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Liu L, Niu K, Yang Z, Song J, Wei D, Zhang R, Tao K. Osteopontin: an indispensable component in common liver, pancreatic, and biliary related disease. J Cancer Res Clin Oncol 2024; 150:508. [PMID: 39572438 PMCID: PMC11582231 DOI: 10.1007/s00432-024-06038-0] [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: 09/09/2024] [Accepted: 11/15/2024] [Indexed: 11/24/2024]
Abstract
BACKGROUND The liver, gallbladder, and pancreas constitute a critically important system of digestive and endocrine organs in the human body, performing essential and complex physiological functions. At present, diseases of this digestive system have a high incidence in the world and is a more common disease. However, osteopontin (OPN) plays a crucial role in common liver, pancreatic, and biliary diseases, and its mechanisms of action merit further exploration and study. METHODS We performed an analysis to assess the role of osteopontin in liver, pancreatic, and biliary diseases, focusing on its significance in these conditions. RESULTS Osteopontin, a profoundly phosphorylated glycoprotein, can be utilized as a diagnostic marker for hepatocellular carcinoma and cholangiopathies. Additionally it assists in the treatment of non-alcoholic fatty liver disease and promotes the proliferation, migration, and invasion of pancreatic cancer cells. Furthermore, osteopontin regulates inflammatory responses in chronic pancreatitis. CONCLUSIONS This review offers a thorough analysis of the genetic and protein architecture of OPN, and elucidates the relationship between osteopontin and liver, pancreatic, and biliary diseases. Furthermore, exclusive focus is lavished on the potential utility of OPN as a biomarker and an innovative therapeutic target in the management of these disorder.
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Affiliation(s)
- Lu Liu
- College of Life Sciences, Northwest University, Xi'an, 710069, China
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China
| | - Kunwei Niu
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China
| | - Zhipeng Yang
- College of Life Sciences, Northwest University, Xi'an, 710069, China
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China
| | - Junbo Song
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China
| | - Dan Wei
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China.
| | - Ruohan Zhang
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China.
| | - Kaishan Tao
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China.
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Das S, Subramaniyam N, Alén R, Komakula SSB, Song Z, Ge X, Han H, Desert R, Athavale D, Magdaleno F, Chen W, Barahona I, Lantvit D, Guzman G, Nieto N. Ablation of secreted phosphoprotein-1 in hepatocytes increases fatty acid oxidation and ameliorates alcohol-associated liver disease. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2024; 48:781-794. [PMID: 38503560 DOI: 10.1111/acer.15304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 01/30/2024] [Accepted: 03/04/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND Previously, we demonstrated that Spp1-/- mice exhibit a greater susceptibility to alcohol-induced liver injury than wild-type (WT) mice. Notably, alcohol triggers the expression of osteopontin (encoded by SPP1) in hepatocytes. However, the specific role of hepatocyte-derived SPP1 in either mitigating or exacerbating alcohol-associated liver disease (AALD) has yet to be elucidated. We hypothesized that hepatocyte-derived SPP1 plays a role in AALD by modulating the regulation of steatosis. METHODS We analyzed hepatic SPP1 expression using four publicly available datasets from patients with alcoholic hepatitis (AH). Additionally, we examined SPP1 expression in the livers of WT mice subjected to either a control or ethanol Lieber-DeCarli (LDC) diet for 6 weeks. We compared the relationship between SPP1 expression and significantly dysregulated genes in AH with controls using correlation and enrichment analyses. To investigate the specific impact of hepatocyte-derived SPP1, we generated hepatocyte-specific Spp1 knock-out (Spp1ΔHep) mice and subjected them to either a control or ethanol Lieber-DeCarli diet for 6 weeks. RESULTS Alcohol induced hepatic SPP1 expression in both humans and mice. Our analysis, focusing on genes correlated with SPP1, revealed an enrichment of fatty acid oxidation (FAO) in three datasets, and peroxisome proliferator-activated receptor signaling in one dataset. Notably, FAO genes correlating with SPP1 were downregulated in patients with AH. Ethanol-fed WT mice exhibited higher serum-free fatty acids (FFAs), adipose tissue lipolysis, and hepatic fatty acid (FA) transporters. In contrast, ethanol-fed Spp1ΔHep mice displayed lower liver triglycerides, FFAs, and serum alanine transaminase and greater FAO gene expression than WT mice, indicating a protective effect against AALD. Primary hepatocytes from Spp1∆Hep mice exhibited heightened expression of genes encoding proteins involved in FAO. CONCLUSIONS Alcohol induces the expression of SPP1 in hepatocytes, leading to impaired FAO and contributing to the development of AALD.
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Affiliation(s)
- Sukanta Das
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | | | - Rosa Alén
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | | | - Zhuolun Song
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Xiaodong Ge
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Hui Han
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Romain Desert
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Dipti Athavale
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Fernando Magdaleno
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Wei Chen
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Ines Barahona
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Daniel Lantvit
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
- Research and Development Service, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
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Han L, Li Q, Du M, Mao X. Bovine milk osteopontin improved intestinal health of pregnant rats fed a high-fat diet through improving bile acid metabolism. J Dairy Sci 2024; 107:24-39. [PMID: 37690710 DOI: 10.3168/jds.2023-23802] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 07/31/2023] [Indexed: 09/12/2023]
Abstract
The main purpose of the current study was to investigate the ameliorative effects of bovine milk osteopontin (bmOPN) on the gut dysfunction of pregnant rats fed a high-fat diet (HFD). Bovine milk osteopontin was supplemented at a dose of 6 mg/kg body weight. Bovine milk osteopontin supplementation during pregnancy reduced colonic inflammation of HFD dams, and it also increased the colonic expression of ZO-1 and claudin-4 of HFD dams. Bovine milk osteopontin significantly enriched the relative abundance of Bacteroidetes, whereas it decreased Proteobacteria, Helicobacteraceae, and Desulfovibrionaceae in feces of HFD dams. The levels of isobutyric acid and pentanoic acid in the HFD + bmOPN group were higher than that of the HFD group. Functional predication analysis of microbial genomes revealed that bmOPN supplementation to HFD pregnancies changed 4 Kyoto Encyclopedia of Genes and Genomes pathways including bile acid biosynthesis. Further, bmOPN enriched hepatic taurochenodeoxycholic acid and tauroursodeoxycholic acid plus taurohyodeoxycholic acid in the gut of HFD maternal rats. Our findings suggested that bmOPN improved the gut health of HFD pregnant rats partially through modulating bile acid biosynthesis.
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Affiliation(s)
- Lihua Han
- Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Qiqi Li
- Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Min Du
- Department of Animal Sciences, Washington State University, Pullman, WA 99163
| | - Xueying Mao
- Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
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Sørensen ES, Christensen B. Milk Osteopontin and Human Health. Nutrients 2023; 15:nu15112423. [PMID: 37299387 DOI: 10.3390/nu15112423] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 05/16/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023] Open
Abstract
Osteopontin (OPN) is a multifunctional protein found in all vertebrates. OPN is expressed in many different cell types, and is consequently found in most tissues and physiological secretions. OPN is involved in a multitude of biological processes, such as activation and regulation of the immune system; biomineralization; tissue-transformative processes, including growth and development of the gut and brain; interaction with bacteria; and many more. OPN is found in the highest concentrations in milk, where it is believed to initiate and regulate developmental, immunological and physiological processes in infants who consume milk. Processes for the isolation of bovine OPN for use in infant formula have been developed, and in recent years, many studies have investigated the effects of the intake of milk OPN. The purpose of this article is to review and compare existing knowledge about the structure and function of milk OPN, with a particular focus on the effects of milk OPN on human health and disease.
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Affiliation(s)
- Esben S Sørensen
- Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark
| | - Brian Christensen
- Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus, Denmark
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Levy E, Marcil V, Tagharist Ép Baumel S, Dahan N, Delvin E, Spahis S. Lactoferrin, Osteopontin and Lactoferrin–Osteopontin Complex: A Critical Look on Their Role in Perinatal Period and Cardiometabolic Disorders. Nutrients 2023; 15:nu15061394. [PMID: 36986124 PMCID: PMC10052990 DOI: 10.3390/nu15061394] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/02/2023] [Accepted: 03/11/2023] [Indexed: 03/18/2023] Open
Abstract
Milk-derived bioactive proteins have increasingly gained attention and consideration throughout the world due to their high-quality amino acids and multiple health-promoting attributes. Apparently, being at the forefront of functional foods, these bioactive proteins are also suggested as potential alternatives for the management of various complex diseases. In this review, we will focus on lactoferrin (LF) and osteopontin (OPN), two multifunctional dairy proteins, as well as to their naturally occurring bioactive LF–OPN complex. While describing their wide variety of physiological, biochemical, and nutritional functionalities, we will emphasize their specific roles in the perinatal period. Afterwards, we will evaluate their ability to control oxidative stress, inflammation, gut mucosal barrier, and intestinal microbiota in link with cardiometabolic disorders (CMD) (obesity, insulin resistance, dyslipidemia, and hypertension) and associated complications (diabetes and atherosclerosis). This review will not only attempt to highlight the mechanisms of action, but it will critically discuss the potential therapeutic applications of the underlined bioactive proteins in CMD.
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Affiliation(s)
- Emile Levy
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
- Department of Nutrition, Université de Montreal, C. P. 6205, succursale Centre-ville, Montreal, QC H3C 3T5, Canada
| | - Valérie Marcil
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
- Department of Nutrition, Université de Montreal, C. P. 6205, succursale Centre-ville, Montreal, QC H3C 3T5, Canada
| | - Sarah Tagharist Ép Baumel
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
- Department of Nutrition, Université de Montreal, C. P. 6205, succursale Centre-ville, Montreal, QC H3C 3T5, Canada
| | - Noam Dahan
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
| | - Edgard Delvin
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
- Biochemistry &Molecular Medicine, Faculty of Medicine, Université de Montreal, C. P. 6205, succursale Centre-ville, Montreal, QC H3C 3T5, Canada
| | - Schohraya Spahis
- Research Centre, CHU Sainte-Justine, 3175 Sainte-Catherine Road, Montreal, QC H3T 1C5, Canada
- Biochemistry &Molecular Medicine, Faculty of Medicine, Université de Montreal, C. P. 6205, succursale Centre-ville, Montreal, QC H3C 3T5, Canada
- Correspondence: ; Tel.: +1-(514)-345-4832
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Ruan H, Tang Q, Zhao X, Zhang Y, Zhao X, Xiang Y, Geng W, Feng Y, Cai W. The levels of osteopontin in human milk of Chinese mothers and its associations with maternal body composition. FOOD SCIENCE AND HUMAN WELLNESS 2022. [DOI: 10.1016/j.fshw.2022.04.033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Das S, Song Z, Han H, Ge X, Desert R, Athavale D, Babu Komakula SS, Magdaleno F, Chen W, Lantvit D, Guzman G, Nieto N. Intestinal Osteopontin Protects From Alcohol-induced Liver Injury by Preserving the Gut Microbiome and the Intestinal Barrier Function. Cell Mol Gastroenterol Hepatol 2022; 14:813-839. [PMID: 35811073 PMCID: PMC9425038 DOI: 10.1016/j.jcmgh.2022.06.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 06/30/2022] [Accepted: 06/30/2022] [Indexed: 12/10/2022]
Abstract
BACKGROUND & AIMS The gut-liver axis plays a key role in the pathogenesis of alcohol-associated liver disease (ALD). We demonstrated that Opn-/- develop worse ALD than wild-type (WT) mice; however, the role of intestinal osteopontin (OPN) in ALD remains unknown. We hypothesized that overexpression of OPN in intestinal epithelial cells (IECs) could ameliorate ALD by preserving the gut microbiome and the intestinal barrier function. METHODS OpnKI IEC, OpnΔIEC, and WT mice were fed control or ethanol Lieber-DeCarli diet for 6 weeks. RESULTS OpnKI IEC but not OpnΔIEC mice showed improved intestinal barrier function and protection from ALD. There were less pathogenic and more beneficial bacteria in ethanol-fed OpnKI IEC than in WT mice. Fecal microbiome transplant (FMT) from OpnKI IEC to WT mice protected from ALD. FMT from ethanol-fed WT to OpnKI IEC mice failed to induce ALD. Antimicrobial peptides, Il33, pSTAT3, aryl hydrocarbon receptor (Ahr), and tight-junction protein expression were higher in IECs from jejunum of ethanol-fed OpnKI IEC than of WT mice. Ethanol-fed OpnKI IEC showed more tryptophan metabolites and short-chain fatty acids in portal serum than WT mice. FMT from OpnKI IEC to WT mice enhanced IECs Ahr and tight-junction protein expression. Oral administration of milk OPN replicated the protective effect of OpnKI IEC mice in ALD. CONCLUSION Overexpression of OPN in IECs or administration of milk OPN maintain the intestinal microbiome by intestinal antimicrobial peptides. The increase in tryptophan metabolites and short-chain fatty acids signaling through the Ahr in IECs, preserve the intestinal barrier function and protect from ALD.
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Affiliation(s)
- Sukanta Das
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Zhuolun Song
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Hui Han
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Xiaodong Ge
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Romain Desert
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Dipti Athavale
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | | | - Fernando Magdaleno
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Wei Chen
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Daniel Lantvit
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois; Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, Illinois; Research Biologist, Research & Development Service, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois.
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De Muynck K, Vanderborght B, Van Vlierberghe H, Devisscher L. The Gut-Liver Axis in Chronic Liver Disease: A Macrophage Perspective. Cells 2021; 10:2959. [PMID: 34831182 PMCID: PMC8616442 DOI: 10.3390/cells10112959] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 10/25/2021] [Accepted: 10/26/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic liver disease (CLD) is a growing health concern which accounts for two million deaths per year. Obesity, alcohol overconsumption, and progressive cholestasis are commonly characterized by persistent low-grade inflammation and advancing fibrosis, which form the basis for development of end-stage liver disease complications, including hepatocellular carcinoma. CLD pathophysiology extends to the intestinal tract and is characterized by intestinal dysbiosis, bile acid dysregulation, and gut barrier disruption. In addition, macrophages are key players in CLD progression and intestinal barrier breakdown. Emerging studies are unveiling macrophage heterogeneity and driving factors of their plasticity in health and disease. To date, in-depth investigation of how gut-liver axis disruption impacts the hepatic and intestinal macrophage pool in CLD pathogenesis is scarce. In this review, we give an overview of the role of intestinal and hepatic macrophages in homeostasis and gut-liver axis disruption in progressive stages of CLD.
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Affiliation(s)
- Kevin De Muynck
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium; (K.D.M.); (B.V.)
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium;
| | - Bart Vanderborght
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium; (K.D.M.); (B.V.)
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium;
| | - Hans Van Vlierberghe
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium;
| | - Lindsey Devisscher
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium; (K.D.M.); (B.V.)
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Jiang R, Tran M, Lönnerdal B. Recombinant Bovine and Human Osteopontin Generated by Chlamydomonas reinhardtii Exhibit Bioactivities Similar to Bovine Milk Osteopontin When Assessed in Mouse Pups Fed Osteopontin-Deficient Milk. Mol Nutr Food Res 2021; 65:e2000644. [PMID: 34050612 DOI: 10.1002/mnfr.202000644] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 05/11/2021] [Indexed: 11/09/2022]
Abstract
SCOPE Osteopontin (OPN), a highly phosphorylated and glycosylated protein, is present in most body fluids, including milk. OPN appears at a high concentration in human milk (130-180 mg L-1 ), but not bovine milk (≈18 mg mL-1 ). It is previously shown that milk OPN is involved in various biological processes and therefore may be a valuable infant formula additive. METHODS AND RESULTS In the present study, recombinant bovine OPN (rbOPN) and recombinant human OPN (rhOPN) are generated in a Chlamydomonas reinhardtii (C. reinhardtii) algal expression system. The rbOPN and rhOPN are phosphorylated but not glycosylated. To assess the bioactivities of rbOPN and rhOPN and compare their bioactivities to those of bovine milk OPN (bmOPN), wild-type (WT) mouse pups nursed by OPN knock-out (KO) dams are orally fed bmOPN, rbOPN, and rhOPN daily from postnatal days 1-21 (P1-21). Effects of these OPNs on development of the brain, intestine, and immune function are evaluated. The results show that rbOPN and rhOPN exhibit effects similar to those of bmOPN as well as mouse milk OPN on stimulating proliferation of the small intestine, increasing brain myelination and cognitive development, and enhancing development of immune function. CONCLUSION rbOPN and rhOPN are likely to provide beneficial bioactivities when added to infant diets.
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Affiliation(s)
- Rulan Jiang
- Department of Nutrition, University of California, Davis, CA, 95616, USA
| | - Miller Tran
- Triton Algae Innovations, San Diego, CA, 92121, USA
| | - Bo Lönnerdal
- Department of Nutrition, University of California, Davis, CA, 95616, USA
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Thapa K, Grewal AS, Kanojia N, Rani L, Sharma N, Singh S. Alcoholic and Non-Alcoholic Liver Diseases: Promising Molecular Drug Targets and their Clinical Development. Curr Drug Discov Technol 2021; 18:333-353. [PMID: 31965945 DOI: 10.2174/1570163817666200121143959] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 11/25/2019] [Accepted: 12/04/2019] [Indexed: 11/22/2022]
Abstract
Alcoholic and non-alcoholic fatty liver diseases have become a serious concern worldwide. Both these liver diseases have an identical pathology, starting from simple steatosis to cirrhosis and, ultimately to hepatocellular carcinoma. Treatment options for alcoholic liver disease (ALD) are still the same as they were 50 years ago which include corticosteroids, pentoxifylline, antioxidants, nutritional support and abstinence; and for non-alcoholic fatty liver disease (NAFLD), weight loss, insulin sensitizers, lipid-lowering agents and anti-oxidants are the only treatment options. Despite broad research in understanding the disease pathophysiology, limited treatments are available for clinical use. Some therapeutic strategies based on targeting a specific molecule have been developed to lessen the consequences of disease and are under clinical investigation. Therefore, focus on multiple molecular targets will help develop an efficient therapeutic strategy. This review comprises a brief overview of the pathogenesis of ALD and NAFLD; recent molecular drug targets explored for ALD and NAFLD that may prove to be effective for multiple therapeutic regimens and also the clinical status of these promising drug targets for liver diseases.
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Affiliation(s)
- Komal Thapa
- Chitkara University School of Basic Sciences, Chitkara University, Himachal Pradesh, India
| | - Ajmer Singh Grewal
- Chitkara University School of Basic Sciences, Chitkara University, Himachal Pradesh, India
| | - Neha Kanojia
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Lata Rani
- Chitkara University School of Basic Sciences, Chitkara University, Himachal Pradesh, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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Song Z, Chen W, Athavale D, Ge X, Desert R, Das S, Han H, Nieto N. Osteopontin Takes Center Stage in Chronic Liver Disease. Hepatology 2021; 73:1594-1608. [PMID: 32986864 PMCID: PMC8106357 DOI: 10.1002/hep.31582] [Citation(s) in RCA: 119] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/25/2020] [Accepted: 09/09/2020] [Indexed: 12/13/2022]
Abstract
Osteopontin (OPN) was first identified in 1986. The prefix osteo- means bone; however, OPN is expressed in other tissues, including liver. The suffix -pontin means bridge and denotes the role of OPN as a link protein within the extracellular matrix. While OPN has well-established physiological roles, multiple "omics" analyses suggest that it is also involved in chronic liver disease. In this review, we provide a summary of the OPN gene and protein structure and regulation. We outline the current knowledge on how OPN is involved in hepatic steatosis in the context of alcoholic liver disease and non-alcoholic fatty liver disease. We describe the mechanisms whereby OPN participates in inflammation and liver fibrosis and discuss current research on its role in hepatocellular carcinoma and cholangiopathies. To conclude, we highlight important points to consider when doing research on OPN and provide direction for making progress on how OPN contributes to chronic liver disease.
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Affiliation(s)
- Zhuolun Song
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Wei Chen
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Dipti Athavale
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Xiaodong Ge
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Romain Desert
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Sukanta Das
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Hui Han
- Department of Pathology, University of Illinois at Chicago, Chicago, IL
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, Chicago, IL,Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL
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Quantitative determination of osteopontin in bovine, buffalo, yak, sheep and goat milk by Ultra-high performance liquid chromatography-tandem mass spectrometry and stable isotope dimethyl labeling. Food Chem 2020; 343:128489. [PMID: 33153809 DOI: 10.1016/j.foodchem.2020.128489] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 09/16/2020] [Accepted: 10/23/2020] [Indexed: 11/20/2022]
Abstract
Osteopontin (OPN) is a multifunctional protein present in different tissues, body fluids and milk. Different milk has different level of OPN content. To determine the amount of osteopontin in bovine, buffalo, yak, sheep and goat milk, we developed an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method to detect an osteopontin signature peptide. The signature peptides selected by searching Uniprot database for trypsin digested osteopontin. The sample preparation procedure includes trypsin digestion, dimethyl labeling of tryptic peptides, purification and concentration of labeled tryptic peptide with solid phase extraction. The limit of detection and limit of quantification are 0.5 mg L-1 and 2.0 mg L-1, respectively. The method has satisfactory analytical performance with a linearity of R2 ≥ 0.998, recoveries of 103.7-111.0%, and precision of 1.8-6.2%. It is also validated and successfully applied to quantifying osteopontin content in bovine, buffalo, yak, sheep and goat milk.
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Xiao J, Zhang R, Wu Y, Wu C, Jia X, Dong L, Liu L, Chen Y, Bai Y, Zhang M. Rice Bran Phenolic Extract Protects against Alcoholic Liver Injury in Mice by Alleviating Intestinal Microbiota Dysbiosis, Barrier Dysfunction, and Liver Inflammation Mediated by the Endotoxin-TLR4-NF-κB Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:1237-1247. [PMID: 31722525 DOI: 10.1021/acs.jafc.9b04961] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Alcoholic liver injury, known as the most general result of chronic alcohol intake, is induced by inflammatory responses, which is activated by intestine-derived endotoxins formed from intestinal dysbiosis. The hepatoprotective activity of rice bran phenolic extract (RBPE) on ethanol-fed mice was investigated for the first time in this study, and the underlying mechanism was explored from gut microbiota, barrier function, and hepatic inflammation. Mice were fed an alcohol-containing liquid diet alone or in mixture with RBPE for 8 weeks. RBPE treatment mitigated ethanol-induced liver damage, evidenced by the declined lipid profile levels and hepatic function markers. Moreover, ethanol intake induced intestinal microbiota dysbiosis, which was attenuated by RBPE supplementation. RBPE treatment improved the alcohol-induced decrease in the expression of ZO-1, Claudin-1, Claudin-4, and Reg3g, revealing the ameliorative effect of RBPE on intestinal barrier dysfunction. Furthermore, RBPE treatment repressed the alcohol-induced trigger of the hepatic endotoxin-TLR4-NF-κB pathway, followed by the mitigated liver inflammation. The findings indicate that RBPE supplementation ameliorates intestinal microbiota dysbiosis and barrier dysfunction, inactivates the endotoxin-TLR4-NF-κB pathway, and represses inflammatory responses in liver, and therefore, intake of RBPE or brown rice may be an effective way to mitigate alcoholic liver injury.
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Affiliation(s)
- Juan Xiao
- College of Food Science and Technology , Hainan University , Haikou 570228 , China
| | - Ruifen Zhang
- Sericultural & Agri-Food Research Institute , Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processings , Guangzhou 510610 , China
| | - Yujiao Wu
- College of Food Science and Technology , Hainan University , Haikou 570228 , China
| | - Chengjunhong Wu
- College of Food Science and Technology , Hainan University , Haikou 570228 , China
| | - Xuchao Jia
- Sericultural & Agri-Food Research Institute , Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processings , Guangzhou 510610 , China
| | - Lihong Dong
- Sericultural & Agri-Food Research Institute , Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processings , Guangzhou 510610 , China
| | - Lei Liu
- Sericultural & Agri-Food Research Institute , Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processings , Guangzhou 510610 , China
| | - Yanxia Chen
- Sericultural & Agri-Food Research Institute , Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processings , Guangzhou 510610 , China
| | - Yajuan Bai
- Sericultural & Agri-Food Research Institute , Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processings , Guangzhou 510610 , China
| | - Mingwei Zhang
- Sericultural & Agri-Food Research Institute , Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processings , Guangzhou 510610 , China
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Tu Y, Zhu S, Wang J, Burstein E, Jia D. Natural compounds in the chemoprevention of alcoholic liver disease. Phytother Res 2019; 33:2192-2212. [PMID: 31264302 DOI: 10.1002/ptr.6410] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 04/29/2019] [Accepted: 05/21/2019] [Indexed: 12/17/2022]
Abstract
Alcoholic liver disease (ALD), caused by excessive consumption of alcohol, is a major cause of chronic liver disease worldwide. Much effort has been expended to explore the pathogenesis of ALD. Hepatic cell injury, oxidative stress, inflammation, regeneration, and bacterial translocation are all involved in the pathogenesis of ALD. Immediate abstinence is the most important therapeutic treatment for affected individuals. However, the medical treatment for ALD had not advanced in a long period. Intriguingly, an increasing body of research indicates the potential of natural compounds in the targeted therapy of ALD. A plethora of dietary natural products such as flavonoids, resveratrol, saponins, and β-carotene are found to exert protective effects on ALD. This occurs through various mechanisms composed of antioxidative, anti-inflammatory, iron chelation, pro-apoptosis, and/or antiproliferation of hepatic stellate cells and hepatocellular carcinoma cells. In this review, we will summarize current knowledge about the pathogenesis and treatments of ALD and focus on the potential of natural compounds in ALD therapies and underlying mechanisms.
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Affiliation(s)
- Yingfeng Tu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Shu Zhu
- Chinese Academy of Science and Technology for Development, Ministry of Science and Technology, Institute of Foresight and Evaluation Research, Beijing, China
| | - Jing Wang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Ezra Burstein
- Department of Internal Medicine, University of Texas, Southwestern Medical Center, Dallas, TX, USA
| | - Da Jia
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
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15
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Jiang R, Lönnerdal B. Osteopontin in human milk and infant formula affects infant plasma osteopontin concentrations. Pediatr Res 2019; 85:502-505. [PMID: 30636771 DOI: 10.1038/s41390-018-0271-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 11/28/2018] [Accepted: 12/12/2018] [Indexed: 12/23/2022]
Abstract
BACKGROUND Osteopontin (OPN), a multifunctional protein, is present abundantly in human milk, but not in bovine milk and infant formulas. A recent randomized clinical trial showed that supplementing infant formula with bovine milk OPN (bOPN) resulted in better immune outcomes. METHODS Human milk OPN (hOPN) concentrations were analyzed by ELISA. Plasma samples were obtained from infants receiving one of four treatments: breast milk (BF), unsupplemented formula (F0), formula supplemented with 65 mg/L bOPN (F65), or with 130 mg/L bOPN (F130). Plasma samples were analyzed for hOPN and bOPN by ELISA. RESULTS The hOPN concentration was high in early lactation (D1 to D8), decreased gradually after D9, and deceased significantly after 1 month. At 4 and 6 months, higher levels of hOPN were found in plasma samples from the BF, F65, and F130 groups than in samples from the F0 group; the plasma bOPN concentration in the F130 group was greater than that in the F65 group. CONCLUSION Dynamic changes in the concentration of milk OPN may reflect infant needs for different amounts of milk OPN for various functions at different developmental stages. Supplemental bOPN in infant formula may exert its beneficial effects by increasing endogenous OPN in plasma.
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Affiliation(s)
- Rulan Jiang
- Department of Nutrition, University of California, Davis, CA, 95616, USA
| | - Bo Lönnerdal
- Department of Nutrition, University of California, Davis, CA, 95616, USA.
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16
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Woo SH, Lee SH, Park JW, Go DM, Kim DY. Osteopontin Protects Colonic Mucosa from Dextran Sodium Sulfate-Induced Acute Colitis in Mice by Regulating Junctional Distribution of Occludin. Dig Dis Sci 2019; 64:421-431. [PMID: 30146676 DOI: 10.1007/s10620-018-5246-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 08/09/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Osteopontin (OPN) has been reported to play an important role in intestinal mucosal protection. Although OPN may have positive effects on tight junctions, the exact relationship between OPN and tight junctions has yet to be elucidated. AIMS To investigate the role of OPN on tight junctions. METHODS We evaluated clinical signs and histopathology of acute colitis induced by dextran sodium sulfate (DSS) in OPN knockout and wild-type (WT) mice in vivo. Expression levels of occludin and zonula occludens-1 were examined using immunofluorescence. For in vitro analysis, an siRNA-mediated OPN-suppressed Caco-2 monolayer was used. Expression levels and patterns of occludin were analyzed by immunofluorescence, and transepithelial electrical resistance (TER) was measured to evaluate barrier function. Triton X-100 fractionation was used to analyze phosphorylated occludin associated with tight junctional localization. RESULTS OPN deficiency resulted in an elevated disease activity index, shortened colon length, and aggravated histological signs in mice with DSS-induced acute colitis compared to WT mice. OPN deficiency decreased occludin expression in the colonic mucosa. In Caco-2 monolayers, OPN suppression reduced junctional occludin and redistributed it into the intracellular compartment with decreased TER. Furthermore, western blot for occludin from Triton X-100 insoluble fraction revealed that OPN suppression reduced the phosphorylated form of occludin, which is actually distributed in the tight junction. CONCLUSIONS Our study showed that OPN is essential for maintaining the tight junction complex by allowing occludin to localize at tight junctions. This could constitute additional evidence that OPN plays a crucial role in intestinal mucosal protection.
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Affiliation(s)
- Sang-Ho Woo
- Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, South Korea
| | - Su-Hyung Lee
- Branch of Carcinogenesis and Metastasis, Research Institute of National Cancer Center, Goyang, Gyeonggi, 10408, South Korea
| | - Jun-Won Park
- Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, 920-1192, Japan
| | - Du-Min Go
- Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, South Korea
| | - Dae-Yong Kim
- Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, South Korea.
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Yang Y, Ai G, Wang M. Alcoholic liver disease and intestinal microecology. Shijie Huaren Xiaohua Zazhi 2019; 27:43-49. [DOI: 10.11569/wcjd.v27.i1.43] [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: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) is damage to the liver that occurs after excessive alcohol use over a long period of time, which is mainly characterized by hepatocyte steatosis and fat storage, and the disease spectrum includes steatosis, steatohepatitis, alcoholic fibrosis, and cirrhosis. Steatosis and early steatohepatitis are reversible after cessation of alcohol use. Although the pathogenesis of ALD is not yet fully understood, many studies have shown that the intestinal microecological dysbiosis is closely related to the occurrence and development of ALD. Chronic alcohol use may cause intestinal microecological dysbiosis by leading to increased intestinal mucosal permeability, intestinal flora imbalance, and bacterial translocation, which can then activate immune response, induce an inflammatory response in the liver, and thus lead to liver damage. Based on this situation, we can adjust the intestinal flora imbalance to achieve the goal of treating ALD by using various methods such as supplementing probiotics or prebiotics, properly using antibiotics, and performing fecal microbiota transplantation. In addition, targeted therapy for intestinal bacterial imbalance has also become a hotspot in current research.
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Affiliation(s)
- Ya Yang
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Guo Ai
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Ming Wang
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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18
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Meng X, Li S, Li Y, Gan RY, Li HB. Gut Microbiota's Relationship with Liver Disease and Role in Hepatoprotection by Dietary Natural Products and Probiotics. Nutrients 2018; 10:E1457. [PMID: 30297615 PMCID: PMC6213031 DOI: 10.3390/nu10101457] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 09/17/2018] [Accepted: 09/26/2018] [Indexed: 12/14/2022] Open
Abstract
A variety of dietary natural products have shown hepatoprotective effects. Increasing evidence has also demonstrated that gut microorganisms play an important role in the hepatoprotection contributed by natural products. Gut dysbiosis could increase permeability of the gut barrier, resulting in translocated bacteria and leaked gut-derived products, which can reach the liver through the portal vein and might lead to increased oxidative stress and inflammation, thereby threatening liver health. Targeting gut microbiota modulation represents a promising strategy for hepatoprotection. Many natural products could protect the liver from various injuries or mitigate hepatic disorders by reverting gut dysbiosis, improving intestinal permeability, altering the primary bile acid, and inhibiting hepatic fatty acid accumulation. The mechanisms underlying their beneficial effects also include reducing oxidative stress, suppressing inflammation, attenuating fibrosis, and decreasing apoptosis. This review discusses the hepatoprotective effects of dietary natural products via modulating the gut microbiota, mainly focusing on the mechanisms of action.
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Affiliation(s)
- Xiao Meng
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangdong Engineering Technology Research Center of Nutrition Translation, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
| | - Sha Li
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China.
| | - Ya Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangdong Engineering Technology Research Center of Nutrition Translation, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
| | - Ren-You Gan
- Department of Food Science & Technology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China.
| | - Hua-Bin Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangdong Engineering Technology Research Center of Nutrition Translation, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
- South China Sea Bioresource Exploitation and Utilization Collaborative Innovation Center, Sun Yat-sen University, Guangzhou 510006, China.
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19
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Jiang R, Prell C, Lönnerdal B. Milk osteopontin promotes brain development by up-regulating osteopontin in the brain in early life. FASEB J 2018; 33:1681-1694. [PMID: 30199283 DOI: 10.1096/fj.201701290rr] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Osteopontin (OPN) is a pleiotropic protein and is abundantly present in milk. Its functions include immune modulation and cellular proliferation and differentiation. OPN is highly expressed in the brain. We investigated the effects of milk-derived OPN on brain development of mouse pups. Wild-type (WT) dams producing OPN+ milk and OPN knockout (KO) dams producing OPN- milk nursed WT pups (OPN+/+), yielding 2 pup treatment groups, OPN+ OPN+/+ and OPN- OPN+/+, for comparison. Preliminary studies supported use of this model by showing high concentrations of OPN in milk of WT dams and no OPN in milk of OPN KO dams, and production of similar amounts of milk by WT and KO dams. The ability of ingested milk OPN to enter the brain was revealed by appearance of orally gavaged [125I]-labeled and antibody-probed milk OPN in brains of pups. Brain OPN mRNA levels were similar in both nursed groups, but the brain OPN protein level was significantly lower in the OPN- OPN+/+ group at postnatal days 6 and 8. Behavior tests showed impaired memory and learning ability in OPN- OPN+/+ pups. In addition, our study revealed increased expression of myelination-related proteins and elevated proliferation and differentiation of NG-2 glia into oligodendrocytes in the brain of OPN+ OPN+/+ pups, accompanied by increased activation of ERK-1/2 and PI3K/Akt signaling. We concluded that milk OPN can play an important role in brain development and behavior in infancy by promoting myelination.-Jiang, R., Prell, C., Lönnerdal, B. Milk osteopontin promotes brain development by up-regulating osteopontin in the brain in early life.
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Affiliation(s)
- Rulan Jiang
- Department of Nutrition, University of California Davis, Davis, California, USA
| | - Christine Prell
- Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany
| | - Bo Lönnerdal
- Department of Nutrition, University of California Davis, Davis, California, USA
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20
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Magdaleno F, Ge X, Fey H, Lu Y, Gaskell H, Blajszczak CC, Aloman C, Fiel MI, Nieto N. Osteopontin deletion drives hematopoietic stem cell mobilization to the liver and increases hepatic iron contributing to alcoholic liver disease. Hepatol Commun 2018; 2:84-98. [PMID: 29404515 PMCID: PMC5776866 DOI: 10.1002/hep4.1116] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 09/11/2017] [Accepted: 09/25/2017] [Indexed: 01/01/2023] Open
Abstract
The aim of this study was to investigate the role of osteopontin (OPN) in hematopoietic stem cell (HPSC) mobilization to the liver and its contribution to alcoholic liver disease (ALD). We analyzed young (14-16 weeks) and old (>1.5 years) wild-type (WT) littermates and global Opn knockout (Opn-/- ) mice for HPSC mobilization to the liver. In addition, WT and Opn-/- mice were chronically fed the Lieber-DeCarli diet for 7 weeks. Bone marrow (BM), blood, spleen, and liver were analyzed by flow cytometry for HPSC progenitors and polymorphonuclear neutrophils (PMNs). Chemokines, growth factors, and cytokines were measured in serum and liver. Prussian blue staining for iron deposits and naphthol AS-D chloroacetate esterase staining for PMNs were performed on liver sections. Hematopoietic progenitors were lower in liver and BM of young compared to old Opn-/- mice. Granulocyte colony-stimulating factor and macrophage colony-stimulating factor were increased in Opn-/- mice, suggesting potential migration of HPSCs from the BM to the liver. Furthermore, ethanol-fed Opn-/- mice showed significant hepatic PMN infiltration and hemosiderin compared to WT mice. As a result, ethanol feeding caused greater liver injury in Opn-/- compared to WT mice. Conclusion: Opn deletion promotes HPSC mobilization, PMN infiltration, and iron deposits in the liver and thereby enhances the severity of ALD. The age-associated contribution of OPN to HPSC mobilization to the liver, the prevalence of PMNs, and accumulation of hepatic iron, which potentiates oxidant stress, reveal novel signaling mechanisms that could be targeted for therapeutic benefit in patients with ALD. (Hepatology Communications 2018;2:84-98).
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Affiliation(s)
| | - Xiaodong Ge
- Department of PathologyUniversity of Illinois at ChicagoChicagoIL
- Division of Liver Diseases, Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNY
| | - Holger Fey
- Division of Digestive DiseasesRush University Medical CenterChicagoIL
| | - Yongke Lu
- Division of Liver Diseases, Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNY
| | - Harriet Gaskell
- Department of PathologyUniversity of Illinois at ChicagoChicagoIL
| | | | - Costica Aloman
- Division of Digestive DiseasesRush University Medical CenterChicagoIL
| | - M. Isabel Fiel
- Department of PathologyIcahn School of Medicine at Mount SinaiNew YorkNY
| | - Natalia Nieto
- Department of PathologyUniversity of Illinois at ChicagoChicagoIL
- Division of Liver Diseases, Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNY
- Department of Medicine, Division of Gastroenterology and HepatologyUniversity of Illinois at ChicagoChicagoIL
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21
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Lu Y, Cederbaum AI. Cytochrome P450s and Alcoholic Liver Disease. Curr Pharm Des 2018; 24:1502-1517. [PMID: 29637855 PMCID: PMC6053342 DOI: 10.2174/1381612824666180410091511] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 03/30/2018] [Accepted: 04/06/2018] [Indexed: 12/19/2022]
Abstract
Alcohol consumption causes liver diseases, designated as Alcoholic Liver Disease (ALD). Because alcohol is detoxified by alcohol dehydrogenase (ADH), a major ethanol metabolism system, the development of ALD was initially believed to be due to malnutrition caused by alcohol metabolism in liver. The discovery of the microsomal ethanol oxidizing system (MEOS) changed this dogma. Cytochrome P450 enzymes (CYP) constitute the major components of MEOS. Cytochrome P450 2E1 (CYP2E1) in MEOS is one of the major ROS generators in liver and is considered to be contributive to ALD. Our labs have been studying the relationship between CYP2E1 and ALD for many years. Recently, we found that human CYP2A6 and its mouse analog CYP2A5 are also induced by alcohol. In mice, the alcohol induction of CYP2A5 is CYP2E1-dependent. Unlike CYP2E1, CYP2A5 protects against the development of ALD. The relationship of CYP2E1, CYP2A5, and ALD is a major focus of this review.
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Affiliation(s)
- Yongke Lu
- Department of Health Sciences, College of Public Health, East Tennessee State University
- Center of Excellence for Inflammation, Infectious Disease and Immunity, East Tennessee State University
| | - Arthur I. Cederbaum
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai
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22
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Saikia P, Roychowdhury S, Bellos D, Pollard KA, McMullen MR, McCullough RL, McCullough AJ, Gholam P, de la Motte C, Nagy LE. Hyaluronic acid 35 normalizes TLR4 signaling in Kupffer cells from ethanol-fed rats via regulation of microRNA291b and its target Tollip. Sci Rep 2017; 7:15671. [PMID: 29142263 PMCID: PMC5688113 DOI: 10.1038/s41598-017-15760-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 11/02/2017] [Indexed: 02/06/2023] Open
Abstract
TLR4 signaling in hepatic macrophages is increased after chronic ethanol feeding. Treatment of hepatic macrophages after chronic ethanol feeding with small-specific sized hyaluronic acid 35 (HA35) normalizes TLR4 signaling; however, the mechanisms for HA35 action are not completely understood. Here we used Next Generation Sequencing of microRNAs to identify negative regulators of TLR4 signaling reciprocally modulated by ethanol and HA35 in hepatic macrophages. Eleven microRNAs were up-regulated by ethanol; only 4 microRNAs, including miR291b, were decreased by HA35. Bioinformatics analysis identified Tollip, a negative regulator of TLR4, as a target of miR291b. Tollip expression was decreased in hepatic macrophages from ethanol-fed rats, but treatment with HA35 or transfection with a miR291b hairpin inhibitor restored Tollip expression and normalized TLR4-stimulated TNFα expression. In peripheral blood monocytes isolated from patients with alcoholic hepatitis, expression of TNFα mRNA was robustly increased in response to challenge with lipopolysaccharide. Importantly, pre-treatment with HA35 reduced TNFα expression by more than 50%. Taken together, we have identified miR291b as a critical miRNA up-regulated by ethanol. Normalization of the miR291b → Tollip pathway by HA35 ameliorated ethanol-induced sensitization of TLR4 signaling in macrophages/monocytes, suggesting that HA35 may be a novel therapeutic agent in the treatment of ALD.
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Affiliation(s)
- Paramananda Saikia
- Center for Liver Disease Research, Department of Pathobiology, Cleveland, OH, USA
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Sanjoy Roychowdhury
- Center for Liver Disease Research, Department of Pathobiology, Cleveland, OH, USA
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Damien Bellos
- Center for Liver Disease Research, Department of Pathobiology, Cleveland, OH, USA
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Katherine A Pollard
- Center for Liver Disease Research, Department of Pathobiology, Cleveland, OH, USA
| | - Megan R McMullen
- Center for Liver Disease Research, Department of Pathobiology, Cleveland, OH, USA
| | - Rebecca L McCullough
- Center for Liver Disease Research, Department of Pathobiology, Cleveland, OH, USA
| | - Arthur J McCullough
- Center for Liver Disease Research, Department of Pathobiology, Cleveland, OH, USA
- Departments of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA
| | - Pierre Gholam
- Department of Gastroenterology and Hepatology, University Hospital, Cleveland, OH, USA
| | - Carol de la Motte
- Center for Liver Disease Research, Department of Pathobiology, Cleveland, OH, USA
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Laura E Nagy
- Center for Liver Disease Research, Department of Pathobiology, Cleveland, OH, USA.
- Departments of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA.
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA.
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23
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Xiao J, Zhang R, Zhou Q, Liu L, Huang F, Deng Y, Ma Y, Wei Z, Tang X, Zhang M. Lychee (Litchi chinensis Sonn.) Pulp Phenolic Extract Provides Protection against Alcoholic Liver Injury in Mice by Alleviating Intestinal Microbiota Dysbiosis, Intestinal Barrier Dysfunction, and Liver Inflammation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2017; 65:9675-9684. [PMID: 29041775 DOI: 10.1021/acs.jafc.7b03791] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Liver injury is the most common consequence of alcohol abuse, which is promoted by the inflammatory response triggered by gut-derived endotoxins produced as a consequence of intestinal microbiota dysbiosis and barrier dysfunction. The aim of this study was to investigate whether modulation of intestinal microbiota and barrier function, and liver inflammation contributes to the hepatoprotective effect of lychee pulp phenolic extract (LPPE) in alcohol-fed mice. Mice were treated with an ethanol-containing liquid diet alone or in combination with LPPE for 8 weeks. LPPE supplementation alleviated ethanol-induced liver injury and downregulated key markers of inflammation. Moreover, LPPE supplementation reversed the ethanol-induced alteration of intestinal microbiota composition and increased the expression of intestinal tight junction proteins, mucus protecting proteins, and antimicrobial proteins. Furthermore, in addition to decreasing serum endotoxin level, LPPE supplementation suppressed CD14 and toll-like receptor 4 expression, and repressed the activation of nuclear factor-κB p65 in the liver. These data suggest that intestinal microbiota dysbiosis, intestinal barrier dysfunction, and liver inflammation are improved by LPPE, and therefore, the intake of LPPE or Litchi pulp may be an effective strategy to alleviate the susceptibility to alcohol-induced hepatic diseases.
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Affiliation(s)
- Juan Xiao
- Sericultural & Agri-Food Research Institute , Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture/Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China
| | - Ruifen Zhang
- Sericultural & Agri-Food Research Institute , Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture/Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China
| | - Qiuyun Zhou
- Institute for Brain Research and Rehabilitation, South China Normal University , Guangzhou 510631, China
| | - Lei Liu
- Sericultural & Agri-Food Research Institute , Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture/Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China
| | - Fei Huang
- Sericultural & Agri-Food Research Institute , Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture/Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China
| | - Yuanyuan Deng
- Sericultural & Agri-Food Research Institute , Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture/Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China
| | - Yongxuan Ma
- Sericultural & Agri-Food Research Institute , Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture/Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China
| | - Zhencheng Wei
- Sericultural & Agri-Food Research Institute , Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture/Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China
| | - Xiaojun Tang
- Sericultural & Agri-Food Research Institute , Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture/Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China
| | - Mingwei Zhang
- Sericultural & Agri-Food Research Institute , Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture/Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China
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Magdaleno F, Blajszczak CC, Nieto N. Key Events Participating in the Pathogenesis of Alcoholic Liver Disease. Biomolecules 2017; 7:biom7010009. [PMID: 28134813 PMCID: PMC5372721 DOI: 10.3390/biom7010009] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 01/20/2017] [Indexed: 12/12/2022] Open
Abstract
Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. It ranges from fatty liver to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. The most prevalent forms of ALD are alcoholic fatty liver, alcoholic hepatitis (AH) and alcoholic cirrhosis, which frequently progress as people continue drinking. ALD refers to a number of symptoms/deficits that contribute to liver injury. These include steatosis, inflammation, fibrosis and cirrhosis, which, when taken together, sequentially or simultaneously lead to significant disease progression. The pathogenesis of ALD, influenced by host and environmental factors, is currently only partially understood. To date, lipopolysaccharide (LPS) translocation from the gut to the portal blood, aging, gender, increased infiltration and activation of neutrophils and bone marrow-derived macrophages along with alcohol plus iron metabolism, with its associated increase in reactive oxygen species (ROS), are all key events contributing to the pathogenesis of ALD. This review aims to introduce the reader to the concept of alcohol-mediated liver damage and the mechanisms driving injury.
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Affiliation(s)
- Fernando Magdaleno
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA.
| | - Chuck C Blajszczak
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA.
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA.
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Wen Y, Jeong S, Xia Q, Kong X. Role of Osteopontin in Liver Diseases. Int J Biol Sci 2016; 12:1121-8. [PMID: 27570486 PMCID: PMC4997056 DOI: 10.7150/ijbs.16445] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2016] [Accepted: 07/08/2016] [Indexed: 12/12/2022] Open
Abstract
Osteopontin (OPN), a multifunctional protein, is involved in numerous pathological conditions including inflammation, immunity, angiogenesis, fibrogenesis and carcinogenesis in various tissues. Extensive studies have elucidated the critical role of OPN in cell signaling such as regulation of cell proliferation, migration, inflammation, fibrosis and tumor progression. In the liver, OPN interacts with integrins, CD44, vimentin and MyD88 signaling, thereby induces infiltration, migration, invasion and metastasis of cells. OPN is highlighted as a chemoattractant for macrophages and neutrophils during injury in inflammatory liver diseases. OPN activates hepatic stellate cells (HSCs) to exert an enhancer in fibrogenesis. The role of OPN in hepatocellular carcinoma (HCC) has also generated significant interests, especially with regards to its role as a diagnostic and prognostic factor. Interestingly, OPN acts an opposing role in liver repair under different pathological conditions. This review summarizes the current understanding of OPN in liver diseases. Further understanding of the pathophysiological role of OPN in cellular interactions and molecular mechanisms associated with hepatic inflammation, fibrosis and cancer may contribute to the development of novel strategies for clinical diagnosis, monitoring and therapy of liver diseases.
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Affiliation(s)
- Yankai Wen
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Seogsong Jeong
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoni Kong
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Rosato V, Abenavoli L, Federico A, Masarone M, Persico M. Pharmacotherapy of alcoholic liver disease in clinical practice. Int J Clin Pract 2016; 70:119-31. [PMID: 26709723 DOI: 10.1111/ijcp.12764] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
AIMS Alcohol is the most commonly used addictive substance and alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide, responsible for 47.9% of all liver chronic deaths. Despite ALD has a significant burden on the health, few therapeutic advances have been made in the last 40 years, particularly in the long-term management of these patients. METHODS we searched in PubMed, Scopus, Google Scholar, and MEDLINE databases to identify relevant English language publications focused on long-term therapy of ALD. RESULTS From the huge literature on this topic, including about 755 studies, 75 were selected as eligible including clinical trials and meta-analysis. CONCLUSIONS Abstinence remains the cornerstone of ALD therapy but it is also the most difficult therapeutic target to achieve and the risk of recidivism is very high at any time. Several drugs (disulfiram, naltrexone, acamprosate, sodium oxybate) have proven to be effective to prevent alcohol relapse and increase the abstinence, although the psychotherapeutic support remains crucial. Baclofen seems to be effective to improve abstinence, showing an excellent safety and tolerability. ALD is often complicated by a state of malnutrition, which is related to a worst mortality. A nutritional therapy may improve survival in cirrhotic patients, reversing muscle wasting, weight loss and specific nutritional deficiencies. While in aggressive forms of alcoholic hepatitis are recommended specific drug treatments, including glucocorticoids or pentoxifylline, for the long-term treatment of ALD, specific treatments aimed at stopping the progression of fibrosis are not yet approved, but there are some future perspective in this field, including probiotics and antibiotics, caspase inhibitors, osteopontin and endocannabinoids.
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Affiliation(s)
- V Rosato
- Internal Medicine and Hepatology Department, Second University of Naples, Naples, Italy
| | - L Abenavoli
- Department of Health Science, University Magna Graecia, Catanzaro, Italy
| | - A Federico
- Gastroenterology and Endoscopy Unit, Second University of Naples, Naples, Italy
| | - M Masarone
- Internal Medicine and Hepatology Unit, University of Salerno, Baronissi, Italy
| | - M Persico
- Internal Medicine and Hepatology Unit, University of Salerno, Baronissi, Italy
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Suraweera DB, Weeratunga AN, Hu RW, Pandol SJ, Hu R. Alcoholic hepatitis: The pivotal role of Kupffer cells. World J Gastrointest Pathophysiol 2015; 6:90-98. [PMID: 26600966 PMCID: PMC4644891 DOI: 10.4291/wjgp.v6.i4.90] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 07/27/2015] [Accepted: 09/08/2015] [Indexed: 02/06/2023] Open
Abstract
Kupffer cells play a central role in the pathogenesis of alcoholic hepatitis (AH). It is believed that alcohol increases the gut permeability that results in raised levels of serum endotoxins containing lipopolysaccharides (LPS). LPS binds to LPS-binding proteins and presents it to a membrane glycoprotein called CD14, which then activates Kupffer cells via a receptor called toll-like receptor 4. This endotoxin mediated activation of Kupffer cells plays an important role in the inflammatory process resulting in alcoholic hepatitis. There is no effective treatment for AH, although notable progress has been made over the last decade in understanding the underlying mechanism of alcoholic hepatitis. We specifically review the current research on the role of Kupffer cells in the pathogenesis of AH and the treatment strategies. We suggest that the imbalance between the pro-inflammatory and the anti-inflammatory process as well as the increased production of reactive oxygen species eventually lead to hepatocyte injury, the final event of alcoholic hepatitis.
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Abstract
Since its initial identification as one of the genes most highly upregulated upon T-cell activation, osteopontin (or Eta-1, as it was designated then) has been demonstrated to have many roles in the regulation of the immune response on multiple levels. It contributes to the development of immune-mediated and inflammatory diseases, and it regulates the host response to infection. In some cases, the mechanisms of these effects have been elucidated, while other mechanistic functions of the protein remain obscure. The protein itself makes these analyses complex, since it binds to a series of different integrins, and in addition to its classically secreted form, an intracellular form of osteopontin has been identified, which participates in several aspects of immune regulation. In this review, we focus on the role of osteopontin in a series of immune-related diseases, particularly those where significant advances have been made in recent years: multiple sclerosis, rheumatoid arthritis, lupus and related diseases, Sjögren's disease, colitis, and 1 area of inflammatory pathology, alcoholic and nonalcoholic liver diseases. A recurring theme in these diseases is a link between osteopontin and pathogenic T cells, particularly T helper 17 cells, where osteopontin produced by dendritic cells supports IL-17 expression, contributing to pathology. In addition, a role for osteopontin in B-cell differentiation is becoming clear. In general, osteopontin contributes to pathology in these diseases, but there are examples where it has a protective role; deciphering the mechanisms underlying these differences and the specific receptors for osteopontin will be a research challenge for the future. Aside from its newly discovered role in the development of Sjögren's disease, the role of osteopontin in inflammatory conditions in the oral cavity is still poorly understood. Elucidation of this role will be of interest.
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Affiliation(s)
- S R Rittling
- The Forsyth Institute, Cambridge, MA, USA Harvard School of Dental Medicine, Boston, MA, USA
| | - R Singh
- The Forsyth Institute, Cambridge, MA, USA
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Song BJ, Akbar M, Abdelmegeed MA, Byun K, Lee B, Yoon SK, Hardwick JP. Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications. Redox Biol 2015; 3:109-23. [PMID: 25465468 PMCID: PMC4297931 DOI: 10.1016/j.redox.2014.10.004] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 10/21/2014] [Accepted: 10/23/2014] [Indexed: 02/06/2023] Open
Abstract
Mitochondria are critically important in providing cellular energy ATP as well as their involvement in anti-oxidant defense, fat oxidation, intermediary metabolism and cell death processes. It is well-established that mitochondrial functions are suppressed when living cells or organisms are exposed to potentially toxic agents including alcohol, high fat diets, smoking and certain drugs or in many pathophysiological states through increased levels of oxidative/nitrative stress. Under elevated nitroxidative stress, cellular macromolecules proteins, DNA, and lipids can undergo different oxidative modifications, leading to disruption of their normal, sometimes critical, physiological functions. Recent reports also indicated that many mitochondrial proteins are modified via various post-translation modifications (PTMs) and primarily inactivated. Because of the recently-emerging information, in this review, we specifically focus on the mechanisms and roles of five major PTMs (namely oxidation, nitration, phosphorylation, acetylation, and adduct formation with lipid-peroxides, reactive metabolites, or advanced glycation end products) in experimental models of alcoholic and nonalcoholic fatty liver disease as well as acute hepatic injury caused by toxic compounds. We also highlight the role of the ethanol-inducible cytochrome P450-2E1 (CYP2E1) in some of these PTM changes. Finally, we discuss translational research opportunities with natural and/or synthetic anti-oxidants, which can prevent or delay the onset of mitochondrial dysfunction, fat accumulation and tissue injury.
Hepatotoxic agents including alcohol and high fat elevate nitroxidative stress. Increased nitroxidative stress promotes post-translational protein modifications. Post-translational protein modifications of many proteins lead to their inactivation. Inactivation of mitochondrial proteins contributes to mitochondrial dysfunction. Mitochondrial dysfunction contributes to necrotic or apoptotic tissue injury.
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Abstract
Alcoholic liver disease (ALD) has been among the leading causes of cirrhosis and liver-related death worldwide for decades. Early discoveries in alcoholic liver disease identified increased levels of bacterial endotoxin in the portal circulation, suggesting a role for gut-derived toxins in ALD. Indeed, alcohol consumption can disrupt the intestinal epithelial barrier and result in increased gut permeability that increasingly is recognized as a major factor in ALD. Bacterial endotoxin, lipopolysaccharide, is a prototypic microbe-derived inflammatory signal that contributes to inflammation in ALD through activation of the Toll-like receptor 4. Recent studies also have shown that alcohol consumption is associated with alterations in the gut microbiome, and the dysbalance of pathogenic and commensal organisms in the intestinal microbiome may contribute to the abnormal gut-liver axis in ALD. Indeed, bacterial decontamination improves ALD both in human and animal models. This short review summarizes recent findings and highlights emerging trends in the gut-liver axis relevant to ALD.
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Affiliation(s)
- Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
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Lazaro R, Wu R, Lee S, Zhu NL, Chen CL, French SW, Xu J, Machida K, Tsukamoto H. Osteopontin deficiency does not prevent but promotes alcoholic neutrophilic hepatitis in mice. Hepatology 2015; 61:129-40. [PMID: 25132354 PMCID: PMC4280361 DOI: 10.1002/hep.27383] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Accepted: 08/14/2014] [Indexed: 12/13/2022]
Abstract
UNLABELLED Alcoholic hepatitis (AH) is a distinct spectrum of alcoholic liver disease (ALD) with intense neutrophilic (polymorphonuclear; PMN) inflammation and high mortality. Although a recent study implicates osteopontin (SPP1) in AH, SPP1 is also shown to have protective effects on experimental ALD. To address this unsettled question, we examined the effects of SPP1 deficiency in male mice given 40% calories derived from ad libitum consumption of the Western diet high in cholesterol and saturated fat and the rest from intragastric feeding of alcohol diet without or with weekly alcohol binge. Weekly binge in this new hybrid feeding model shifts chronic ASH with macrophage inflammation and perisinusoidal and pericellular fibrosis to AH in 57% (15 of 26) of mice, accompanied by inductions of chemokines (Spp1, Cxcl1, and interleukin [Il]-17a), progenitor genes (Cd133, Cd24, Nanog, and epithelial cell adhesion molecule), PMN infiltration, and clinical features of AH, such as hypoalbuminemia, bilirubinemia, and splenomegaly. SPP1 deficiency does not reduce AH incidence and inductions of progenitor and fibrogenic genes, but rather enhances the Il-17a induction and PMN infiltration in some mice. Furthermore, in the absence of SPP1, chronic ASH mice without weekly binge begin to develop AH. CONCLUSION These results suggest that SPP1 has a protective, rather than causal, role for experimental AH reproduced in our model.
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Affiliation(s)
- Raul Lazaro
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California
| | - Raymond Wu
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California
| | - Sunyoung Lee
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California
| | - Nian-Ling Zhu
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California
| | - Chia-Lin Chen
- Southern California Research Center for ALPD and Cirrhosis,Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California
| | - Samuel W. French
- Southern California Research Center for ALPD and Cirrhosis,Harbor-UCLA Medical Center, Los Angeles, California, USA
| | - Jun Xu
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California
| | - Keigo Machida
- Southern California Research Center for ALPD and Cirrhosis,Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California,Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA
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Zhong W, Zhou Z. Alterations of the gut microbiome and metabolome in alcoholic liver disease. World J Gastrointest Pathophysiol 2014; 5:514-522. [PMID: 25400995 PMCID: PMC4231516 DOI: 10.4291/wjgp.v5.i4.514] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2014] [Revised: 07/01/2014] [Accepted: 09/10/2014] [Indexed: 02/06/2023] Open
Abstract
Alcohol consumption is one of the leading causes of liver diseases and liver-related death worldwide. The gut is a habitat for billions of microorganisms which promotes metabolism and digestion in their symbiotic relationship with the host. Alterations of gut microbiome by alcohol consumption are referred to bacterial overgrowth, release of bacteria-derived products, and/or changed microbiota equilibrium. Alcohol consumption also perturbs the function of gastrointestinal mucosa and elicits a pathophysiological condition. These adverse effects caused by alcohol may ultimately result in a broad change of gastrointestinal luminal metabolites such as bile acids, short chain fatty acids, and branched chain amino acids. Gut microbiota alterations, metabolic changes produced in a dysbiotic intestinal environment, and the host factors are all critical contributors to the development and progression of alcoholic liver disease. This review summarizes recent findings of how alcohol-induced alterations of gut microbiota and metabolome, and discusses the mechanistic link between gastrointestinal dyshomeostasis and alcoholic liver injury.
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Weng S, Zhou L, Han L, Yuan Y. Expression and purification of non-tagged recombinant mouse SPP1 in E. coli and its biological significance. Bioengineered 2014; 5:405-8. [PMID: 25482081 DOI: 10.4161/bioe.34424] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Secreted phosphoprotein 1 (SPP1) is a multifunctional protein expressed by cells from a large variety of tissues. It is involved in many physiological and pathological processes, including bone metabolism, inflammation progress, tumor metastasis, injury repair, and hyperoxia-induced injury. Native SPP1 from multiple species have been isolated from the milk and urine, and recombinant SPP1 with different tags have been expressed and purified from bacteria. In our study, DNA fragments corresponding to mouse SPP1 without signal peptide were built into the pET28a(+) vector, and non-tagged recombinant mouse SPP1 (rmSPP1) was expressed in Escherichia coli BL21(DE3). rmSPP1 was purified using a novel tri-step procedure, and the product features high purity and low endotoxin level. rmSPP1 can effectively increase hepatocellular carcinoma cell (HCC) proliferation in vitro, demonstrating its biological activity.
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Affiliation(s)
- Shunyan Weng
- a Shanghai Key Laboratory of Veterinary Biotechnology; College of Agriculture and Biology ; Shanghai Jiao Tong University ; Shanghai , P.R. China
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Abstract
Alcoholic hepatitis is an acute manifestation of alcoholic liver disease with mortality as high as 40-50% in severe cases. Patients usually have a history of prolonged alcohol abuse with or without a known history of liver disease. Although there is significant range in severity at presentation, patients with severe alcoholic hepatitis typically present with anorexia, fatigue, fever, jaundice, and ascites. The use of either pentoxifylline or corticosteroids in those with severe disease (Maddrey's discriminate function >32) has significant mortality benefit. The addition of N-acetylcysteine to corticosteroids decreases the incidences of hepatorenal syndrome, infection, and short-term mortality, but does not appear to significantly affect 6-month mortality. Nutritional support with high-calorie, high-protein diet is recommended in all patients screening positive for malnutrition. Liver transplantation for a highly selected group of patients with severe alcoholic hepatitis may be an option in the future, but is not currently recommended or available at most transplant institutions.
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Williams JA, Manley S, Ding WX. New advances in molecular mechanisms and emerging therapeutic targets in alcoholic liver diseases. World J Gastroenterol 2014; 20:12908-12933. [PMID: 25278688 PMCID: PMC4177473 DOI: 10.3748/wjg.v20.i36.12908] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 03/07/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease is a major health problem in the United States and worldwide. Chronic alcohol consumption can cause steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Significant progress has been made to understand key events and molecular players for the onset and progression of alcoholic liver disease from both experimental and clinical alcohol studies. No successful treatments are currently available for treating alcoholic liver disease; therefore, development of novel pathophysiological-targeted therapies is urgently needed. This review summarizes the recent progress on animal models used to study alcoholic liver disease and the detrimental factors that contribute to alcoholic liver disease pathogenesis including miRNAs, S-adenosylmethionine, Zinc deficiency, cytosolic lipin-1β, IRF3-mediated apoptosis, RIP3-mediated necrosis and hepcidin. In addition, we summarize emerging adaptive protective effects induced by alcohol to attenuate alcohol-induced liver pathogenesis including FoxO3, IL-22, autophagy and nuclear lipin-1α.
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Ge X, Leung TM, Arriazu E, Lu Y, Urtasun R, Christensen B, Fiel MI, Mochida S, Sørensen ES, Nieto N. Osteopontin binding to lipopolysaccharide lowers tumor necrosis factor-α and prevents early alcohol-induced liver injury in mice. Hepatology 2014; 59:1600-16. [PMID: 24214181 PMCID: PMC3966944 DOI: 10.1002/hep.26931] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Accepted: 11/06/2013] [Indexed: 12/16/2022]
Abstract
UNLABELLED Although osteopontin (OPN) is induced in alcoholic patients, its role in the pathophysiology of alcoholic liver disease (ALD) remains unclear. Increased translocation of lipopolysaccharide (LPS) from the gut is key for the onset of ALD because it promotes macrophage infiltration and activation, tumor necrosis factor-α (TNFα) production, and liver injury. Since OPN is protective for the intestinal mucosa, we postulated that enhancing OPN expression in the liver and consequently in the blood and/or in the gut could protect from early alcohol-induced liver injury. Wild-type (WT), OPN knockout (Opn(-/-)), and transgenic mice overexpressing OPN in hepatocytes (Opn(HEP) Tg) were fed either the control or the ethanol Lieber-DeCarli diet. Ethanol increased hepatic, plasma, biliary, and fecal OPN more in Opn(HEP) Tg than in WT mice. Steatosis was less in ethanol-treated Opn(HEP) Tg mice as shown by decreased liver-to-body weight ratio, hepatic triglycerides, the steatosis score, oil red-O staining, and lipid peroxidation. There was also less inflammation and liver injury as demonstrated by lower alanine aminotransferase (ALT) activity, hepatocyte ballooning degeneration, LPS levels, the inflammation score, and the number of macrophages and TNFα(+) cells. To establish if OPN could limit LPS availability and its noxious effects in the liver, binding studies were performed. OPN showed binding affinity for LPS which prevented macrophage activation, reactive oxygen, and nitrogen species generation and TNFα production. Treatment with milk OPN (m-OPN) blocked LPS translocation in vivo and protected from early alcohol-induced liver injury. CONCLUSION Natural induction plus forced overexpression of OPN in the liver or treatment with m-OPN protect from early alcohol-induced liver injury by blocking the gut-derived LPS and TNFα effects in the liver.
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Affiliation(s)
- Xiaodong Ge
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA
| | - Tung-Ming Leung
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA
| | - Elena Arriazu
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA
| | - Yongke Lu
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA
| | - Raquel Urtasun
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA
| | - Brian Christensen
- Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10, Aarhus Science Park, DK-8000 Denmark
| | - Maria Isabel Fiel
- Department of Pathology, Mount Sinai School of Medicine, 1468 Madison Avenue, Room 15-28A, New York, NY 10029, USA
| | - Satoshi Mochida
- Gastroenterology and Hepatology, Internal Medicine, Saitama Medical School, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama 350-0495, Japan
| | - Esben S. Sørensen
- Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10, Aarhus Science Park, DK-8000 Denmark
| | - Natalia Nieto
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA
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Expression and purification of bioactive high-purity recombinant mouse SPP1 in Escherichia coli. Appl Biochem Biotechnol 2014; 173:421-32. [PMID: 24664233 DOI: 10.1007/s12010-014-0849-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2013] [Accepted: 03/05/2014] [Indexed: 01/15/2023]
Abstract
Secreted phosphoprotein 1 (SPP1) is a phosphorylated acidic glycoprotein. It is broadly expressed in a variety of tissues, and it is involved in a number of physiological and pathological events, including cancer metastasis, tissues remodeling, pro-inflammation regulation, and cell survival. SPP1 has shown its function of protecting tissues and organs against injury and wound, giving itself potentials to become a therapy target or giving its antibodies of other counter-acting reagents potentials to become drug candidates. Non-tagged (native) recombinant SPP1 would be valuable in therapeutic and pharmaceutical researches. In our study, mouse Spp1 DNA fragment without signal peptide was built in pET28a(+) vector and transformed into Escherichia coli BL21 (DE3). The recombinant mouse SPP1 (rmSPP1) was then expressed in bacteria upon induction by isopropyl β-D-thiogalactopyranoside (IPTG). The abundance of rmSPP1 was increased using isoelectric precipitation and ammonium sulfate fractionation methods, and anion and cation exchange chromatography was employed to further purify rmSPP1. Finally, we got rmSPP1 product with 12.8 % productivity, 97 % purity, satisfactory bioactivity, and low endotoxin content.
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Suppression of tumour growth by orally administered osteopontin is accompanied by alterations in tumour blood vessels. Br J Cancer 2014; 110:1269-77. [PMID: 24473400 PMCID: PMC3950862 DOI: 10.1038/bjc.2014.10] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 12/11/2013] [Accepted: 12/13/2013] [Indexed: 12/16/2022] Open
Abstract
Background: The integrin-binding protein osteopontin is strongly associated with tumour development, yet is an abundant dietary component as a constituent of human and bovine milk. Therefore, we tested the effect of orally administered osteopontin (o-OPN) on the development of subcutaneous tumours in mice. Methods: Bovine milk osteopontin was administered in drinking water to tumour-bearing immune-competent mice. Tumour growth, proliferation, necrosis, apoptosis and blood vessel size and number were measured. Expression of the α9 integrin was determined. Results: o-OPN suppressed tumour growth, increased the extent of necrosis, and induced formation of abnormally large blood vessels. Anti-OPN reactivity detected in the plasma of OPN-null mice fed OPN suggested that tumour-blocking peptides were absorbed during digestion, but the o-OPN effect was likely distinct from that of an RGD peptide. Expression of the α9 integrin was detected on both tumour cells and blood vessels. Potential active peptides from the α9 binding site of OPN were identified by mass spectrometry following in vitro digestion, and injection of these peptides suppressed tumour growth. Conclusions: These results suggest that peptides derived from o-OPN are absorbed and interfere with tumour growth and normal vessel development. o-OPN-derived peptides that target the α9 integrin are likely involved.
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Christensen B, Sørensen E. Osteopontin is highly susceptible to cleavage in bovine milk and the proteolytic fragments bind the αVβ3-integrin receptor. J Dairy Sci 2014; 97:136-46. [DOI: 10.3168/jds.2013-7223] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Accepted: 10/06/2013] [Indexed: 11/19/2022]
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Lu Y, Ward SC, Nieto N. Ethanol plus the Jo2 Fas agonistic antibody-induced liver injury is attenuated in mice with partial ablation of argininosuccinate synthase. Alcohol Clin Exp Res 2013; 38:649-56. [PMID: 24224890 DOI: 10.1111/acer.12309] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Accepted: 09/24/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND Argininosuccinate synthase (ASS) is an enzyme shared by the urea cycle and the l-citrulline/nitric oxide (NO·) cycle. ASS is the rate-limiting enzyme in the urea cycle and along with nitric oxide synthase 2 (NOS2), it endows cells with the l-citrulline/NO· salvage pathway to continuously supply l-arginine from l-citrulline for sustained NO· generation. Thus, ASS conditions NO· synthesis by NOS2. Because of the relevance of NOS2 activation for liver injury, we examined the contribution of ASS to NO· generation and how it impacts liver injury. METHODS Wild-type (WT) mice and Ass(+/-) mice (Ass(-/-) mice are lethal) were intraperitoneally injected with ethanol (EtOH) at a dose of 2.5 g/kg of body weight twice a day for 3 days. Two hours after the last dose of EtOH, mice were administered the agonistic Jo2 anti-mouse Fas monoclonal antibody (Ab) at a dose of 0.2 μg/g of body weight. Mice were sacrificed 8 hours after the Jo2 Ab injection. Markers of nitrosative and oxidative stress as well as liver damage were analyzed. RESULTS EtOH plus Jo2 injection induced liver injury as shown by serum alanine aminotransferase and aspartate aminotransferase activity, liver pathology, TUNEL, and cleaved caspase-3 were lower in Ass(+/-) mice compared with WT mice, suggesting that ASS contributes to EtOH plus Jo2-mediated liver injury. CYP2E1 induction, glutathione depletion, and elevated thiobarbituric acid reactive substances were comparable in both groups of mice, suggesting that CYP2E1-mediated oxidative stress is not linked to ASS-induced liver injury. In contrast, NOS2 induction, 3-nitrotyrosine adducts formation and elevated nitrites, nitrates, and S-nitrosothiols were higher in livers from WT mice than from Ass(+/-) mice. CONCLUSION Decreased nitrosative stress causes lower EtOH plus Jo2-induced liver injury in Ass(+/-) mice.
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Affiliation(s)
- Yongke Lu
- Division of Liver Diseases , Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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