation. Fibrosis is the histologic feature most associated with liver-related morbidity and mortality in patients with NASH, and treatment options remain limited. In previous studies, we discovered that acid ceramidase (aCDase) is a potent antifibrotic target using human hepatic stellate cells (HSCs) and models of hepatic fibrogenesis. Using two dietary mouse models, we demonstrate that depletion of aCDase in HSC reduces fibrosis without worsening metabolic features of NASH, including steatosis, inflammation, and insulin resistance. Consistently, pharmacologic inhibition of aCDase ameliorates fibrosis but does not alter metabolic parameters. The findings suggest that targeting aCDase is a viable therapeutic option to reduce fibrosis in patients with NASH.
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Affiliation(s)
- Amy Yu
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Carson Cable
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Sachin Sharma
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Mahbubul H. Shihan
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Aras N. Mattis
- Department of Pathology, University of California, San Francisco, San Francisco, CA, United States
- The Liver Center, University of California, San Francisco, San Francisco, CA, United States
| | - Izolda Mileva
- Department of Medicine and Biochemistry and the Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, United States
| | - Yusuf A. Hannun
- Department of Medicine and Biochemistry and the Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, United States
| | - Caroline C. Duwaerts
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
- The Liver Center, University of California, San Francisco, San Francisco, CA, United States
| | - Jennifer Y. Chen
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
- The Liver Center, University of California, San Francisco, San Francisco, CA, United States
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17
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Rodríguez‐García C, Sánchez‐Quesada C, Algarra I, Gaforio JJ. Differential Immunometabolic Effects of High-Fat Diets Containing Coconut, Sunflower, and Extra Virgin Olive Oils in Female Mice. Mol Nutr Food Res 2022; 66:e2200082. [PMID: 35848367 PMCID: PMC9787653 DOI: 10.1002/mnfr.202200082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 07/06/2022] [Indexed: 12/30/2022]
Abstract
SCOPE To compare the effects of three high-fat diets (HFDs) based on coconut, sunflower, or extra virgin olive oils (EVOOs) on adipose tissue, metabolism, and inflammation. METHODS AND RESULTS Mice are fed for 16 weeks on their respective HFD. HFD based on coconut oil produces significantly lower body weight than EVOO- or sunflower oil-based HFDs. Furthermore, the coconut oil HFD leads to metabolic disturbances such as reduction of circulating leptin and adiponectin concentrations, hypertriglyceridemia, hepatomegaly, and liver triglyceride accumulation. Likewise, this diet produces an increase in serum pro-inflammatory cytokines (interleukin 6 [IL-6] and tumor necrosis factor-α [TNF-α]). In white (WAT) and brown (BAT) adipose tissue, the HFD based on coconut oil does not cause significant changes in the expression of studied proteins related to thermogenesis (uncoupling protein 1 [UCP-1]), mitochondrial biogenesis, and browning (peroxisome proliferator-activated receptor-γ coactivator 1α [PGC-1α] and nuclear factor E2-related factor 2 [Nrf2]). However, the HFD based on EVOO induces upregulation of UCP-1, PGC-1α, and Nrf2 expression in BAT, increases the expression of UCP-1 and PGC-1α in inguinal WAT, and enhances the expression of PGC-1α in epididymal WAT. CONCLUSIONS An HFD based on coconut oil could reduce circulating leptin and adiponectin concentrations, increase the liver fat content, raise serum triglycerides, and promote inflammation by increasing circulating pro-inflammatory cytokines, while an EVOO-based HFD could increase thermogenic activity.
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Affiliation(s)
- Carmen Rodríguez‐García
- Department of Health Sciences, Faculty of Experimental SciencesUniversity of JaénJaén23071Spain
- University Institute of Research in Olive Groves and Olive Oils University of JaenCampus las Lagunillas, s/nJaén23071Spain
| | - Cristina Sánchez‐Quesada
- Department of Health Sciences, Faculty of Experimental SciencesUniversity of JaénJaén23071Spain
- University Institute of Research in Olive Groves and Olive Oils University of JaenCampus las Lagunillas, s/nJaén23071Spain
- Agri‐food Campus of International Excellence (ceiA3)Córdoba14071Spain
| | - Ignacio Algarra
- Department of Health Sciences, Faculty of Experimental SciencesUniversity of JaénJaén23071Spain
| | - José J. Gaforio
- Department of Health Sciences, Faculty of Experimental SciencesUniversity of JaénJaén23071Spain
- University Institute of Research in Olive Groves and Olive Oils University of JaenCampus las Lagunillas, s/nJaén23071Spain
- Agri‐food Campus of International Excellence (ceiA3)Córdoba14071Spain
- CIBER Epidemiología y Salud Pública (CIBER‐ESP)Instituto de Salud Carlos IIIMadrid28029Spain
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18
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The role of some lipids and their metabolites in programmed cell death (lipoapoptosis). ACTA BIOMEDICA SCIENTIFICA 2022. [DOI: 10.29413/abs.2022-7.4.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
In recent years, the understanding of the mechanisms involved in the regulation of lipoapoptosis signaling pathways has expanded considerably. However, many mechanisms of apoptosis induction by lipids as well as molecules mediating intracellular and systemic signals belonging to AOS/enzyme-dependent phospholipid metabolites are not completely clear.This review summarizes the current understanding of the mechanisms of apoptotic cell death induction by some lipid molecules. Literature search was performed in the database “PubMed”, “eLIBRARY” using key words: “apoptosis”, “lipids”, “fatty acids”, “eicosanoids”, “reactive oxygen species”.A brief characterization of the signaling pathways of apoptosis is given. The role of reactive oxygen species and their dependent products of lipid peroxidation in the regulation of the main signaling pathways of apoptosis are shown. Particular attention is paid to the product of phospholipid metabolism – 4-hydroxynonenal.Pro- and anti-apoptotic effects of some prostaglandins are demonstrated. Arguments are presented that prostaglandins of series J and D are pro-apoptotic in most cells, and this effect depends on activation of the prostanoid receptor DP2 and on reduction of AKT kinase activity. In contrast, the E-series prostaglandins and hydroxyecosatetraenoic acid act opposite to the J-series and D-series prostaglandins, reducing apoptosis by activating AKT and increasing Bcl-2 protein expression.The role of individual fatty acids involved in the initiation and transduction of pro-apoptotic and anti-apoptotic signals is assessed. It was shown that saturated fatty acids have the maximum damaging potential than their unsaturated counterparts. An in-depth understanding and deciphering of the mechanisms by which lipids and their metabolites modulate the activation of signaling pathways of programmed cell death can help to develop therapeutic strategies to prevent a number of diseases associated with impaired regulation of apoptosis.
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19
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Miclea I. Secondary Metabolites with Biomedical Applications from Plants of the Sarraceniaceae Family. Int J Mol Sci 2022; 23:9877. [PMID: 36077275 PMCID: PMC9456395 DOI: 10.3390/ijms23179877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 11/17/2022] Open
Abstract
Carnivorous plants have fascinated researchers and hobbyists for centuries because of their mode of nutrition which is unlike that of other plants. They are able to produce bioactive compounds used to attract, capture and digest prey but also as a defense mechanism against microorganisms and free radicals. The main purpose of this review is to provide an overview of the secondary metabolites with significant biological activity found in the Sarraceniaceae family. The review also underlines the necessity of future studies for the biochemical characterization of the less investigated species. Darlingtonia, Heliamphora and Sarracenia plants are rich in compounds with potential pharmaceutical and medical uses. These belong to several classes such as flavonoids, with flavonol glycosides being the most abundant, monoterpenes, triterpenes, sesquiterpenes, fatty acids, alkaloids and others. Some of them are well characterized in terms of chemical properties and biological activity and have widespread commercial applications. The review also discusses biological activity of whole extracts and commercially available products derived from Sarraceniaceae plants. In conclusion, this review underscores that Sarraceniaceae species contain numerous substances with the potential to advance health. Future perspectives should focus on the discovery of new molecules and increasing the production of known compounds using biotechnological methods.
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Affiliation(s)
- Ileana Miclea
- Department of Fundamental Sciences, Faculty of Animal Science and Biotechnology, University of Agricultural Sciences and Veterinary Medicine, 400372 Cluj-Napoca, Romania
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20
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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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21
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Contribution of specific ceramides to obesity-associated metabolic diseases. Cell Mol Life Sci 2022; 79:395. [PMID: 35789435 PMCID: PMC9252958 DOI: 10.1007/s00018-022-04401-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/20/2022] [Accepted: 05/26/2022] [Indexed: 12/04/2022]
Abstract
Ceramides are a heterogeneous group of bioactive membrane sphingolipids that play specialized regulatory roles in cellular metabolism depending on their characteristic fatty acyl chain lengths and subcellular distribution. As obesity progresses, certain ceramide molecular species accumulate in metabolic tissues and cause cell-type-specific lipotoxic reactions that disrupt metabolic homeostasis and lead to the development of cardiometabolic diseases. Several mechanisms for ceramide action have been inferred from studies in vitro, but only recently have we begun to better understand the acyl chain length specificity of ceramide-mediated signaling in the context of physiology and disease in vivo. New discoveries show that specific ceramides affect various metabolic pathways and that global or tissue-specific reduction in selected ceramide pools in obese rodents is sufficient to improve metabolic health. Here, we review the tissue-specific regulation and functions of ceramides in obesity, thus highlighting the emerging concept of selectively inhibiting production or action of ceramides with specific acyl chain lengths as novel therapeutic strategies to ameliorate obesity-associated diseases.
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22
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Gao Y, Wang C, Wang K, He C, Hu K, Liang M. The effects and molecular mechanism of heat stress on spermatogenesis and the mitigation measures. Syst Biol Reprod Med 2022; 68:331-347. [PMID: 35722894 DOI: 10.1080/19396368.2022.2074325] [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] [Indexed: 10/18/2022]
Abstract
Under normal conditions, to achieve optimal spermatogenesis, the temperature of the testes should be 2-6 °C lower than body temperature. Cryptorchidism is one of the common pathogenic factors of male infertility. The increase of testicular temperature in male cryptorchidism patients leads to the disorder of body regulation and balance, induces the oxidative stress response of germ cells, destroys the integrity of sperm DNA, yields morphologically abnormal sperm, and leads to excessive apoptosis of germ cells. These physiological changes in the body can reduce sperm fertility and lead to male infertility. This paper describes the factors causing testicular heat stress, including lifestyle and behavioral factors, occupational and environmental factors (external factors), and clinical factors caused by pathological conditions (internal factors). Studies have shown that wearing tight pants or an inappropriate posture when sitting for a long time in daily life, and an increase in ambient temperature caused by different seasons or in different areas, can cause an increase in testicular temperature, induces testicular oxidative stress response, and reduce male fertility. The occurrence of cryptorchidism causes pathological changes within the testis and sperm, such as increased germ cell apoptosis, DNA damage in sperm cells, changes in gene expression, increase in chromosome aneuploidy, and changes in Na+/K+-ATPase activity, etc. At the end of the article, we list some substances that can relieve oxidative stress in tissues, such as trigonelline, melatonin, R. apetalus, and angelica powder. These substances can protect testicular tissue and relieve the damage caused by excessive oxidative stress.
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Affiliation(s)
- Yuanyuan Gao
- School of Life Science, Bengbu Medical College, Bengbu, People's Republic of China
| | - Chen Wang
- School of Life Science, Bengbu Medical College, Bengbu, People's Republic of China
| | - Kaixian Wang
- School of Life Science, Bengbu Medical College, Bengbu, People's Republic of China
| | - Chaofan He
- School of Life Science, Bengbu Medical College, Bengbu, People's Republic of China
| | - Ke Hu
- School of Life Science, Bengbu Medical College, Bengbu, People's Republic of China
| | - Meng Liang
- School of Life Science, Bengbu Medical College, Bengbu, People's Republic of China
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23
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Saraswathi V, Kumar N, Ai W, Gopal T, Bhatt S, Harris EN, Talmon GA, Desouza CV. Myristic Acid Supplementation Aggravates High Fat Diet-Induced Adipose Inflammation and Systemic Insulin Resistance in Mice. Biomolecules 2022; 12:739. [PMID: 35740864 PMCID: PMC9220168 DOI: 10.3390/biom12060739] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 05/19/2022] [Accepted: 05/20/2022] [Indexed: 12/12/2022] Open
Abstract
Saturated fatty acids (SFAs) are considered to be detrimental to human health. One of the SFAs, myristic acid (MA), is known to exert a hypercholesterolemic effect in mice as well as humans. However, its effects on altering adipose tissue (AT) inflammation and systemic insulin resistance (IR) in obesity are still unclear. Here, we sought to determine the effects of a high fat (HF) diet supplemented with MA on obesity-associated metabolic disorders in mice. Wild-type C57BL/6 mice were fed a HF diet in the presence or absence of 3% MA for 12 weeks. Plasma lipids, plasma adipokines, AT inflammation, systemic IR, glucose homeostasis, and hepatic steatosis were assessed. The body weight and visceral adipose tissue (VAT) mass were significantly higher in mice receiving the HF+MA diet compared to HF diet-fed controls. Plasma total cholesterol levels were marginally increased in HF+MA-fed mice compared to controls. Fasting blood glucose was comparable between HF and HF+MA-fed mice. Interestingly, the plasma insulin and HOMA-IR index, a measure of insulin resistance, were significantly higher in HF+MA-fed mice compared to HF controls. Macrophage and inflammatory markers were significantly elevated in the AT and AT-derived stromal vascular cells upon MA feeding. Moreover, the level of circulating resistin, an adipokine promoting insulin resistance, was significantly higher in HF+MA-fed mice compared with HF controls. The insulin tolerance test revealed that the IR was higher in mice receiving the MA supplementation compared to HF controls. Moreover, the glucose tolerance test showed impairment in systemic glucose homeostasis in MA-fed mice. Analyses of liver samples showed a trend towards an increase in liver TG upon MA feeding. However, markers of oxidative stress and inflammation were reduced in the liver of mice fed an MA diet compared to controls. Taken together, our data suggest that chronic administration of MA in diet exacerbates obesity-associated insulin resistance and this effect is mediated in part, via increased AT inflammation and increased secretion of resistin.
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Affiliation(s)
- Viswanathan Saraswathi
- Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; (N.K.); (W.A.); (T.G.); (S.B.); (C.V.D.)
- Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
| | - Narendra Kumar
- Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; (N.K.); (W.A.); (T.G.); (S.B.); (C.V.D.)
- Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
| | - Weilun Ai
- Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; (N.K.); (W.A.); (T.G.); (S.B.); (C.V.D.)
- Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
| | - Thiyagarajan Gopal
- Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; (N.K.); (W.A.); (T.G.); (S.B.); (C.V.D.)
- Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
| | - Saumya Bhatt
- Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; (N.K.); (W.A.); (T.G.); (S.B.); (C.V.D.)
- Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
| | - Edward N. Harris
- Department of Biochemistry, University of Nebraska, Lincoln, NE 68588, USA;
| | - Geoffrey A. Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Cyrus V. Desouza
- Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; (N.K.); (W.A.); (T.G.); (S.B.); (C.V.D.)
- Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
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24
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Torres S, Segalés P, García-Ruiz C, Fernández-Checa JC. Mitochondria and the NLRP3 Inflammasome in Alcoholic and Nonalcoholic Steatohepatitis. Cells 2022; 11:1475. [PMID: 35563780 PMCID: PMC9105698 DOI: 10.3390/cells11091475] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 04/18/2022] [Accepted: 04/25/2022] [Indexed: 12/12/2022] Open
Abstract
Alcoholic (ASH) and nonalcoholic steatohepatitis (NASH) are advanced stages of fatty liver disease and two of the most prevalent forms of chronic liver disease. ASH and NASH are associated with significant risk of further progression to cirrhosis and hepatocellular carcinoma (HCC), the most common type of liver cancer, and a major cause of cancer-related mortality. Despite extensive research and progress in the last decades to elucidate the mechanisms of the development of ASH and NASH, the pathogenesis of both diseases is still poorly understood. Mitochondrial damage and activation of inflammasome complexes have a role in inducing and sustaining liver damage. Mitochondrial dysfunction produces inflammatory factors that activate the inflammasome complexes. NLRP3 inflammasome (nucleotide-binding oligomerization domain-like receptor protein 3) is a multiprotein complex that activates caspase 1 and the release of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and interleukin-18 (IL-18), and contributes to inflammatory pyroptotic cell death. The present review, which is part of the issue "Mitochondria in Liver Pathobiology", provides an overview of the role of mitochondrial dysfunction and NLRP3 activation in ASH and NASH.
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Affiliation(s)
- Sandra Torres
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Paula Segalés
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Carmen García-Ruiz
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - José C. Fernández-Checa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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25
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Jiang LP, Sun HZ. Long-chain saturated fatty acids and its interaction with insulin resistance and the risk of nonalcoholic fatty liver disease in type 2 diabetes in Chinese. Front Endocrinol (Lausanne) 2022; 13:1051807. [PMID: 36568120 PMCID: PMC9768420 DOI: 10.3389/fendo.2022.1051807] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 11/23/2022] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION This study aimed to explore relationships between long-chain saturated fatty acids (LSFAs) and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes (T2D); and whether insulin action had an interactive effect with LSFAs on NAFLD progression. METHODS From April 2018 to April 2019, we extracted the electronic medical records of 481 patients with T2D who meet the inclusion and exclusion criteria from the Second Affiliated Hospital of Dalian Medical University. Ultrasound was used to estimate NAFLD at admission. Logistic regression analysis were used to estimate odds ratios (OR) and 95% confidence intervals (CI). The additive interaction was carried out to estimate interactions between LSFAs and insulin resistance (IR) in NAFLD patients with T2D. RESULTS Myristic acid (14:0) and palmitic acid (16:0) were positively associated with the risk of NAFLD (OR for myristic acid (14:0): 7.516, 3.557-15.882 and OR for palmitic acid (16:0): 4.071, 1.987-8.343, respectively). After adjustment for traditional risk factors, these associations were slightly attenuated but still highly significant. Co-presence of myristic acid (14:0)>72.83 μmol/L and IR>4.89 greatly increased OR of NAFLD to 9.691 (4.113-22.833). Similarly, co-presence of palmitic acid (16:0)>3745.43μmol/L and IR>4.89 greatly increased OR of NAFLD to 6.518(2.860-14.854). However, stearic acid (18:0) and risk of NAFLD have no association. Moreover, there was no association between very-long-chain SFAs (VLSFAs) and risk of NAFLD. DISCUSSION Myristic acid (14:0) and palmitic acid (16:0) were positively associated with the risk of NAFLD in T2D patients in China. High IR amplified the effect of high myristic acid (14:0) and high palmitic acid (16:0) on NAFLD.
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Affiliation(s)
- Li-Peng Jiang
- Department of Radiation Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Hong-Zhi Sun
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
- Key Laboratory of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou Medical University, Jinzhou, China
- *Correspondence: Hong-Zhi Sun,
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26
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Manifold Roles of Ceramide Metabolism in Non-Alcoholic Fatty Liver Disease and Liver Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1372:157-168. [DOI: 10.1007/978-981-19-0394-6_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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27
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Parthasarathy G, Malhi H. Assessment of Lipotoxic Endoplasmic Reticulum (ER) Stress in Nonalcoholic Steatohepatitis (NASH). Methods Mol Biol 2022; 2455:243-254. [PMID: 35212999 PMCID: PMC9333415 DOI: 10.1007/978-1-0716-2128-8_19] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Hepatocyte lipotoxicity is a hallmark of nonalcoholic steatohepatitis (NASH), and lipid induced liver injury occurs, in part, via activation of endoplasmic reticulum (ER) stress. Consequently, the unfolded protein response (UPR) is initiated, driven by three key ER transmembrane proteins, resulting in downstream responses that are dynamic and interconnected. Thus, careful interrogation of these pathways is required to investigate the complex role of ER stress in NASH. Herein, we describe different mechanisms of, and in vitro assays for assessment of lipotoxic ER stress in mouse hepatocytes.
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Affiliation(s)
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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28
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Borek-Dorosz A, Pieczara A, Czamara K, Stojak M, Matuszyk E, Majzner K, Brzozowski K, Bresci A, Polli D, Baranska M. What is the ability of inflamed endothelium to uptake exogenous saturated fatty acids? A proof-of-concept study using spontaneous Raman, SRS and CARS microscopy. Cell Mol Life Sci 2022; 79:593. [PMID: 36380212 PMCID: PMC9666316 DOI: 10.1007/s00018-022-04616-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 10/16/2022] [Accepted: 10/27/2022] [Indexed: 11/17/2022]
Abstract
Endothelial cells (EC) in vivo buffer and regulate the transfer of plasma fatty acid (FA) to the underlying tissues. We hypothesize that inflammation could alter the functionality of the EC, i.e., their capacity and uptake of different FA. The aim of this work is to verify the functionality of inflamed cells by analyzing their ability to uptake and accumulate exogenous saturated FA. Control and inflammatory human microvascular endothelial cells stimulated in vitro with two deuterium-labeled saturated FA (D-FA), i.e., palmitic (D31-PA) and myristic (D27-MA) acids. Cells were measured both by spontaneous and stimulated Raman imaging to extract detailed information about uptaken FA, whereas coherent anti-Stokes Raman scattering and fluorescence imaging showed the global content of FA in cells. Additionally, we employed atomic force microscopy to obtain a morphological image of the cells. The results indicate that the uptake of D-FA in inflamed cells is dependent on their concentration and type. Cells accumulated D-FA when treated with a low concentration, and the effect was more pronounced for D27-MA, in normal cells, but even more so, in inflamed cells. In the case of D31-PA, a slightly increased uptake was observed for inflamed cells when administered at higher concentration. The results provide a better understanding of the EC inflammation and indicate the impact of the pathological state of the EC on their capacity to buffer fat. All the microscopic methods used showed complementarity in the analysis of FA uptake by EC, but each method recognized this process from a different perspective.
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Affiliation(s)
| | - Anna Pieczara
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| | - Krzysztof Czamara
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| | - Marta Stojak
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| | - Ewelina Matuszyk
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| | - Katarzyna Majzner
- Faculty of Chemistry, Jagiellonian University, 2 Gronostajowa Str., 30-387 Krakow, Poland ,Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| | - Krzysztof Brzozowski
- Faculty of Chemistry, Jagiellonian University, 2 Gronostajowa Str., 30-387 Krakow, Poland
| | - Arianna Bresci
- Physics Department, Politecnico di Milano, Piazza Leonardo da Vinci, 32, 20133 Milan, Italy
| | - Dario Polli
- Physics Department, Politecnico di Milano, Piazza Leonardo da Vinci, 32, 20133 Milan, Italy ,Institute for Photonics and Nanotechnology at CNR (CNR-IFN), Piazza Leonardo da Vinci, 32, 20133 Milan, Italy
| | - Malgorzata Baranska
- Faculty of Chemistry, Jagiellonian University, 2 Gronostajowa Str., 30-387 Krakow, Poland ,Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
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29
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Masetto Antunes M, Godoy G, Curi R, Vergílio Visentainer J, Barbosa Bazotte R. The Myristic Acid:Docosahexaenoic Acid Ratio Versus the n-6 Polyunsaturated Fatty Acid:n-3 Polyunsaturated Fatty Acid Ratio as Nonalcoholic Fatty Liver Disease Biomarkers. Metab Syndr Relat Disord 2021; 20:69-78. [PMID: 34813379 DOI: 10.1089/met.2021.0107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
It is well established that diets containing an increased omega-6 polyunsaturated fatty acid (n-6 PUFA) to omega-3 polyunsaturated fatty acid (n-3 PUFA) ratios are linked to inflammation and chronic diseases such as nonalcoholic fatty liver disease (NAFLD). However, the influence of an elevated n-6 PUFA:n-3 PUFA ratio in the tissues requires clarification. Herein, we identified primary experimental and clinical studies where it is possible to compare the performance of the myristic acid (Myr):docosahexaenoic acid (DHA) and n-6 PUFA:n-3 PUFA ratios in the liver and/or serum as potential NAFLD biomarkers. Articles were included if quantitative values of n-6 PUFA, n-3 PUFA, Myr, DHA, and information about liver inflammation or liver disease progression parameters were provided. Overall, most experimental (91.6%) and clinical studies (87.5%) reported higher Myr:DHA ratios associated with inflammation and/or NAFLD progression than the n-6 PUFA:n-3 PUFA ratio. We conclude that the Myr:DHA ratio represents a better biomarker of NAFLD than the n-6 PUFA:n-3 PUFA ratio. Future studies are necessary for verifying this observation.
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Affiliation(s)
- Marina Masetto Antunes
- Post-Graduation Program in Pharmaceutical Sciences, State University of Maringá, Maringá, Brazil
| | - Guilherme Godoy
- Post-Graduation Program in Pharmaceutical Sciences, State University of Maringá, Maringá, Brazil
| | - Rui Curi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil
| | | | - Roberto Barbosa Bazotte
- Post-Graduation Program in Pharmaceutical Sciences, State University of Maringá, Maringá, Brazil.,Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Brazil
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30
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Yki-Järvinen H, Luukkonen PK, Hodson L, Moore JB. Dietary carbohydrates and fats in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2021; 18:770-786. [PMID: 34257427 DOI: 10.1038/s41575-021-00472-y] [Citation(s) in RCA: 139] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/14/2021] [Indexed: 02/06/2023]
Abstract
The global prevalence of nonalcoholic fatty liver disease (NAFLD) has dramatically increased in parallel with the epidemic of obesity. Controversy has emerged around dietary guidelines recommending low-fat-high-carbohydrate diets and the roles of dietary macronutrients in the pathogenesis of metabolic disease. In this Review, the topical questions of whether and how dietary fats and carbohydrates, including free sugars, differentially influence the accumulation of liver fat (specifically, intrahepatic triglyceride (IHTG) content) are addressed. Focusing on evidence from humans, we examine data from stable isotope studies elucidating how macronutrients regulate IHTG synthesis and disposal, alter pools of bioactive lipids and influence insulin sensitivity. In addition, we review cross-sectional studies on dietary habits of patients with NAFLD and randomized controlled trials on the effects of altering dietary macronutrients on IHTG. Perhaps surprisingly, evidence to date shows no differential effects between free sugars, with both glucose and fructose increasing IHTG in the context of excess energy. Moreover, saturated fat raises IHTG more than polyunsaturated or monounsaturated fats, with adverse effects on insulin sensitivity, which are probably mediated in part by increased ceramide synthesis. Taken together, the data support the use of diets that have a reduced content of free sugars, refined carbohydrates and saturated fat in the treatment of NAFLD.
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Affiliation(s)
- Hannele Yki-Järvinen
- Department of Medicine, Helsinki University Hospital and University of Helsinki, Helsinki, Finland. .,Minerva Foundation Institute for Medical Research, Helsinki, Finland.
| | - Panu K Luukkonen
- Department of Medicine, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland.,Department of Internal Medicine, Yale University, New Haven, CT, USA
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.,National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Oxford, UK
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31
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López-Bautista F, Barbero-Becerra VJ, Ríos MY, Ramírez-Cisneros MÁ, Sánchez-Pérez CA, Ramos-Ostos MH, Uribe M, Chávez-Tapia NC, Juárez-Hernández E. Dietary consumption and serum pattern of bioactive fatty acids in NAFLD patients. Ann Hepatol 2021; 19:482-488. [PMID: 32717363 DOI: 10.1016/j.aohep.2020.06.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/15/2020] [Accepted: 06/15/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION AND OBJECTIVES Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome. Some dietary fatty acids have showed different bioactive functions in metabolic syndrome. The aim of this study is to determine the dietary consumption patterns and serum percentage of bioactive fatty acids in NAFLD patients. PATIENTS AND METHODS Cross-sectional study with NAFLD patients and non-NAFLD patients. Dietary consumption of bioactive fatty acids was assessed by a food frequency questionnaire. NAFLD and liver fibrosis were diagnosed by transient elastography. The identification of serum bioactive fatty acids was achieved by gas chromatography-mass spectrometry (%). Bioactive fatty acids consumption was correlated with NAFLD clinical characteristics with the Spearman correlation analysis. RESULTS A total of 299 patients were included, whose mean of age and body mass index were 44.2±9.9 years and 25.9±3.8kg/m2, respectively. The consumption of bioactive fatty acids was no different regarding the presence of NAFLD; however, the consumption of stearic and linoleic fatty acids was higher in relation with NAFLD severity (p≤0.05). The consumption of myristic acid was higher in patients with fibrosis (p=0.02). Serum percentage and dietary consumption did not show correlations. CONCLUSION Dietary consumption of bioactive fatty acids is different according to NAFLD severity. Individualized diets according to NAFLD severity could be successful in order to prevent liver injury-related outcomes.
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Affiliation(s)
- Fabiola López-Bautista
- Molecular Biology Department, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | | | | | | | | | - Martha H Ramos-Ostos
- Integral Diagnosis and Treatment Center, Medica Sur Clinic and Foundation, Mexico City, Mexico
| | - Misael Uribe
- Gastroenterology and Obesity Department, Medica Sur Clinic and Foundation, Mexico City, Mexico
| | | | - Eva Juárez-Hernández
- Translational Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico.
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Lou Y, He X, Deng M, Hu X, Yang X, Liu L, Hu Y, He L, Wang J, Zhang L, Zhao Q, Lu X, Qiu Y. Elevation of Serum Cytokine Profiles and Liver Metabolomic Normalization in Early Convalescence of COVID-19 Patients. Front Med (Lausanne) 2021; 8:626633. [PMID: 34307393 PMCID: PMC8292617 DOI: 10.3389/fmed.2021.626633] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 06/04/2021] [Indexed: 12/22/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) has become a global public health concern. We aimed to study the cytokine profile during the convalescent phase and its association with liver functions. We performed a retrospective study to investigate the longitudinal dynamic serum cytokine, liver function, and metabolomic profiles, as well as their potential correlations, from the viral replication phase to early convalescence. Our results demonstrated that liver injury was common. Liver injury was significantly associated with higher levels of interleukin (IL)-6 and IL-10 (p < 0.05). However, alanine aminotransferase levels decreased during the first week after hospital discharge (p < 0.01). In parallel, T-cell and B-cell immune response-stimulating cytokine IL-4, but not IL-2, was significantly elevated (p < 0.05). Furthermore, interferon-γ (IFN-γ) and tumor necrosis factor-α (TFN-α) levels increased, in contrast to the decrease in IL-6 and IL-10 levels; liver function returned to normal. The metabolomic analysis supported active recovery during early convalescence of COVID-19 patients that had distinct metabolic profiles associated with the hepatic tricarboxylic acid cycle, amino acid metabolism, and lipid metabolism. In addition, we identified a metabolomic association of IL-4 with liver repair. Our findings suggest that discharged patients continue to recover from the physiological effects of COVID-19, and the association of IL-4, IL-6, and IL-10 levels with metabolic changes and liver function repair may have important implications for clinical manifestations and treatment of COVID-19.
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Affiliation(s)
- Yan Lou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Key Laboratory for Drug Evaluation and Clinical Research of Zhejiang Province, Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | | | | | | | | | | | | | | | | | | | | | | | - Yunqing Qiu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Key Laboratory for Drug Evaluation and Clinical Research of Zhejiang Province, Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Gong Y, Yang J, Wei S, Yang R, Gao L, Shao S, Zhao J. Lipotoxicity suppresses the synthesis of growth hormone in pituitary somatotrophs via endoplasmic reticulum stress. J Cell Mol Med 2021; 25:5250-5259. [PMID: 33943005 PMCID: PMC8178284 DOI: 10.1111/jcmm.16532] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 03/04/2021] [Accepted: 03/20/2021] [Indexed: 02/06/2023] Open
Abstract
Lipotoxicity has been shown to cause dysfunction of many organs and tissues. However, it is unclear whether lipotoxicity is harmful to the somatotrophs, a kind of cell that synthesize growth hormone (GH) in the pituitary. In this study, we performed an epidemiological study, serum levels of triglyceride (TG) and GH showed a negative correlation, even after adjustment for potential confounders. In an animal study, male Sprague‐Dawley rats were fed a high‐fat diet (HFD) or a control diet for 28 weeks. HFD rats showed impaired GH synthesis, resulting in a decrease in circulating GH levels. The expression of pituitary Pit‐1, a key transcription factor of GH, was inhibited. We found that the inositol‐requiring enzyme 1α (IRE1α) pathway of endoplasmic reticulum (ER) stress was triggered in HFD rat pituitary glands and palmitic acid‐treated GH3 cells, respectively. On the contrary, applying 4‐phenyl butyric acid (4‐PBA) to alleviate ER stress or 4µ8c to specifically block the IRE1α pathway attenuated the impairment of both Pit‐1 and GH expression. In conclusion, we demonstrated that lipotoxicity directly inhibits the synthesis of GH, probably by reducing Pit‐1 expression. The IRE1α signaling pathway of ER stress may play an important role in this process.
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Affiliation(s)
- Ying Gong
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China.,Shandong Institute of Endocrine and Metabolic Disease, Jinan, China
| | - Jianmei Yang
- Department of Pediatric Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Shuoshuo Wei
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China.,Shandong Institute of Endocrine and Metabolic Disease, Jinan, China
| | - Rui Yang
- Experimental Animal Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Ling Gao
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China.,Shandong Institute of Endocrine and Metabolic Disease, Jinan, China.,Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Shanshan Shao
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China.,Shandong Institute of Endocrine and Metabolic Disease, Jinan, China.,Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jiajun Zhao
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China.,Shandong Institute of Endocrine and Metabolic Disease, Jinan, China.,Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common liver pathology worldwide due to the rising prevalence of obesity. This term includes changes from simple steatosis to steatohepatitis and fibrosis. It was previously thought to be a hepatic manifestation of metabolic syndrome, but recent literature describes this relation as much more complex and bi-directional. Development of NAFLD is associated with other metabolic syndrome components but it can also exacerbate insulin resistance and increase cardiovascular risk. Recently a lot of attention is brought to the role of lipids and lipotoxicity in pathogenesis and progression of non-alcoholic fatty disease. It seems that some lipid classes can be protective against liver injury while others are harmful in excessive amounts. This study presents an overview of the main lipids involved in the pathogenesis of non-alcoholic fatty liver disease and summarizes their association with lipotoxicity, insulin resistance, oxidative stress and other processes responsible for its progression.
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35
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Krishna S, Raghavan S, DasGupta R, Palakodeti D. tRNA-derived fragments (tRFs): establishing their turf in post-transcriptional gene regulation. Cell Mol Life Sci 2021; 78:2607-2619. [PMID: 33388834 PMCID: PMC11073306 DOI: 10.1007/s00018-020-03720-7] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/02/2020] [Accepted: 11/24/2020] [Indexed: 02/06/2023]
Abstract
Transfer RNA (tRNA)-derived fragments (tRFs) are an emerging class of conserved small non-coding RNAs that play important roles in post-transcriptional gene regulation. High-throughput sequencing of multiple biological samples have identified heterogeneous species of tRFs with distinct functionalities. These small RNAs have garnered a lot of scientific attention due to their ubiquitous expression and versatility in regulating various biological processes. In this review, we highlight our current understanding of tRF biogenesis and their regulatory functions. We summarize the diverse modes of biogenesis through which tRFs are generated and discuss the mechanism through which different tRF species regulate gene expression and the biological implications. Finally, we conceptualize research areas that require focus to strengthen our understanding of the biogenesis and function of tRFs.
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Affiliation(s)
- Srikar Krishna
- Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India
- SASTRA University, Thirumalaisamudram, Thanjavur, India
| | - Srikala Raghavan
- Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India.
| | - Ramanuj DasGupta
- Precision Oncology, Genome Institute of Singapore, Singapore City, Singapore.
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de Almeida-Souza CB, Antunes MM, Carbonera F, Godoy G, da Silva MARCP, Masi LN, Visentainer JV, Curi R, Bazotte RB. A High-Fat Diet Induces Lower Systemic Inflammation than a High-Carbohydrate Diet in Mice. Metab Syndr Relat Disord 2021; 19:296-304. [PMID: 33570478 DOI: 10.1089/met.2020.0116] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Background: We previously established that male Swiss mice (Mus musculus) receiving a high-fat diet (HFD) during 8 weeks exhibit similar caloric ingestion and body weight (grams) compared with mice fed a high-carbohydrate diet (HCD). HFD mice exhibit a lower inflammatory state than an HCD in the liver, skeletal muscle, and brain. In addition, we demonstrated that HFD and HCD modulated fatty acids (FA) composition in these tissues. In this study, our objective was to compare HFD mice and HCD mice in terms of systemic inflammation. Methods: Saturated FA (SFA), monounsaturated FA, omega-6 polyunsaturated FA (n-6 PUFA), and n-3 PUFA were evaluated at the time points 0, 1, 7, 14, 28, and 56 days after starting the administration of the diets. We investigated n-6 PUFA:n-3 PUFA, SFA:n-3 PUFA, palmitic acid:α-linolenic acid (ALA), and myristic acid:docosahexaenoic acid (DHA) ratios as potential serum biomarkers of systemic inflammation. We also measured the serum levels of basic fibroblast growth factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), inducible protein 10 (IP-10), interferon gamma (IFN-γ), interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, macrophage inflammatory protein-1α (MIP-1-α), monocyte chemotactic protein 1 (MCP-1), monokine induced by IFN-γ (MIG), and tumor necrosis factor α (TNF-α). Results: The HFD group had lower (P < 0.05) n-6 PUFA:n-3 PUFA, palmitic acid:ALA, myristic acid:DHA ratios, and lower plasma levels of proinflammatory cytokines (IFN-γ, MIG, GM-CSF, and IL-6). Conclusion: The HFD mice showed lower systemic inflammation compared with a caloric ingestion-body weight-matched control HCD mice.
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Affiliation(s)
| | - Marina M Antunes
- Post-Graduate Program in Pharmaceutical Sciences, State University of Maringá, Maringá, Brazil
| | - Fabiana Carbonera
- Department of Chemistry, State University of Maringá, Maringá, Brazil
| | - Guilherme Godoy
- Post-Graduate Program in Pharmaceutical Sciences, State University of Maringá, Maringá, Brazil
| | - Maria A R C P da Silva
- Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Brazil
| | - Laureane N Masi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil
| | | | - Rui Curi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil
| | - Roberto B Bazotte
- Post-Graduate Program in Pharmaceutical Sciences, State University of Maringá, Maringá, Brazil.,Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Brazil
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LI RONGSONG, ADAMI ALESSANDRA, CHANG CHIHCHIANG, TSENG CHIHONG, HSIAI TZUNGK, ROSSITER HARRYB. Serum Acylglycerols Inversely Associate with Muscle Oxidative Capacity in Severe COPD. Med Sci Sports Exerc 2021; 53:10-18. [PMID: 32694368 PMCID: PMC7737871 DOI: 10.1249/mss.0000000000002441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
PURPOSE Chronic obstructive pulmonary disease (COPD) is associated with altered metabolism and body composition that accompany poor outcomes. We aimed to determine whether metabolic derangements in COPD are associated with skeletal muscle deconditioning and/or physical inactivity, independent of pulmonary obstruction. METHODS We characterized serum metabolites associated with muscle oxidative capacity or physical activity in 44 COPD patients (forced expiratory volume in 1 s [FEV1] = 61% ± 4% predicted) and 63 current and former smokers with normal spirometry (CON) (FEV1 = 93% ± 2% predicted). Medial gastrocnemius oxidative capacity was assessed at rest from the recovery rate constant (k) of muscle oxygen consumption using near-infrared spectroscopy. Step counts and physical activity (average vector magnitude units [VMU] per minute) were measured over 5-7 d using triaxial accelerometry. Untargeted prime and lipid metabolites were measured using liquid chromatography and mass spectrometry. RESULTS Muscle k (1.12 ± 0.05 vs 1.68 ± 0.06 min, P < 0.0001, d = 1.58) and VMU per minute (170 ± 26 vs 450 ± 50 VMU per minute, P = 0.004, d = 1.04) were lower in severe COPD (FEV1 < 50% predicted, n = 14-16) compared with CON (n = 56-60). A total of 129 prime metabolites and 470 lipids with known identity were quantified. Using sex as a covariate, lipidomics revealed 24 differentially expressed lipids (19 sphingomyelins) in COPD, consequent to a diminished sex difference of sphingomyelins in COPD (false discovery rate [FDR] < 0.05, n = 44). Total, and some individual, fatty acid concentrations were greater in severe COPD than CON (FDR < 0.05, n = 16, d = 0.56-1.02). After adjusting for FEV1% predicted, we observed that grouped diacylglycerides (ρ = -0.745, FDR = 0.03) and triacylglycerides (ρ = -0.811, FDR = 0.01) were negatively associated with muscle oxidative capacity, but not physical activity, in severe COPD (n = 14). CONCLUSION Strong negative associations relate impaired mitochondrial function to the accumulation of serum aclyglycerides in severe COPD.
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Affiliation(s)
- RONGSONG LI
- College of Health Science and Environmental Engineering, Shenzhen Technology University, Shenzhen, Guangdong, CHINA
| | - ALESSANDRA ADAMI
- Department of Kinesiology, University of Rhode Island, Kingston, RI
- Rehabilitation Clinical Trials Center, Division of Respiratory and Critical Care Physiology and Medicine, The Lundquist Institute for Biomedical Innovation at Harbor–UCLA Medical Center, Torrance, CA
| | - CHIH-CHIANG CHANG
- Department of Medicine, West Los Angeles VA Healthcare System, University of California, Los Angeles, CA
| | - CHI-HONG TSENG
- Department of Medicine, West Los Angeles VA Healthcare System, University of California, Los Angeles, CA
| | - TZUNG K. HSIAI
- Department of Medicine, West Los Angeles VA Healthcare System, University of California, Los Angeles, CA
| | - HARRY B. ROSSITER
- Rehabilitation Clinical Trials Center, Division of Respiratory and Critical Care Physiology and Medicine, The Lundquist Institute for Biomedical Innovation at Harbor–UCLA Medical Center, Torrance, CA
- Faculty of Biological Sciences, University of Leeds, Leeds, UNITED KINGDOM
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Leung KL, Sanchita S, Pham CT, Davis BA, Okhovat M, Ding X, Dumesic P, Grogan TR, Williams KJ, Morselli M, Ma F, Carbone L, Li X, Pellegrini M, Dumesic DA, Chazenbalk GD. Dynamic changes in chromatin accessibility, altered adipogenic gene expression, and total versus de novo fatty acid synthesis in subcutaneous adipose stem cells of normal-weight polycystic ovary syndrome (PCOS) women during adipogenesis: evidence of cellular programming. Clin Epigenetics 2020; 12:181. [PMID: 33228780 PMCID: PMC7686698 DOI: 10.1186/s13148-020-00970-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 11/05/2020] [Indexed: 12/11/2022] Open
Abstract
Background Normal-weight polycystic ovary syndrome (PCOS) women exhibit adipose resistance in vivo accompanied by enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with accelerated lipid accumulation per cell in vitro. The present study examines chromatin accessibility, RNA expression and fatty acid (FA) synthesis during SC abdominal ASC differentiation into adipocytes in vitro of normal-weight PCOS versus age- and body mass index-matched normoandrogenic ovulatory (control) women to study epigenetic/genetic characteristics as well as functional alterations of PCOS and control ASCs during adipogenesis. Results SC abdominal ASCs from PCOS women versus controls exhibited dynamic chromatin accessibility during adipogenesis, from significantly less chromatin accessibility at day 0 to greater chromatin accessibility by day 12, with enrichment of binding motifs for transcription factors (TFs) of the AP-1 subfamily at days 0, 3, and 12. In PCOS versus control cells, expression of genes governing adipocyte differentiation (PPARγ, CEBPα, AGPAT2) and function (ADIPOQ, FABP4, LPL, PLIN1, SLC2A4) was increased two–sixfold at days 3, 7, and 12, while that involving Wnt signaling (FZD1, SFRP1, and WNT10B) was decreased. Differential gene expression in PCOS cells at these time points involved triacylglycerol synthesis, lipid oxidation, free fatty acid beta-oxidation, and oxidative phosphorylation of the TCA cycle, with TGFB1 as a significant upstream regulator. There was a broad correspondence between increased chromatin accessibility and increased RNA expression of those 12 genes involved in adipocyte differentiation and function, Wnt signaling, as well as genes involved in the triacylglycerol synthesis functional group at day 12 of adipogenesis. Total content and de novo synthesis of myristic (C14:0), palmitic (C16:0), palmitoleic (C16:1), and oleic (C18:1) acid increased from day 7 to day 12 in all cells, with total content and de novo synthesis of FAs significantly greater in PCOS than controls cells at day 12. Conclusions In normal-weight PCOS women, dynamic chromatin remodeling of SC abdominal ASCs during adipogenesis may enhance adipogenic gene expression as a programmed mechanism to promote greater fat storage.
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Affiliation(s)
- Karen L Leung
- Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Smriti Sanchita
- Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Catherine T Pham
- Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Brett A Davis
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Sciences University, Portland, OR, 97239, USA
| | - Mariam Okhovat
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Sciences University, Portland, OR, 97239, USA
| | - Xiangming Ding
- Technology Center for Genomics and Bioinformatics, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | | | - Tristan R Grogan
- Department of Medicine Statistics Core, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Kevin J Williams
- UCLA Lipidomics Lab, Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Marco Morselli
- Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Feiyang Ma
- Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Lucia Carbone
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Sciences University, Portland, OR, 97239, USA.,Department of Molecular and Medical Genetics, Oregon Health and Sciences University, Portland, OR, 97239, USA.,Department of Medical Information and Clinical Epidemiology, Oregon Health and Sciences University, Portland, OR, 97239, USA.,Division of Genetics, Oregon National Primate Research Center, Beaverton, OR, 97006, USA
| | - Xinmin Li
- Technology Center for Genomics and Bioinformatics, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Matteo Pellegrini
- Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Daniel A Dumesic
- Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Gregorio D Chazenbalk
- Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
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A Lipidomic Signature Complements Stemness Features Acquisition in Liver Cancer Cells. Int J Mol Sci 2020; 21:ijms21228452. [PMID: 33182805 PMCID: PMC7709039 DOI: 10.3390/ijms21228452] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/06/2020] [Accepted: 11/09/2020] [Indexed: 12/16/2022] Open
Abstract
Lipid catabolism and anabolism changes play a role in stemness acquisition by cancer cells, and cancer stem cells (CSCs) are particularly dependent on the activity of the enzymes involved in these processes. Lipidomic changes could play a role in CSCs’ ability to cause disease relapse and chemoresistance. The exploration of lipid composition and metabolism changes in CSCs in the context of hepatocellular cancer (HCC) is still incomplete and their lipidomic scenario continues to be elusive. We aimed to evaluate through high-throughput mass spectrometry (MS)-based lipidomics the levels of the members of the six major classes of sphingolipids and phospholipids in two HCC cell lines (HepG2 and Huh-7) silenced for the expression of histone variant macroH2A1 (favoring stemness acquisition), or silenced for the expression of focal adhesion tyrosine kinase (FAK) (hindering aggressiveness and stemness). Transcriptomic changes were evaluated by RNA sequencing as well. We found definite lipidomic and transcriptomic changes in the HCC lines upon knockdown (KD) of macroH2A1 or FAK, in line with the acquisition or loss of stemness features. In particular, macroH2A1 KD increased total sphingomyelin (SM) levels and decreased total lysophosphatidylcholine (LPC) levels, while FAK KD decreased total phosphatidylcholine (PC) levels. In conclusion, in HCC cell lines knocked down for specific signaling/epigenetic processes driving opposite stemness potential, we defined a lipidomic signature that hallmarks hepatic CSCs to be exploited for therapeutic strategies.
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Diao P, Wang X, Jia F, Kimura T, Hu X, Shirotori S, Nakamura I, Sato Y, Nakayama J, Moriya K, Koike K, Gonzalez FJ, Aoyama T, Tanaka N. A saturated fatty acid-rich diet enhances hepatic lipogenesis and tumorigenesis in HCV core gene transgenic mice. J Nutr Biochem 2020; 85:108460. [PMID: 32992072 DOI: 10.1016/j.jnutbio.2020.108460] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 05/25/2020] [Accepted: 06/16/2020] [Indexed: 02/07/2023]
Abstract
Previous studies suggested that high consumption of saturated fatty acid (SFA) is a risk factor for liver cancer. However, it remains unclear how dietary SFA affects liver tumorigenesis. This study aimed to investigate the impact of a SFA-rich diet on hepatic tumorigenesis using hepatitis C virus core gene transgenic (HCVcpTg) mice that spontaneously developed hepatic steatosis and tumors with aging. Male HCVcpTg mice were treated for 15 months with a purified control diet or SFA-rich diet prepared by replacing soybean oil in the control diet with hydrogenated coconut oil, and phenotypic changes were assessed. In this special diet, almost all dietary fatty acids were SFA. Long-term feeding of SFA-rich diet to HCVcpTg mice increased hepatic steatosis, liver dysfunction, and the prevalence of liver tumors, likely due to stimulation of de novo lipogenesis, activation of the pro-inflammatory and pro-oncogenic transcription factor nuclear factor-kappa B (NF-κB), enhanced c-Jun N-terminal kinase/activator protein 1 (JNK/AP-1) signaling and induction of the oncogenes cyclin D1 and p62/sequestosome 1. The SFA-rich diet did not affect liver fibrosis or autophagy. Collectively, long-term SFA-rich diet consumption promoted hepatic tumorigenesis mainly through activation of lipogenesis, NF-κB, and JNK/AP-1 signaling. We therefore propose that HCV-infected patients should avoid excessive intake of SFA-rich foods to prevent liver cancer.
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Affiliation(s)
- Pan Diao
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
| | - Xiaojing Wang
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan; Department of Gastroenterology, Lishui Hospital, Zhejiang University School of Medicine, Lishui, Zhejiang, People's Republic of China
| | - Fangping Jia
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takefumi Kimura
- Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Xiao Hu
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan; Department of Pathophysiology, Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Saki Shirotori
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
| | - Ibuki Nakamura
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yoshiko Sato
- Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Jun Nakayama
- Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Kyoji Moriya
- Department of Infection Control and Prevention, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Frank J Gonzalez
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Toshifumi Aoyama
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
| | - Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan; Research Center for Social Systems, Shinshu University, Matsumoto, Japan.
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tBHQ Induces a Hormetic Response That Protects L6 Myoblasts against the Toxic Effect of Palmitate. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:3123268. [PMID: 32509140 PMCID: PMC7246405 DOI: 10.1155/2020/3123268] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 04/20/2020] [Indexed: 12/27/2022]
Abstract
Nutritional status, in particular overweight and obesity, as well as sedentarism and high-fat diet consumption, are important risk factors to develop chronic diseases, which have a higher impact on the elderly's health. Therefore, these nutritional problems have become a concern to human healthspan and longevity. The fatty acids obtained thru the diet or due to fatty acid synthesis during obesity accumulate within the body generating toxicity and cell death. Fat is not only stored in adipose tissue, but it can also be stored in skeletal muscle. Palmitic acid (PA) has been reported as one of the most important saturated free fatty acids; it is associated to chronic oxidative stress and increased mitochondrial ROS production causing cell death by apoptosis. In skeletal muscle, palmitate has been associated with various pathophysiological consequences, which lead to muscle deterioration during aging and obesity. Since molecules that modify redox state have been proven to prevent cellular damage by inducing a hormetic response, the aim of this study was to evaluate if tert-butylhydroquinone (tBHQ) could activate an antioxidant hormetic response that would be able to protect L6 myoblasts from palmitate toxic effect. Our results provide evidence that tBHQ is able to protect L6 myoblasts against the toxicity induced by sodium palmitate due to a synergistic activation of different signaling pathways such as Nrf2 and NF-κB.
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Xu C, Song D, Holck AL, Zhou Y, Liu R. Identifying Lipid Metabolites Influenced by Oleic Acid Administration Using High-Performance Liquid Chromatography-Mass Spectrometry-Based Lipidomics. ACS OMEGA 2020; 5:11314-11323. [PMID: 32478219 PMCID: PMC7254503 DOI: 10.1021/acsomega.9b04402] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 04/14/2020] [Indexed: 05/09/2023]
Abstract
Oleic acid (OA), one of the most important monounsaturated fatty acids, possesses protective properties against chronic liver disease (CLD) development, but the underlying metabolic metabolism remains unknown. HPLC-MS-based lipidomics was utilized to identify and quantify the endogenously altered lipid metabolites when hepatocytes were exposed to OA administration. The identified lipids could be grouped into 22 lipid classes; of which, 10 classes were significantly influenced by the OA treatment: lysophosphatidylcholine (LPC), phosphatidylglycerol (PG), ceramides (Cer), hexosylceramides (Hex1Cer), dihexosylceramides (Hex2Cer), cholesterol ester (ChE), and coenzyme (Co) were decreased, while diglyceride (DG), triglyceride (TG), and acyl carnitine (AcCa) were increased. In addition, as the variable importance in projection (VIP) list (VIP > 1.0 and P < 0.05) showed, 478 lipid species showed significant difference with OA administration, and these molecules could be potential biomarkers in conjunction with OA administration. In summary, our results provided a novel perspective to understand the influences of OA administration by investigating endogenous altered levels of lipid metabolites via lipidomics.
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Affiliation(s)
- Chao Xu
- College
of Food Science and Technology, Nanjing
Agricultural University, Nanjing 210095, China
| | - Dan Song
- College
of Food Science and Technology, Nanjing
Agricultural University, Nanjing 210095, China
| | - Askild L. Holck
- NOFIMA
- Norwegian Institute of Food, Fisheries and Aquaculture Research, P.O. Box 210, N-1431 Aas, Norway
| | - Youyou Zhou
- College
of Food Science and Technology, Nanjing
Agricultural University, Nanjing 210095, China
| | - Rong Liu
- College
of Food Science and Technology, Nanjing
Agricultural University, Nanjing 210095, China
- National
Center for International Research on Animal Gut Nutrition, Nanjing 210095, China
- Jiangsu
Collaborative Innovation Center of Meat Production and Processing, Nanjing 210095, China
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Exogenous Liposomal Ceramide-C6 Ameliorates Lipidomic Profile, Energy Homeostasis, and Anti-Oxidant Systems in NASH. Cells 2020; 9:cells9051237. [PMID: 32429478 PMCID: PMC7290333 DOI: 10.3390/cells9051237] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/05/2020] [Accepted: 05/13/2020] [Indexed: 02/07/2023] Open
Abstract
In non-alcoholic steatohepatitis (NASH), many lines of investigation have reported a dysregulation in lipid homeostasis, leading to intrahepatic lipid accumulation. Recently, the role of dysfunctional sphingolipid metabolism has also been proposed. Human and animal models of NASH have been associated with elevated levels of long chain ceramides and pro-apoptotic sphingolipid metabolites, implicated in regulating fatty acid oxidation and inflammation. Importantly, inhibition of de novo ceramide biosynthesis or knock-down of ceramide synthases reverse some of the pathology of NASH. In contrast, cell permeable, short chain ceramides have shown anti-inflammatory actions in multiple models of inflammatory disease. Here, we investigated non-apoptotic doses of a liposome containing short chain C6-Ceramide (Lip-C6) administered to human hepatic stellate cells (hHSC), a key effector of hepatic fibrogenesis, and an animal model characterized by inflammation and elevated liver fat content. On the basis of the results from unbiased liver transcriptomic studies from non-alcoholic fatty liver disease patients, we chose to focus on adenosine monophosphate activated kinase (AMPK) and nuclear factor-erythroid 2-related factor (Nrf2) signaling pathways, which showed an abnormal profile. Lip-C6 administration inhibited hHSC proliferation while improving anti-oxidant protection and energy homeostasis, as indicated by upregulation of Nrf2, activation of AMPK and an increase in ATP. To confirm these in vitro data, we investigated the effect of a single tail-vein injection of Lip-C6 in the methionine-choline deficient (MCD) diet mouse model. Lip-C6, but not control liposomes, upregulated phospho-AMPK, without inducing liver toxicity, apoptosis, or exacerbating inflammatory signaling pathways. Alluding to mechanism, mass spectrometry lipidomics showed that Lip-C6-treatment reversed the imbalance in hepatic phosphatidylcholines and diacylglycerides species induced by the MCD-fed diet. These results reveal that short-term Lip-C6 administration reverses energy/metabolic depletion and increases protective anti-oxidant signaling pathways, possibly by restoring homeostatic lipid function in a model of liver inflammation with fat accumulation.
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Kim TY, Kim D, Yoon J, Kim S, Yi SW, Oh WT, Park JY, Kim H, Kang M, Lee JB, Sung H. External Self‐Closing Tube to Occlude a Vessel Gradually as a Therapeutic Means of Portosystemic Shunt. ADVANCED THERAPEUTICS 2020. [DOI: 10.1002/adtp.202000039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Tae Young Kim
- Department of Medical EngineeringYonsei University College of Medicine 50‐1 Yonsei‐ro, Seodaemun‐gu Seoul 03722 Republic of Korea
| | - Dae‐Hyun Kim
- Department of Medical EngineeringYonsei University College of Medicine 50‐1 Yonsei‐ro, Seodaemun‐gu Seoul 03722 Republic of Korea
| | - Jeong‐Kee Yoon
- Department of Medical EngineeringYonsei University College of Medicine 50‐1 Yonsei‐ro, Seodaemun‐gu Seoul 03722 Republic of Korea
| | - Surim Kim
- Department of Medical EngineeringYonsei University College of Medicine 50‐1 Yonsei‐ro, Seodaemun‐gu Seoul 03722 Republic of Korea
| | - Se Won Yi
- TMD Lab., Co., Ltd. 50‐1 Yonsei‐ro, Seodaemun‐gu Seoul 03722 Republic of Korea
| | - Won Taek Oh
- TMD Lab., Co., Ltd. 50‐1 Yonsei‐ro, Seodaemun‐gu Seoul 03722 Republic of Korea
| | - Ju Young Park
- TMD Lab., Co., Ltd. 50‐1 Yonsei‐ro, Seodaemun‐gu Seoul 03722 Republic of Korea
| | - Hye‐Seon Kim
- Department of Medical EngineeringYonsei University College of Medicine 50‐1 Yonsei‐ro, Seodaemun‐gu Seoul 03722 Republic of Korea
| | - Mi‐Lan Kang
- TMD Lab., Co., Ltd. 50‐1 Yonsei‐ro, Seodaemun‐gu Seoul 03722 Republic of Korea
| | - Jung Bok Lee
- Department of Biological ScienceSookmyung Women's University Seoul 04310 Republic of Korea
| | - Hak‐Joon Sung
- Department of Medical EngineeringYonsei University College of Medicine 50‐1 Yonsei‐ro, Seodaemun‐gu Seoul 03722 Republic of Korea
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Chen W, Shao S, Cai H, Han J, Guo T, Fu Y, Yu C, Zhao M, Bo T, Yao Z, Zhao J, Zhang Q, Xu G, Hu C, Gao L. Comparison of Erythrocyte Membrane Lipid Profiles between NAFLD Patients with or without Hyperlipidemia. Int J Endocrinol 2020; 2020:9501826. [PMID: 33014047 PMCID: PMC7519187 DOI: 10.1155/2020/9501826] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 07/21/2020] [Accepted: 08/25/2020] [Indexed: 02/08/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) and hyperlipidemia (HL) are common metabolic disorders due to overnutrition and obesity. NAFLD is often associated with hyperlipidemia. The aim of this study was to identify and compare the erythrocyte membrane lipids profile in NAFLD patients with or without HL. Methods. A total of 112 subjects (with similar age and body mass index) were divided into four groups: (1) normal controls, (2) NAFLD alone, (3) HL alone, and (4) NAFLD combined with HL (NAFLD + HL). Lipid was extracted from the erythrocyte membrane, and lipid profiles of subjects were analyzed by liquid chromatography mass spectrometry (LC-MS). Results. Data sets from 103 subjects were adopted for lipidomic analysis. Significant changes of lipid species were observed in patient groups, especially in the HL group and NAFLD + HL group. The HL group showed increased level of most lipid species, and decreased level of most lipid species was observed in the NAFLD + HL group. The weight percent of myristic acid, stearic acid, erucic acid, and docosahexaenoic acid also showed distinct variation between different groups. Conclusions. NAFLD, HL, and NAFLD + HL all had an impact on lipid profiling of the erythrocyte membrane. The influence of NAFLD alone is less important compared with HL. Some lipids should be highlighted because of their specific role in cell function and systemic metabolism.
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Affiliation(s)
- Wenbin Chen
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong University, Jinan, China
- Scientific Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Shanshan Shao
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
| | - Hu Cai
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
| | - Jie Han
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
| | - Tian Guo
- Shandong University, Jinan, China
| | - Yilin Fu
- Shandong University, Jinan, China
| | - Chunxiao Yu
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
| | - Meng Zhao
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong University, Jinan, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Tao Bo
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong University, Jinan, China
- Scientific Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zhenyu Yao
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
| | - Jiajun Zhao
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
| | - Qunye Zhang
- Key Laboratory of Cardiovascular Remodeling and Function Research Chinese Ministry of Education and Ministry of Public Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Guowang Xu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Jinan, China
| | - Chunxiu Hu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Jinan, China
| | - Ling Gao
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Shandong University, Jinan, China
- Scientific Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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Yoo HJ, Jung KJ, Kim M, Kim M, Kang M, Jee SH, Choi Y, Lee JH. Liver Cirrhosis Patients Who Had Normal Liver Function Before Liver Cirrhosis Development Have the Altered Metabolic Profiles Before the Disease Occurrence Compared to Healthy Controls. Front Physiol 2019; 10:1421. [PMID: 31803070 PMCID: PMC6877605 DOI: 10.3389/fphys.2019.01421] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 11/04/2019] [Indexed: 12/12/2022] Open
Abstract
Liver cirrhosis (LC) is the final usual outcome of liver damage induced by various chronic liver diseases. Because of asymptomatic nature of LC, it is usually diagnosed at late and advanced stages, and patients are easy to miss the best timing for treatment. Thus, the early detection of LC is needed. In the prospective Korean Cancer Prevention Study-II (K-II), we aimed to identify valuable biomarkers for LC using metabolomics to distinguish subjects with incident LC (LC group) from subjects free from LC (control group) during a mean 7-year follow-up period. Metabolic alterations were investigated using baseline serum specimens acquired from 94 subjects with incident LC and 180 age- and sex-matched LC-free subjects via ultra-performance liquid chromatography (UPLC)-linear-trap quardrupole (LTQ)-Orbitrap mass spectrometry (MS). As a result of the metabolic analysis, 46 metabolites were identified. Among them, 11 and 18 metabolite level showed a significant increase and decrease, respectively, in the LC group compared to the control group. Nine metabolic pathways, including glyoxylate and dicarboxylate metabolism, amino acid metabolism, fatty acid metabolism, linoleic acid metabolism, α-linolenic acid metabolism, and arachidonic acid metabolism, were significantly different between the two groups. Logistic regression demonstrated that the LC emergence was independently affected by serum levels of myristic acid, palmitic acid, linoleic acid, eicosapentaenoic acid (EPA), lysophosphatidic acid (LPA) (18:1), glycolic acid, lysophosphatidylcholine (lysoPC) (22:6), and succinylacetone (R 2 = 0.837, P < 0.001). This prospective study revealed that dysregulation of various metabolism had the clinical relevance on the LC development. Moreover, myristic acid, palmitic acid, linoleic acid, EPA, LPA (18:1), glycolic acid, lysoPC (22:6), and succinylacetone were emerged as independent variables influencing the incidence of LC. The results support that the early biomarkers found in this study may useful for predicting and remedying the risk of LC.
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Affiliation(s)
- Hye Jin Yoo
- National Leading Research Laboratory of Clinical Nutrigenetics/Nutrigenomics, Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, South Korea
- Research Center for Silver Science, Institute of Symbiotic Life-TECH, Yonsei University, Seoul, South Korea
| | - Keum Ji Jung
- Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, South Korea
| | - Minkyung Kim
- Research Center for Silver Science, Institute of Symbiotic Life-TECH, Yonsei University, Seoul, South Korea
| | - Minjoo Kim
- Research Center for Silver Science, Institute of Symbiotic Life-TECH, Yonsei University, Seoul, South Korea
| | - Minsik Kang
- National Leading Research Laboratory of Clinical Nutrigenetics/Nutrigenomics, Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, South Korea
| | - Sun Ha Jee
- Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, South Korea
| | - Yoonjeong Choi
- Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, South Korea
| | - Jong Ho Lee
- National Leading Research Laboratory of Clinical Nutrigenetics/Nutrigenomics, Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, South Korea
- Research Center for Silver Science, Institute of Symbiotic Life-TECH, Yonsei University, Seoul, South Korea
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Yang RX, Pan Q, Liu XL, Zhou D, Xin FZ, Zhao ZH, Zhang RN, Zeng J, Qiao L, Hu CX, Xu GW, Fan JG. Therapeutic effect and autophagy regulation of myriocin in nonalcoholic steatohepatitis. Lipids Health Dis 2019; 18:179. [PMID: 31639005 PMCID: PMC6805575 DOI: 10.1186/s12944-019-1118-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 09/12/2019] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Ceramide plays pathogenic roles in nonalcoholic fatty liver disease (NAFLD) via multiple mechanisms, and as such inhibition of ceramide de novo synthesis in the liver may be of therapeutically beneficial in patients with NAFLD. In this study, we aimed to explore whether inhibition of ceramide signaling by myriocin is beneficial in animal model of NAFLD via regulating autophagy. METHODS Sprague Dawley rats were randomly divided into three groups: standard chow (n = 10), high-fat diet (HFD) (n = 10) or HFD combined with oral administration of myriocin (0.3 mg/kg on alternate days for 8 weeks) (n = 10). Liver histology and autophagy function were measured. HepG2 cells were incubated with fatty acid with or without myriocin treatment. Lipid accumulation and autophagy markers in the HepG2 cells were analyzed. Serum ceramide changes were studied in 104 subjects consisting healthy adults, liver biopsy-proven patients with NAFLD and liver biopsy-proven patients with chronic hepatitis B (CHB). RESULTS Myriocin reversed the elevated body weight and serum transaminases and alleviated dyslipidemia in HFD fed rats. Myriocin treatment significantly attenuated liver pathology including steatosis, lobular inflammation and ballooning. By qPCR analysis, it was revealed that myriocin corrected the expression pattern of fatty acid metabolism associated genes including Fabp1, Pparα, Cpt-1α and Acox-2. Further, myriocin also restored the impaired hepatic autophagy function in rats with HFD-induced NASH, and this has been verified in HepG2 cells. Among the sphingolipid species that we screened in lipidomic profiles, significantly increased ceramide was observed in NASH patients as compared to the controls and non-NASH patients, regardless of whether or not they have active CHB. CONCLUSIONS Ceramide may play an important regulatory role in the autophagy function in the pathogenesis of NASH. Hence, blockade of ceramide signaling by myriocin may be of therapeutically beneficial in NASH. TRIAL REGISTRATION Registration ID: ChiCTR-DDT-13003983 . Data of registration: 13 May, 2013, retrospectively registered.
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Affiliation(s)
- Rui-Xu Yang
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China
| | - Qin Pan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China
| | - Xiao-Lin Liu
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China
| | - Da Zhou
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China
| | - Feng-Zhi Xin
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China
| | - Ze-Hua Zhao
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China
| | - Rui-Nan Zhang
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China
| | - Jing Zeng
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China
| | - Liang Qiao
- Storr Liver Centre, Westmead Institute for Medical Research, the University of Sydney at Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Chun-Xiu Hu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China
| | - Guo-Wang Xu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China. .,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, 200092, China.
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Yi H, Xu D, Wu X, Xu F, Lin L, Zhou H. Isosteviol Protects Free Fatty Acid- and High Fat Diet-Induced Hepatic Injury via Modulating PKC-β/p66Shc/ROS and Endoplasmic Reticulum Stress Pathways. Antioxid Redox Signal 2019; 30:1949-1968. [PMID: 30484323 PMCID: PMC6486675 DOI: 10.1089/ars.2018.7521] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Aims: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases. However, there are no approved pharmacotherapies for the treatment of NAFLD other than managing life style and controlling diets. Extensive studies have demonstrated that multiple mechanisms are involved in free fatty acid (FFA)- and high fat diet (HFD)-induced hepatic injury, including mitochondrial dysfunction, activation of oxidative stress and endoplasmic reticulum (ER) stress, and lysosome dysfunction. A previous study reported that Isosteviol (ISV), a derivative of stevioside, prevents HFD-induced hepatic injury. However, the underlying mechanisms remain unclear. Results: In this study, we examined the potential cellular/molecular mechanisms underlying ISV-mediated protective effect against FFA-/HFD-induced hepatic lipotoxicity by using both in vitro primary rat hepatocytes and the in vivo rat NAFLD model. The results indicated that ISV inhibits FFA-/HFD-induced hepatic injury via reducing oxidative and ER stress. Specifically, ISV inhibited the expression, activation, and mitochondrial translocation of Src-homology-2-domain-containing transforming protein 1 (p66Shc), an adapter protein that mediates oxidative stress-induced injury and is a substrate of protein kinase C-β (PKC-β), via inhibition of PKC-β activity. However, ISV had no effect on the expression and activity of peptidyl-prolyl cis-trans isomerase and serine/threonine protein phosphatase 2A, isomerase and phosphorylase of p66Shc. In addition, ISV also inhibited FFA-induced ER stress and decreased ER-mitochondrial interaction. Innovation and Conclusion: We first identified that ISV prevents FFA-/HFD-induced hepatic injury through modulating PKC-β/p66Shc/oxidative and ER stress pathways. ISV represents a promising therapeutic agent for NAFLD in the future. Antioxid. Redox Signal. 30, 1949-1968.
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Affiliation(s)
- Hongwei Yi
- 1 Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China
| | - Deyi Xu
- 1 Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China
| | - Xudong Wu
- 2 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Fang Xu
- 2 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Lin Lin
- 1 Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China
| | - Huiping Zhou
- 3 Department of Microbiology and Immunology, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia
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Bennett MK, Wallington-Beddoe CT, Pitson SM. Sphingolipids and the unfolded protein response. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:1483-1494. [PMID: 31176037 DOI: 10.1016/j.bbalip.2019.06.002] [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: 02/20/2019] [Revised: 05/29/2019] [Accepted: 06/01/2019] [Indexed: 12/17/2022]
Abstract
The unfolded protein response (UPR) is a response by the endoplasmic reticulum to stress, classically caused by any disruption to cell homeostasis that results in an accumulation in unfolded proteins. However, there is an increasing body of research demonstrating that the UPR can also be activated by changes in lipid homeostasis, including changes in sphingolipid metabolism. Sphingolipids are a family of bioactive lipids with important roles in both the formation and integrity of cellular membranes, and regulation of key cellular processes, including cell proliferation and apoptosis. Bi-directional interactions between sphingolipids and the UPR have now been observed in a range of diseases, including cancer, diabetes and liver disease. Determining how these two key cellular components influence each other could play an important role in deciphering the causes of these diseases and potentially reveal new therapeutic approaches.
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Affiliation(s)
- Melissa K Bennett
- Centre for Cancer Biology, University of South Australia and SA Pathology, UniSA CRI Building, North Tce, Adelaide, SA 5001, Australia
| | - Craig T Wallington-Beddoe
- Centre for Cancer Biology, University of South Australia and SA Pathology, UniSA CRI Building, North Tce, Adelaide, SA 5001, Australia; Adelaide Medical School, University of Adelaide, Adelaide, SA 5001, Australia; Flinders Medical Centre, Bedford Park, SA 5042, Australia; College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia
| | - Stuart M Pitson
- Centre for Cancer Biology, University of South Australia and SA Pathology, UniSA CRI Building, North Tce, Adelaide, SA 5001, Australia; Adelaide Medical School, University of Adelaide, Adelaide, SA 5001, Australia; School of Biological Sciences, University of Adelaide, Adelaide, SA 5000, Australia.
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50
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Rohrbach TD, Asgharpour A, Maczis MA, Montefusco D, Cowart LA, Bedossa P, Sanyal AJ, Spiegel S. FTY720/fingolimod decreases hepatic steatosis and expression of fatty acid synthase in diet-induced nonalcoholic fatty liver disease in mice. J Lipid Res 2019; 60:1311-1322. [PMID: 31110049 DOI: 10.1194/jlr.m093799] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 05/16/2019] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver dysfunction, is a metabolic disease that begins with steatosis. Sphingolipid metabolites, particularly ceramide and sphingosine-1-phosphate (S1P), have recently received attention for their potential roles in insulin resistance and hepatic steatosis. FTY720/fingolimod, a prodrug for the treatment of multiple sclerosis, is phosphorylated in vivo to its active phosphorylated form by sphingosine kinase 2 and has been shown to interfere with the actions of S1P and to inhibit ceramide biosynthesis. Therefore, in this study we investigated the effects of FTY720 in a diet-induced animal model of NAFLD (DIAMOND) that recapitulates the hallmarks of the human disease. The oral administration of FTY720 to these mice fed a high-fat diet and sugar water improved glucose tolerance and reduced steatosis. In addition to decreasing liver triglycerides, FTY720 also reduced hepatic sphingolipid levels, including ceramides, monohexosylceramides, and sphingomyelins, particularly the C16:0 and C24:1 species, as well as S1P and dihydro-S1P. FTY720 administration decreased diet-induced fatty acid synthase (FASN) expression in DIAMOND mice without affecting other key enzymes in lipogenesis. FTY720 had no effect on the expression of SREBP-1c, which transcriptionally activates FASN. However, in agreement with the notion that the active phosphorylated form of FTY720 is an inhibitor of histone deacetylases, FTY720-P accumulated in the liver, and histone H3K9 acetylation was markedly increased in these mice. Hence, FTY720 might be useful for attenuating FASN expression and triglyceride accumulation associated with steatosis.
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Affiliation(s)
- Timothy D Rohrbach
- Department of Biochemistry and Molecular Biology Virginia Commonwealth University School of Medicine, Richmond, VA
| | - Amon Asgharpour
- Division of Gastroenterology, Hepatology, and Nutrition Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA
| | - Melissa A Maczis
- Department of Biochemistry and Molecular Biology Virginia Commonwealth University School of Medicine, Richmond, VA
| | - David Montefusco
- Department of Biochemistry and Molecular Biology Virginia Commonwealth University School of Medicine, Richmond, VA
| | - L Ashley Cowart
- Department of Biochemistry and Molecular Biology Virginia Commonwealth University School of Medicine, Richmond, VA.,Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, VA
| | - Pierre Bedossa
- Division of Gastroenterology, Hepatology, and Nutrition Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology, and Nutrition Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA
| | - Sarah Spiegel
- Department of Biochemistry and Molecular Biology Virginia Commonwealth University School of Medicine, Richmond, VA
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