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Faheem H, Alawadhi R, Basha EH, Ismail R, Ibrahim HA, Elshamy AM, Motawea SM, Seleem MA, Elkordy A, Homouda AA, Khaled HE, Aboeida RA, Abdel Ghafar MT, Rizk FH, El-Harty YM. Ameliorating immune-dependent inflammation and apoptosis by targeting TLR4/MYD88/NF-κB pathway by celastrol mitigates the diabetic reproductive dysfunction. Physiol Genomics 2025; 57:103-114. [PMID: 39510137 DOI: 10.1152/physiolgenomics.00072.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 10/10/2024] [Accepted: 10/10/2024] [Indexed: 11/15/2024] Open
Abstract
This study aimed to examine the protective effect of celastrol on testicular dysfunction in diabetic rats and the potential underlying mechanisms. All rats included in the study were divided into four groups: a control group treated with sodium citrate buffer and vehicle), a celastrol-treated control group, a streptozotocin (STZ)-induced diabetic group following insulin resistance, and a celastrol-treated diabetic group. Serum glucose, triglyceride, total cholesterol, high-density lipoprotein cholesterol, interleukin (IL)-1β, tumor necrosis factor-α, and testosterone levels were measured. In addition, the levels of testicular homogenate superoxide dismutase and malondialdehyde were assessed. Furthermore, testicular tissue relative toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), and myeloid differentiation factor 88 (MYD88) expressions were quantitatively measured using polymerase chain reaction. Histopathological and immunohistochemical studies were also conducted. The results revealed that treatment with celastrol significantly reduced TLR4, MyD88, and NF-κB expressions, and the levels of inflammatory mediators such as tumor necrosis factor-α and IL-1β in the testicular tissue of treated rats. These findings suggest that celastrol has the potential to be effective in the treatment of diabetes-induced testicular injury by inhibiting testicular inflammation, apoptosis, and oxidative stress.NEW & NOTEWORTHY Celastrol inhibits the production of proinflammatory cytokines in the testicular tissue by specifically targeting the TLR4/MyD88/NF-κB signaling cascade pathways. This indicates that celastrol may serve as a promising new therapeutic target for treating diabetic reproductive dysfunction.
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Affiliation(s)
- Heba Faheem
- Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Rana Alawadhi
- Science Department, College of Basic Education, PAAET, Ardhiya, Kuwait
| | - Eman H Basha
- Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt
- Department of Basic Medical Sciences-Physiology, Faculty of Medicine, Ibn Sina University for Medical Sciences, Amman, Jordan
| | - Radwa Ismail
- Department of Anatomy and Embryology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Hoda A Ibrahim
- Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Amira M Elshamy
- Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Shaimaa M Motawea
- Department of Anatomy and Embryology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Monira A Seleem
- Department of Medical Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Alaa Elkordy
- Department of Neuropsychiatry, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Abdallah A Homouda
- Department of Urology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Howayda E Khaled
- Department of Zoology, Faculty of Science, Suez University, Suez, Egypt
| | - Reham A Aboeida
- Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | - Fatma H Rizk
- Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Yasmeen M El-Harty
- Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt
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Yang S, Zou Y, Zhong C, Zhou Z, Peng X, Tang C. Dual role of pyroptosis in liver diseases: mechanisms, implications, and therapeutic perspectives. Front Cell Dev Biol 2025; 13:1522206. [PMID: 39917567 PMCID: PMC11798966 DOI: 10.3389/fcell.2025.1522206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 01/10/2025] [Indexed: 02/09/2025] Open
Abstract
Pyroptosis, a form of programmed cell death induced by inflammasome with a mechanism distinct from that of apoptosis, occurs via one of the three pathway types: classical, non-classical, and granzyme A/B-dependent pyroptosis pathways. Pyroptosis is implicated in various diseases, notably exhibiting a dual role in liver diseases. It facilitates the clearance of damaged hepatocytes, preventing secondary injury, and triggers immune responses to eliminate pathogens and damaged cells. Conversely, excessive pyroptosis intensifies inflammatory responses, exacerbates hepatocyte damage and promotes the activation and proliferation of hepatic stellate cells, accelerating liver fibrosis. Furthermore, by sustaining an inflammatory state, impacts the survival and proliferation of cancer cells. This review comprehensively summarizes the dual role of pyroptosis in liver diseases and its therapeutic strategies, offering new theoretical foundations and practical guidance for preventing and treating of liver diseases.
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Affiliation(s)
| | | | | | - Zuoqiong Zhou
- State Key Laboratory of Developmental Biology of Freshwater Fish, Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, College of Physical Education, Hunan Normal University, Changsha, China
| | - Xiyang Peng
- State Key Laboratory of Developmental Biology of Freshwater Fish, Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, College of Physical Education, Hunan Normal University, Changsha, China
| | - Changfa Tang
- State Key Laboratory of Developmental Biology of Freshwater Fish, Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, College of Physical Education, Hunan Normal University, Changsha, China
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Allam MM, Ibrahim RM, El Gazzar WB, Said MA. Dipeptedyl peptidase-4 (DPP-4) inhibitor downregulates HMGB1/TLR4/NF-κB signaling pathway in a diabetic rat model of non-alcoholic fatty liver disease. Arch Physiol Biochem 2024; 130:87-95. [PMID: 34543583 DOI: 10.1080/13813455.2021.1975758] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023]
Abstract
CONTEXT Inflammatory and immune pathways play a crucial role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD). Sitagliptin blocks the dipeptidyl peptidase-4 (DPP-4) enzyme, mechanisms that alter inflammatory pathways and the innate immune system, and by which Sitagliptin affects the pathogenesis of NAFLD weren't previously discussed. OBJECTIVE This study aims to understand the interaction between Sitagliptin and innate immune response in order to meliorate NAFLD. METHODS Thirty- two Wistar male albino rats were categorised into four groups. Rats have received a standard diet or a high-fat diet either with or without Sitagliptin. Serum HMGB1, protein and mRNA expressions of hepatic TLR4 and NF-κB, inflammatory cytokines, and histopathological changes were analysed. RESULTS An ameliorative action of Sitagliptin in NAFLD was demonstrated via decreasing HMGB1-mediated TLR4/NF-κB signalling in order to suppress inflammation and reduce insulin resistance. CONCLUSION Sitagliptin may in fact prove to be a beneficial therapeutic intervention in NAFLD.
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Affiliation(s)
- Mona M Allam
- Department of Physiology, Faculty of Medicine, Benha University, Benha City, Egypt
| | - Reham M Ibrahim
- Department of Physiology, Faculty of Medicine, Benha University, Benha City, Egypt
| | - Walaa Bayoumie El Gazzar
- Department of Basic Medical Sciences, Faculty of Medicine, Hashemite University, Zarqa, Jordan
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Benha City, Egypt
| | - Mona A Said
- Department of Physiology, Faculty of Medicine, Benha University, Benha City, Egypt
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Li S, Zhou X, Chen R, Zhang Q, Sun Y, Chen H. Effect of natural polysaccharides on alcoholic liver disease: A review. Int J Biol Macromol 2023; 251:126317. [PMID: 37595705 DOI: 10.1016/j.ijbiomac.2023.126317] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 08/08/2023] [Accepted: 08/11/2023] [Indexed: 08/20/2023]
Abstract
In this study, we systematically collected relevant literature in the past five years on the intervention of natural polysaccharides in alcoholic liver disease (ALD) and reviewed the pharmacological activities and potential mechanisms of action. Natural polysaccharides are effective in preventing liver tissue degeneration, inhibiting the alcohol-induced expression of inflammatory factors, inactivation of antioxidant enzymes, and abnormal hepatic lipid deposition. Natural polysaccharides regulate the expression of proteins, such as tight junction proteins, production of small molecule metabolites, and balance of intestinal flora in the intestinal tract to alleviate ALD. Natural polysaccharides also exert therapeutic effects by modulating inflammatory, oxidative, lipid metabolism, and other pathways in the liver. Natural polysaccharides also inhibit alcohol-induced intestinal abnormalities by regulating intestinal flora and feeding back into the liver via the gut-liver axis. However, existing research on natural polysaccharides has many shortcomings: for example, most of the natural polysaccharides for testing are total polysaccharides or crude polysaccharides, progress in research on in vivo metabolic processes and mechanisms is slow, and the degree of industrialisation is insufficient. Finally, we discuss the difficulties in studying natural polysaccharides and future directions to provide a theoretical basis for their development and application.
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Affiliation(s)
- Siyu Li
- Key Laboratory for Information System of Mountainous Areas and Protection of Ecological Environment, Guizhou Normal University, Guiyang 550001, China; Guizhou Engineering Laboratory for Quality Control&Evaluation Technology of Medicine, Guizhou Normal University, Guiyang 550001, China
| | - Xin Zhou
- Key Laboratory for Information System of Mountainous Areas and Protection of Ecological Environment, Guizhou Normal University, Guiyang 550001, China; Guizhou Engineering Laboratory for Quality Control&Evaluation Technology of Medicine, Guizhou Normal University, Guiyang 550001, China
| | - Ruhai Chen
- Key Laboratory for Information System of Mountainous Areas and Protection of Ecological Environment, Guizhou Normal University, Guiyang 550001, China; Guizhou Engineering Laboratory for Quality Control&Evaluation Technology of Medicine, Guizhou Normal University, Guiyang 550001, China
| | - Qiurong Zhang
- Key Laboratory for Information System of Mountainous Areas and Protection of Ecological Environment, Guizhou Normal University, Guiyang 550001, China; Guizhou Engineering Laboratory for Quality Control&Evaluation Technology of Medicine, Guizhou Normal University, Guiyang 550001, China
| | - Yu Sun
- Key Laboratory for Information System of Mountainous Areas and Protection of Ecological Environment, Guizhou Normal University, Guiyang 550001, China; Guizhou Engineering Laboratory for Quality Control&Evaluation Technology of Medicine, Guizhou Normal University, Guiyang 550001, China
| | - Huaguo Chen
- Key Laboratory for Information System of Mountainous Areas and Protection of Ecological Environment, Guizhou Normal University, Guiyang 550001, China; Guizhou Engineering Laboratory for Quality Control&Evaluation Technology of Medicine, Guizhou Normal University, Guiyang 550001, China.
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Wikan N, Tocharus J, Oka C, Sivasinprasasn S, Chaichompoo W, Suksamrarn A, Tocharus C. The capsaicinoid nonivamide suppresses the inflammatory response and attenuates the progression of steatosis in a NAFLD-rat model. J Biochem Mol Toxicol 2023; 37:e23279. [PMID: 36541345 DOI: 10.1002/jbt.23279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 04/28/2022] [Accepted: 12/08/2022] [Indexed: 12/24/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is relatively associated with comorbidities in obesity and metabolic inflammation. Low-grade inflammation following the high-fat diet (HFD)-induced NAFLD can promote the development of nonalcoholic steatohepatitis (NASH) through particularly liver-resident immune cell recruitment and hepatic nuclear factor kappa B (NF-κB) pathway. Therefore, inflammatory intervention may contribute to NASH reduction. Pelargonic acid vanillylamide (PAVA) or nonivamide is one of the pungent capsaicinoids of Capsicum species and has been found in chili peppers. Our previous study demonstrated that PAVA improved hepatic function, decreased oxidative stress and reduced apoptotic cell death but the insight role of PAVA on NAFLD is still unclear. Thus, this study aimed to investigate the underlying anti-inflammatory mechanism of PAVA in an NAFLD-rat model. Male Sprague Dawley rats were fed with normal diet or HFD for 16 weeks. Then high-fat rats were given vehicle or PAVA (1 mg/kg/day) for another 4 weeks. We found that PAVA alleviated hepatic inflammation associated with the reducing toll-like receptor 4/NF-κB pathway, showing significantly lower recruitment of cluster of differentiation 44. PAVA also maintained activity of insulin signaling pathway, and attenuated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome formation. NAFLD progresses to NASH through transforming growth factor (TGF-β1), and also recovery to simple stage followed by PAVA suppresses pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, interleukin-6, and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway. Therefore, our findings suggest that PAVA provides a novel therapeutic approach for NAFLD and slows the progression to NASH.
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Affiliation(s)
- Naruemon Wikan
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Jiraporn Tocharus
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Chio Oka
- Functional Genomics and Medicine, Division of Biological Science, Nara Institute of Science and Technology, Ikoma, Nara, Japan
| | | | - Waraluck Chaichompoo
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Apichart Suksamrarn
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Chainarong Tocharus
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand
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Wu D, Li J, Fan Z, Wang L, Zheng X. Resveratrol ameliorates oxidative stress, inflammatory response and lipid metabolism in common carp ( Cyprinus carpio) fed with high-fat diet. Front Immunol 2022; 13:965954. [PMID: 36405693 PMCID: PMC9669426 DOI: 10.3389/fimmu.2022.965954] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 10/21/2022] [Indexed: 12/02/2023] Open
Abstract
High-fat diet is regarded as crucial inducers of oxidative stress, inflammation, and metabolic imbalance. In order to investigate the ameliorative potential of resveratrol against the progression of liver injury towards steatohepatitis, common carp (Cyprinus carpio) were distributed into six experimental groups and were fed with a normal-fat diet, a high-fat diet, and supplemented with resveratrol (0.8, 1.6, 2.4, and 3.2 g/kg diet) for 8 weeks. The high-fat diet decreased the antioxidant capacities, as well as causing the inflammatory response and lipid deposition of common carp. Resveratrol induced a marked elevation in the final body weight, weight gain rate, condition factor and significant decrease in the feed conversion ratio. Moreover, dietary resveratrol showed a significant decrease in the alanine aminotransferase, aspartate aminotransferase, triglyceride and low-density lipoprotein levels, which was accompanied by an increase in high-density lipoprotein concentration in serum. A significant elevation in total superoxide dismutase, catalase, glutathione peroxidase and a decreased malondialdehyde content were observed, along with a substantial elevation in antioxidant activities were found. Additionally, fish fed with resveratrol had an up-regulation of hepatic catalase, copper, zinc superoxide dismutase, glutathione peroxidase 1a, and glutathione peroxidase 1b gene expression via Nrf2 signaling pathway. Expectedly, our results also demonstrated that resveratrol regulates hepatic lipid metabolism in fish by inhibiting the expression of hepatic lipogenesis genes (acetyl-CoA carboxylase 1, fatty acid synthase, and sterol regulatory element binding protein 1), fatty acid uptake-related genes of lipoprotein lipase, and β-oxidation-related genes via PPAR-γ signaling pathway. Furthermore, dietary resveratrol reduced inflammation, as evident by down-regulating the interleukin-1β, interleukin-6, interleukin-8, and tumor necrosis factor-α expression levels and upregulating the interleukin-10 and transforming growth factor-β2 expression levels via NF-κB signaling pathway. As a whole, our results demonstrated that resveratrol defensed the impacts against high-fat diet on the serum biochemical, hepatic antioxidants, inflammation, and lipid metabolism.
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Affiliation(s)
| | | | | | - Liansheng Wang
- Key Laboratory of Aquatic Animal Diseases and Immune Technology of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
| | - Xianhu Zheng
- Key Laboratory of Aquatic Animal Diseases and Immune Technology of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin, China
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Zhu X, Mu K, Wan Y, Zhang L. Evolutionary history of the NLR gene families across lophotrochozoans. Gene 2022; 843:146807. [PMID: 35964873 DOI: 10.1016/j.gene.2022.146807] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 08/01/2022] [Accepted: 08/06/2022] [Indexed: 11/29/2022]
Abstract
NOD-like receptor (NLR) genes are critical innate immune receptors in animals and plants. Lophotrochozoans represent one of the most species-rich superphyla that includes molluscs, segmented worms, flatworms, bryozoans, and other invertebrates, which is crucial to our understanding of immune system evolution in bilaterians. However, NLRs have not been systematically described in lophotrochozoans. We annotated 185 NLRs in 29 lophotrochozoan genomes, and analyzed their domain organization, phylogenetic distribution, molecular evolution, and gene expression. We found that all the 24 molluscan genomes studied encoded no more than three NLRs. None of these molluscan NLRs represented an inducible expression pattern under the infection of eight pathogens; some molluscan NLRs showed developmental stage-specific expression patterns. Instead, 29 molluscan incomplete NLR (incNLR) genes, encoding for proteins absent in the NACHT domain were upregulated under pathogen infection. We also documented the species-specific expansion of NLRs in the clades Polychaeta and Pteriidae. Our study revealed that gene duplication, domain shuffling, gene loss, and novel expression pattern played important roles in the molecular evolution of NLRs.
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Affiliation(s)
- Xiaofei Zhu
- State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou, China; CAS and Shandong Province Key Laboratory of Experimental Marine Biology & Center of Deep Sea Research, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Kang Mu
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology & Center of Deep Sea Research, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; University of Chinese Academy of Sciences, Beijing, China
| | - Yi Wan
- State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan University, Haikou, China
| | - Linlin Zhang
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology & Center of Deep Sea Research, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; University of Chinese Academy of Sciences, Beijing, China.
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Yi YS. Regulatory Roles of Caspase-11 Non-Canonical Inflammasome in Inflammatory Liver Diseases. Int J Mol Sci 2022; 23:4986. [PMID: 35563377 PMCID: PMC9104167 DOI: 10.3390/ijms23094986] [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] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 04/28/2022] [Accepted: 04/28/2022] [Indexed: 12/11/2022] Open
Abstract
An inflammatory response consists of two consecutive steps: priming and triggering, to prepare and activate inflammatory responses, respectively. The cardinal feature of the triggering step is the activation of intracellular protein complexes called inflammasomes, which provide a platform for the activation of inflammatory signaling pathways. Despite many studies demonstrating the regulatory roles of canonical inflammasomes in inflammatory liver diseases, the roles of newly discovered non-canonical inflammasomes in inflammatory liver diseases are still largely unknown. Recent studies have reported the regulatory roles of the caspase-11 non-canonical inflammasome in inflammatory liver diseases, providing strong evidence that the caspase-11 non-canonical inflammasome may play key roles in the pathogenesis of inflammatory liver diseases. This review comprehensively discusses the emerging roles of the caspase-11 non-canonical inflammasome in the pathogenesis of inflammatory liver diseases, focusing on non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and inflammatory liver injuries and its underlying mechanisms. This review highlights the current knowledge on the regulatory roles of the caspase-11 non-canonical inflammasome in inflammatory liver diseases, providing new insights into the development of potential therapeutics to prevent and treat inflammatory liver diseases by targeting the caspase-11 non-canonical inflammasome.
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Affiliation(s)
- Young-Su Yi
- Department of Life Sciences, Kyonggi University, Suwon 16227, Korea
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9
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Onishchenko NA, Gonikova ZZ, Nikolskaya AO, Kirsanova LA, Sevastianov VI. Programmed cell death and liver diseases. RUSSIAN JOURNAL OF TRANSPLANTOLOGY AND ARTIFICIAL ORGANS 2022; 24:72-88. [DOI: 10.15825/1995-1191-2022-1-72-88] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Cell death represents the most critical pathologic entity in liver disease, which dictates pathologic consequences such as inflammation, fibrosis, and cell transformation. We analyzed the conclusions of studies on the involvement of different types of programmed cell death (PCD) in the pathogenesis of liver diseases. Three main forms of PCD (autophagy, apoptosis, necrosis) and five additional, still insufficiently studied PCD – necroptosis, ferroptosis, pyroptosis, partanatosis and entosis – observed in the liver in various acute and chronic diseases are considered. The involvement of several PCD at once in the development of any one pathology and one type of PCD in different pathologies was established. This indicates the existence of cross-regulation of metabolism in the liver cells with different levels of damage in the formation of the main dominant type of PCD. Available results indicate the possibility of attenuation (correction) of functional and morphological manifestations of PCD in the organ by controlled blocking of effector-mediated PCD pathways, as well as targeted induction of autophagy, anti-apoptotic and anti-necrotic mechanisms in liver cells.
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Affiliation(s)
- N. A. Onishchenko
- Shumakov National Medical Research Center of Transplantology and Artificial Organs
| | - Z. Z. Gonikova
- Shumakov National Medical Research Center of Transplantology and Artificial Organs
| | - A. O. Nikolskaya
- Shumakov National Medical Research Center of Transplantology and Artificial Organs
| | - L. A. Kirsanova
- Shumakov National Medical Research Center of Transplantology and Artificial Organs
| | - V. I. Sevastianov
- Shumakov National Medical Research Center of Transplantology and Artificial Organs
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Abstract
The involvement of inflammasomes in the proinflammatory response observed in chronic liver diseases, such as alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), is widely recognized. Although there are different types of inflammasomes, most studies to date have given attention to NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) in the pathogenesis of ALD, NAFLD/nonalcoholic steatohepatitis, and fibrosis. Canonical inflammasomes are intracellular multiprotein complexes that are assembled after the sensing of danger signals and activate caspase-1, which matures interleukin (IL)-1β, IL-18, and IL-37 and also induces a form of cell death called pyroptosis. Noncanonical inflammasomes activate caspase-11 to induce pyroptosis. We discuss the different types of inflammasomes involved in liver diseases with a focus on (a) signals and mechanisms of inflammasome activation, (b) the role of different types of inflammasomes and their products in the pathogenesis of liver diseases, and (c) potential therapeutic strategies targeting components of the inflammasomes or cytokines produced upon inflammasome activation.
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Affiliation(s)
- Marcelle de Carvalho Ribeiro
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA; ,
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA; ,
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11
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Akkaya I, Oylumlu E, Ozel I, Uzel G, Durmus L, Ciraci C. NLRC4 Inflammasome-Mediated Regulation of Eosinophilic Functions. Immune Netw 2022; 21:e42. [PMID: 35036029 PMCID: PMC8733190 DOI: 10.4110/in.2021.21.e42] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 10/26/2021] [Accepted: 10/29/2021] [Indexed: 12/01/2022] Open
Abstract
Eosinophils play critical roles in the maintenance of homeostasis in innate and adaptive immunity. Although primarily known for their roles in parasitic infections and the development of Th2 cell responses, eosinophils also play complex roles in other immune responses ranging from anti-inflammation to defense against viral and bacterial infections. However, the contributions of pattern recognition receptors in general, and NOD-like receptors (NLRs) in particular, to eosinophil involvement in these immune responses remain relatively underappreciated. Our in vivo studies demonstrated that NLRC4 deficient mice had a decreased number of eosinophils and impaired Th2 responses after induction of an allergic airway disease model. Our in vitro data, utilizing human eosinophilic EoL-1 cells, suggested that TLR2 induction markedly induced pro-inflammatory responses and inflammasome forming NLRC4 and NLRP3. Moreover, activation by their specific ligands resulted in caspase-1 cleavage and mature IL-1β secretion. Interestingly, Th2 responses such as secretion of IL-5 and IL-13 decreased after transfection of EoL-1 cells with short interfering RNAs targeting human NLRC4. Specific induction of NLRC4 with PAM3CSK4 and flagellin upregulated the expression of IL-5 receptor and expression of Fc epsilon receptors (FcεR1α, FcεR2). Strikingly, activation of the NLRC4 inflammasome also promoted expression of the costimulatory receptor CD80 as well as expression of immunoregulatory receptors PD-L1 and Siglec-8. Concomitant with NLRC4 upregulation, we found an increase in expression and activation of matrix metalloproteinase (MMP)-9, but not MMP-2. Collectively, our results present new potential roles of NLRC4 in mediating a variety of eosinopilic functions.
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Affiliation(s)
- Ilgin Akkaya
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul 34469, Turkey
| | - Ece Oylumlu
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul 34469, Turkey
| | - Irem Ozel
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul 34469, Turkey
| | - Goksu Uzel
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul 34469, Turkey
| | - Lubeyne Durmus
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul 34469, Turkey
| | - Ceren Ciraci
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul 34469, Turkey.,Inflammation Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
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12
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Li T, Su G, Zhao Y. Anti-hepatic fibrosis effects of AD-2 affecting the Raf-MEK signaling pathway and inflammatory factors in thioacetamide-induced liver injury. J Food Sci 2021; 86:2753-2765. [PMID: 33928646 DOI: 10.1111/1750-3841.15731] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 02/12/2021] [Accepted: 03/22/2021] [Indexed: 02/06/2023]
Abstract
25-Hydroxylprotopanaxadiol-3β, 12β, 20-triol (25-OH-PPD or AD-2) belongs to dammarane ginsenoside, and is commonly obtained from the acidic hydrolysate of total ginsensides of Panax ginseng. This study investigated the potential mechanism of AD-2 toward improving thioacetamide (TAA)-induced hepatic fibrosis in mice. Mice were divided into seven groups: control group, TAA model group, TAA + AD-2 (5, 10, and 20 mg/kg) groups, TAA + silymarin (100 mg/kg) group, and TAA + Fu Fang Biejia (FFBj; 300 mg/kg) group. All mice were treated to intraperitoneal TAA injection to establish a hepatic fibrosis model, and drugs were administered orally. The mechanism and related pathways underlying the AD-2-mediated action against hepatic fibrosis were explored by Western blotting and immunohistochemical staining. After AD-2 treatment, the expression levels of Lipin-1, SREBP1, and F4/80 significantly decreased, meanwhile the protein expressions levels of IL1β, IL1R1, IL18, Bax, Bid, Bcl-2, and cFlips also decreased. Furthermore, AD-2 inhibited RAF and MEK pathways. The results demonstrate that AD-2 can alleviate hepatic fibrosis. The mechanism is likely related to the regulation of lipid accumulation, inflammatory response, apoptosis pathway, and Raf-MEK signaling pathways, which provide a basis for clinical research for the treatment of hepatic fibrosis. PRACTICAL APPLICATION: Ginsenoside is one of the main active ingredients of ginseng, and can alleviate the symptoms of various diseases, for example, hepatic fibrosis. This paper mainly used Western blotting to explore its possible mechanism of action. The goal was to provide a reference for the development of traditional Chinese medicines for hepatic fibrosis.
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Affiliation(s)
- Tao Li
- Shenyang Pharmaceutical University, Shenyang, China
| | - GuangYue Su
- Shenyang Pharmaceutical University, Shenyang, China
| | - YuQing Zhao
- Shenyang Pharmaceutical University, Shenyang, China
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da Silva IV, Cardoso C, Martínez-Banaclocha H, Casini A, Pelegrín P, Soveral G. Aquaporin-3 is involved in NLRP3-inflammasome activation contributing to the setting of inflammatory response. Cell Mol Life Sci 2021; 78:3073-3085. [PMID: 33231721 PMCID: PMC11073090 DOI: 10.1007/s00018-020-03708-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 10/23/2020] [Accepted: 11/11/2020] [Indexed: 12/11/2022]
Abstract
Inflammasomes are large immune multiprotein complexes that tightly regulate the production of the pro-inflammatory cytokines, being dependent on cell regulatory volume mechanisms. Aquaporins (AQPs) are protein channels that facilitate the transport of water and glycerol (aquaglyceroporins) through membranes, essential for cell volume regulation. Although these membrane proteins are highly expressed in monocytes and macrophages, their role in the inflammatory process is still unclear. Here, we investigated the role of aquaglyceroporin AQP3 in NLRP3-inflammasome activation by complementary approaches based either on shRNA silencing or on AQP3 selective inhibition. The latter has been achieved using a reported potent gold-based inhibitor, Auphen. AQP3 inhibition or silencing partially blocked LPS-priming and decreased production of IL-6, proIL-1β, and TNF-α, suggesting the possible involvement of AQP3 in macrophage priming by Toll-like receptor 4 engagement. Moreover, AQP3-dependent cell reswelling increased IL-1β release through caspase-1 activation. NLRP3-inflammasome activation induced by reswelling, nigericin, and ATP was also blocked when AQP3 was inhibited or silenced. Altogether, these data point towards AQPs as potential players in the setting of the inflammatory response.
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Affiliation(s)
- Inês Vieira da Silva
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal
- Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, 1649-003, Lisboa, Portugal
| | - Carlos Cardoso
- Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, 1649-003, Lisboa, Portugal
- Clinical Chemistry Laboratory, Dr. Joaquim Chaves, 1495-148, Algés, Portugal
| | - Helios Martínez-Banaclocha
- Molecular Inflammation Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Hospital Clínico Universitario Virgen de La Arrixaca, Carretera Buenavista, 30120, Murcia, Spain
| | - Angela Casini
- Department of Chemistry, Technical University of Munich, Lichtenbergstr. 4, 85748, Garching b. München, Germany
| | - Pablo Pelegrín
- Molecular Inflammation Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Hospital Clínico Universitario Virgen de La Arrixaca, Carretera Buenavista, 30120, Murcia, Spain.
| | - Graça Soveral
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
- Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, 1649-003, Lisboa, Portugal.
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Shojaie L, Iorga A, Dara L. Cell Death in Liver Diseases: A Review. Int J Mol Sci 2020; 21:ijms21249682. [PMID: 33353156 PMCID: PMC7766597 DOI: 10.3390/ijms21249682] [Citation(s) in RCA: 181] [Impact Index Per Article: 36.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 12/11/2022] Open
Abstract
Regulated cell death (RCD) is pivotal in directing the severity and outcome of liver injury. Hepatocyte cell death is a critical event in the progression of liver disease due to resultant inflammation leading to fibrosis. Apoptosis, necrosis, necroptosis, autophagy, and recently, pyroptosis and ferroptosis, have all been investigated in the pathogenesis of various liver diseases. These cell death subroutines display distinct features, while sharing many similar characteristics with considerable overlap and crosstalk. Multiple types of cell death modes can likely coexist, and the death of different liver cell populations may contribute to liver injury in each type of disease. This review addresses the known signaling cascades in each cell death pathway and its implications in liver disease. In this review, we describe the common findings in each disease model, as well as the controversies and the limitations of current data with a particular focus on cell death-related research in humans and in rodent models of alcoholic liver disease, non-alcoholic fatty liver disease and steatohepatitis (NASH/NAFLD), acetaminophen (APAP)-induced hepatotoxicity, autoimmune hepatitis, cholestatic liver disease, and viral hepatitis.
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Affiliation(s)
- Layla Shojaie
- Division of Gastrointestinal & Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (L.S.); (A.I.)
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Andrea Iorga
- Division of Gastrointestinal & Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (L.S.); (A.I.)
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Lily Dara
- Division of Gastrointestinal & Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (L.S.); (A.I.)
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Correspondence:
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Protective Effects of MitoTEMPO on Nonalcoholic Fatty Liver Disease via Regulating Myeloid-Derived Suppressor Cells and Inflammation in Mice. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9329427. [PMID: 32802885 PMCID: PMC7414374 DOI: 10.1155/2020/9329427] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 07/02/2020] [Accepted: 07/08/2020] [Indexed: 12/21/2022]
Abstract
MitoTEMPO, a mitochondrial antioxidant, has protective effects on liver-related diseases. However, the role of MitoTEMPO on nonalcoholic fatty liver disease (NAFLD) and its possible mechanisms are largely unknown. Here, we investigated the effects of MitoTEMPO on NAFLD using high fat diet- (HFD-) induced obese mice as animal models. MitoTEMPO was intraperitoneally injected into HFD mice. Liver morphological changes were observed by H&E and Oil Red O staining, and the frequency of MDSCs in peripheral blood was analyzed by flow cytometry. Moreover, real-time quantitative PCR, western blot, and immunohistochemistry were conducted to detect the mRNA and protein expressions in the liver tissues. The results showed that the hepatic steatosis in liver tissues of HFD mice injected with MitoTEMPO was significantly ameliorated. Additionally, MitoTEMPO reduced the frequency of CD11b+Gr-1+ MDSCs in peripheral circulation and decreased Gr-1+ cell accumulation in the livers. Further studies demonstrated that MitoTEMPO administration suppressed the mRNA and protein expressions of MDSC-associated proinflammatory mediators, such as monocyte chemoattractant protein-1 (MCP-1), S100 calcium-binding protein A8 (S100A8), and S100 calcium-binding protein A9 (S100A9). Our results suggest that MitoTEMPO appears to be a potential chemical compound affecting certain immune cells and further ameliorates inflammation in obese-associated NAFLD.
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The P2X7 Receptor and NLRP3 Axis in Non-Alcoholic Fatty Liver Disease: A Brief Review. Cells 2020; 9:cells9041047. [PMID: 32331389 PMCID: PMC7226571 DOI: 10.3390/cells9041047] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/17/2020] [Accepted: 04/20/2020] [Indexed: 12/20/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and its prevalence is reaching epidemic characteristics both in adults and in children. The increase of NAFLD prevalence parallels that of obesity, now representing the major cause of liver inflammation, increasing the risk of cirrhosis and hepatocarcinoma. Furthermore, NAFLD is a risk factor for cardiovascular diseases and type 2 diabetes, two of the major leading causes of morbidity and mortality in western countries. Thus a significant amount of studies have dealt with the evaluation of the possible molecular mechanisms leading to NAFLD and its inflammatory consequences within the liver, the non-alcoholic steatohepatitis, and cirrhosis. The inflammasome is a key player in the inflammation and fibrogenic responses in many different tissues, including the liver. The activation of the NLRP3 inflammasome requires the activation by extracellular adenosine tri-phosphate (ATP) of a specific purinergic receptor named P2X7 located in the target cells, although other pathways have been described. To this regard, extracellular ATP acts as an internal danger signal coming from damaged cells participating in the activation of the inflammatory process, a signaling pathway common to many different tissues. Here, we briefly review the involvement of the P2X7 receptor/inflammasome NLRP3 axis in the pathophysiological events leading to NAFLD and its inflammatory and fibrotic evolutions, reporting the possible therapeutical strategies targeting the P2X7 receptor/NLRP3 inflammasome.
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Dwivedi DK, Jena GB. NLRP3 inhibitor glibenclamide attenuates high-fat diet and streptozotocin-induced non-alcoholic fatty liver disease in rat: studies on oxidative stress, inflammation, DNA damage and insulin signalling pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2020; 393:705-716. [PMID: 31834465 DOI: 10.1007/s00210-019-01773-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 11/12/2019] [Indexed: 12/14/2022]
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is much higher in diabetic and obese individuals. Combined exposure of high-fat diet (HFD) and single low-dose streptozotocin (STZ) was used to induce type II diabetes-associated NAFLD, as it better replicates the human pathology of fatty liver. Glibenclamide (GLB) is a potent NLRP3 inflammasome inhibitor and possesses anti-inflammatory and anti-oxidant properties. So it was pertinent to investigate its hepatoprotective potential against NAFLD in rat. HFD was provided to rat for 17 consecutive weeks and glibenclamide (GLB; 0.5 and 2.5 mg/kg/day, orally) was administered for the last 12 consecutive weeks. Establishment of NAFLD was clearly indicated by significant increase in liver weight, glucose, triglyceride, cholesterol, % glycosylated haemoglobin and insulin levels, and GLB intervention reduced the same. GLB restored HFD-induced significant increase in ROS, MDA and decrease in GSH. Histopathological studies revealed the macro- and micro-vascular steatosis and mild degree of inflammation in HFD-fed rat compared with control, and GLB intervention reduced the same. HFD exposure significantly increased the DNA damage and apoptosis compared with control, and GLB intervention reduced the same. Immunohistochemical and immunoblotting findings showed that GLB improved the hepatic expressions of inflammatory markers (NLRP3, ASC, caspase-1, IL-1β, NF-κB), anti-oxidant markers (SOD, catalase) and insulin signalling markers (p-AKT, p-GSK-3β, p-IRS). Hepatoprotective effects of GLB was mediated by decreasing the levels of glucose, triglycerides, cholesterol, DNA damage, apoptosis and inflammatory markers, and by improving the anti-oxidant status and insulin signalling pathway in HFD fed rat.
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Affiliation(s)
- Durgesh Kumar Dwivedi
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S., Nagar, Punjab, 160062, India
| | - G B Jena
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S., Nagar, Punjab, 160062, India.
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Kurniawan DW, Storm G, Prakash J, Bansal R. Role of spleen tyrosine kinase in liver diseases. World J Gastroenterol 2020; 26:1005-1019. [PMID: 32205992 PMCID: PMC7081001 DOI: 10.3748/wjg.v26.i10.1005] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 01/14/2020] [Accepted: 02/28/2020] [Indexed: 02/06/2023] Open
Abstract
Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase expressed in most hematopoietic cells and non-hematopoietic cells and play a crucial role in both immune and non-immune biological responses. SYK mediate diverse cellular responses via an immune-receptor tyrosine-based activation motifs (ITAMs)-dependent signalling pathways, ITAMs-independent and ITAMs-semi-dependent signalling pathways. In liver, SYK expression has been observed in parenchymal (hepatocytes) and non-parenchymal cells (hepatic stellate cells and Kupffer cells), and found to be positively correlated with the disease severity. The implication of SYK pathway has been reported in different liver diseases including liver fibrosis, viral hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis and hepatocellular carcinoma. Antagonism of SYK pathway using kinase inhibitors have shown to attenuate the progression of liver diseases thereby suggesting SYK as a highly promising therapeutic target. This review summarizes the current understanding of SYK and its therapeutic implication in liver diseases.
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Affiliation(s)
- Dhadhang Wahyu Kurniawan
- Department of Biomaterials Science and Technology, Faculty of Science and Technology, Technical Medical Centre, University of Twente, Enschede 7500, the Netherlands
- Department of Pharmacy, Universitas Jenderal Soedirman, Purwokerto 53132, Indonesia
| | - Gert Storm
- Department of Biomaterials Science and Technology, Faculty of Science and Technology, Technical Medical Centre, University of Twente, Enschede 7500, the Netherlands
- Department of Pharmaceutics, University of Utrecht, Utrecht 3454, the Netherlands
| | - Jai Prakash
- Department of Biomaterials Science and Technology, Faculty of Science and Technology, Technical Medical Centre, University of Twente, Enschede 7500, the Netherlands
| | - Ruchi Bansal
- Department of Biomaterials Science and Technology, Faculty of Science and Technology, Technical Medical Centre, University of Twente, Enschede 7500, the Netherlands
- Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Enschede 7500, the Netherlands
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Yu LY, Li WY, Lin J. Juglanin improves lipid metabolism disorder, liver injury, and intestinal integrity in nonalcoholic fatty liver mice. Shijie Huaren Xiaohua Zazhi 2020; 28:113-121. [DOI: 10.11569/wcjd.v28.i4.113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The potential therapeutic effects of Juglanin in nonalcoholic fatty liver disease (NAFLD) have not been clearly explored.
AIM To evaluate the therapeutic effects of Juglanin in NAFLD by using a mouse model fed a high-fat diet (HFD).
METHODS C57BL/6 mice were divided into a standard diet group, an HFD group, and low-, medium-, and high-dose Juglanin treatment groups. After administration, blood samples and tissues (liver and small intestine) were collected for biochemical and histological measurements.
RESULTS Juglanin attenuated the HFD-induced hepatic histomorphological changes and lipid deposition and reduced the contents of serum aspartate aminotransferase, alanine transaminase, and cholesterol, as well as the levels of blood glucose, serum insulin, and homeostasis assessment of insulin resistance. Juglanin significantly improved the metabolic damage induced with an HFD, increased the mRNA levels of liver peroxisome proliferator-activated receptor α and its downstream regulatory gene fibroblast growth factor 21, and increased the phosphorylation level of acetyl CoA carboxylase and the mRNA level of carnitine-palmitoyl transferase. In addition, Juglanin also reduced liver inflammation and restored intestinal barrier integrity and function with regard to decreasing FITC-dextran permeability and increasing the expression of tight junction protein zonula occludens-1 in small intestinal tissues.
CONCLUSION Juglanin can restore NAFLD-induced steatosis, reduce liver inflammation, restore glucose homeostasis, and improve intestinal integrity in mice.
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Affiliation(s)
- Ling-Yan Yu
- Emergency Center, Taizhou Hospital, Taizhou Grace Medical Center (Group), Taizhou 317000, Zhejiang Province, China
| | - Wei-Ying Li
- Department of Injection, Taizhou Hospital, Taizhou Grace Medical Center (Group), Taizhou 317000, Zhejiang Province, China
| | - Jia Lin
- School of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang Province, China
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Cellular Interplay as a Consequence of Inflammatory Signals Leading to Liver Fibrosis Development. Cells 2020; 9:cells9020461. [PMID: 32085494 PMCID: PMC7072785 DOI: 10.3390/cells9020461] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 02/10/2020] [Accepted: 02/15/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammation has been known to be an important driver of fibrogenesis in the liver and onset of hepatic fibrosis. It starts off as a process meant to protect the liver from further damage, but it can become the main promoter of liver fibrosis. There are many inflammation-related pathways activated during liver fibrosis that lead to hepatic stellate cells (HSCs) activation and collagen-deposition in the liver. Such events are mostly modulated upstream of HSCs and involve signals from hepatocytes and innate immune cells. One particular event is represented by cell death during liver injury that generates multiple inflammatory signals that further trigger sterile inflammation and enhancement of inflammatory response. The assembly of inflammasome that responds to danger-associated molecular patterns (DAMPs) stimulates the release of pro-inflammatory cytokines and at the same time, initiates programmed cell death called pyroptosis. This review focuses on cellular and molecular mechanisms responsible for initiation and progress of inflammation in the liver.
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Parthasarathy G, Revelo X, Malhi H. Pathogenesis of Nonalcoholic Steatohepatitis: An Overview. Hepatol Commun 2020; 4:478-492. [PMID: 32258944 PMCID: PMC7109346 DOI: 10.1002/hep4.1479] [Citation(s) in RCA: 295] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 12/21/2019] [Indexed: 12/11/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous group of liver diseases characterized by the accumulation of fat in the liver. The heterogeneity of NAFLD is reflected in a clinical and histologic spectrum where some patients develop isolated steatosis of the liver, termed nonalcoholic fatty liver, whereas others develop hepatocyte injury, ballooning, inflammation, and consequent fibrosis, termed nonalcoholic steatohepatitis (NASH). Systemic insulin resistance is a major driver of hepatic steatosis in NAFLD. Lipotoxicity of accumulated lipids along with activation of the innate immune system are major drivers of NASH. Lipid‐induced sublethal and lethal stress culminates in the activation of inflammatory processes, such as the release of proinflammatory extracellular vesicles and cell death. Innate and adaptive immune mechanisms involving macrophages, dendritic cells, and lymphocytes are central drivers of inflammation that recognize damage‐ and pathogen‐associated molecular patterns and contribute to the progression of the inflammatory cascade. While the activation of the innate immune system and the recruitment of proinflammatory monocytes into the liver in NASH are well known, the exact signals that lead to this remain less well defined. Further, the contribution of other immune cell types, such as neutrophils and B cells, is an area of intense research. Many host factors, such as the microbiome and gut–liver axis, modify individual susceptibility to NASH. In this review, we discuss lipotoxicity, inflammation, and the contribution of interorgan crosstalk in NASH pathogenesis.
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Affiliation(s)
| | - Xavier Revelo
- Department of Integrative Biology and Physiology University of Minnesota Minneapolis MN
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology Mayo Clinic Rochester MN
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Boeckmans J, Natale A, Rombaut M, Buyl K, Rogiers V, De Kock J, Vanhaecke T, Rodrigues RM. Anti-NASH Drug Development Hitches a Lift on PPAR Agonism. Cells 2019; 9:E37. [PMID: 31877771 PMCID: PMC7016963 DOI: 10.3390/cells9010037] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 12/15/2019] [Accepted: 12/17/2019] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) affects one-third of the population worldwide, of which a substantial number of patients suffer from non-alcoholic steatohepatitis (NASH). NASH is a severe condition characterized by steatosis and concomitant liver inflammation and fibrosis, for which no drug is yet available. NAFLD is also generally conceived as the hepatic manifestation of the metabolic syndrome. Consequently, well-established drugs that are indicated for the treatment of type 2 diabetes and hyperlipidemia are thought to exert effects that alleviate the pathological features of NASH. One class of these drugs targets peroxisome proliferator-activated receptors (PPARs), which are nuclear receptors that play a regulatory role in lipid metabolism and inflammation. Therefore, PPARs are now also being investigated as potential anti-NASH druggable targets. In this paper, we review the mechanisms of action and physiological functions of PPARs and discuss the position of the different PPAR agonists in the therapeutic landscape of NASH. We particularly focus on the PPAR agonists currently under evaluation in clinical phase II and III trials. Preclinical strategies and how refinement and optimization may improve PPAR-targeted anti-NASH drug testing are also discussed. Finally, potential caveats related to PPAR agonism in anti-NASH therapy are stipulated.
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Gan M, Shen L, Fan Y, Tan Y, Zheng T, Tang G, Niu L, Zhao Y, Chen L, Jiang D, Li X, Zhang S, Zhu L. MicroRNA-451 and Genistein Ameliorate Nonalcoholic Steatohepatitis in Mice. Int J Mol Sci 2019; 20:E6084. [PMID: 31816816 PMCID: PMC6928943 DOI: 10.3390/ijms20236084] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 11/13/2019] [Accepted: 11/22/2019] [Indexed: 01/18/2023] Open
Abstract
Effective, targeted therapy for chronic liver disease nonalcoholic steatohepatitis (NASH) is imminent. MicroRNAs (miRNAs) are a potential therapeutic target, and natural products that regulate miRNA expression may be a safe and effective treatment strategy for liver disease. Here, we investigated the functional role of miR-451 and the therapeutic effects of genistein in the NASH mouse model. MiR-451 was downregulated in various types of liver inflammation, and subsequent experiments showed that miR-451 regulates liver inflammation via IL1β. Genistein is a phytoestrogen with anti-inflammatory and anti-oxidant effects. Interestingly, we found that the anti-inflammatory effects of genistein were related to miR-451 and was partially antagonized by the miR-451 inhibitor. MiR-451 overexpression or genistein treatment inhibited IL1β expression and inflammation. Taken together, this study shows that miR-451 has a protective effect on hepatic inflammation, and genistein can be used as a natural promoter of miR-451 to ameliorate NASH.
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Affiliation(s)
- Mailin Gan
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Linyuan Shen
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Yuan Fan
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Ya Tan
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
- Institute of Animal Husbandry and Veterinary, Guizhou Academy of Agricultural Science, Guiyang 550005, China
| | - Ting Zheng
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Guoqing Tang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Lili Niu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Ye Zhao
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Lei Chen
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Dongmei Jiang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Xuewei Li
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Shunhua Zhang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
| | - Li Zhu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
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Wu J, Lin S, Wan B, Velani B, Zhu Y. Pyroptosis in Liver Disease: New Insights into Disease Mechanisms. Aging Dis 2019; 10:1094-1108. [PMID: 31595205 PMCID: PMC6764727 DOI: 10.14336/ad.2019.0116] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 01/16/2019] [Indexed: 12/12/2022] Open
Abstract
There has been increasing interest in pyroptosis as a novel form of pro-inflammatory programmed cell death. The mechanism of pyroptosis is significantly different from other forms of cell death in its morphological and biochemical features. Pyroptosis is characterized by the activation of two different types of caspase enzymes-caspase-1 and caspase-4/5/11, and by the occurrence of a proinflammatory cytokine cascade and an immune response. Pyroptosis participates in the immune defense mechanisms against intracellular bacterial infections. On the other hand, excessive inflammasome activation can induce sterile inflammation and eventually cause some diseases, such as acute or chronic hepatitis and liver fibrosis. The mechanism and biological significance of this novel form of cell death in different liver diseases will be evaluated in this review. Specifically, we will focus on the role of pyroptosis in alcoholic and non-alcoholic fatty liver disease, as well as in liver failure. Finally, the therapeutic implications of pyroptosis in liver diseases will be discussed.
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Affiliation(s)
- Jiali Wu
- Liver research center of the First Affiliated Hospital of Fujian Medical University, Fujian 350005, China
| | - Su Lin
- Liver research center of the First Affiliated Hospital of Fujian Medical University, Fujian 350005, China
| | - Bo Wan
- Faculty of Life Sciences and Medicine, King’s College London, London SE1 1UL, United Kingdom
| | - Bharat Velani
- Basildon and Thurrock University Hospitals NHS Foundation Trust, Nethermayne, Basildon, Essex SS16 5NL, United Kingdom
| | - Yueyong Zhu
- Liver research center of the First Affiliated Hospital of Fujian Medical University, Fujian 350005, China
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Zhao P, Han SN, Arumugam S, Yousaf MN, Qin Y, Jiang JX, Torok NJ, Chen Y, Mankash MS, Liu J, Li J, Iwakiri Y, Ouyang X. Digoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation. Am J Physiol Gastrointest Liver Physiol 2019; 317:G387-G397. [PMID: 31411894 PMCID: PMC6842989 DOI: 10.1152/ajpgi.00054.2019] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The cardiac glycoside digoxin was identified as a potent suppressor of pyruvate kinase isoform 2-hypoxia-inducible factor-α (PKM2-HIF-1α) pathway activation in liver injury mouse models via intraperitoneal injection. We have assessed the therapeutic effects of digoxin to reduce nonalcoholic steatohepatitis (NASH) by the clinically relevant oral route in mice and analyzed the cellular basis for this effect with differential involvement of liver cell subsets. C57BL/6J male mice were placed on a high-fat diet (HFD) for 10 wk and started concurrently with the gavage of digoxin (2.5, 0.5, 0.125 mg/kg twice a week) for 5 wk. Digoxin significantly reduced HFD-induced hepatic damage, steatosis, and liver inflammation across a wide dosage range. The lowest dose of digoxin (0.125 mg/kg) showed significant protective effects against liver injury and sterile inflammation. Consistently, digoxin attenuated HIF-1α sustained NLRP3 inflammasome activation in macrophages. We have reported for the first time that PKM2 is upregulated in hepatocytes with hepatic steatosis, and digoxin directly improved hepatocyte mitochondrial dysfunction and steatosis. Mechanistically, digoxin directly bound to PKM2 and inhibited PKM2 targeting HIF-1α transactivation without affecting PKM2 enzyme activation. Thus, oral digoxin showed potential to therapeutically inhibit liver injury in NASH through the regulation of PKM2-HIF-1α pathway activation with involvement of multiple cell types. Because of the large clinical experience with oral digoxin, this may have significant clinical applicability in human NASH.NEW & NOTEWORTHY This study is the first to assess the therapeutic efficacy of oral digoxin on nonalcoholic steatohepatitis (NASH) in a high-fat diet (HFD) mouse model and to determine the divergent of cell type-specific effects. Oral digoxin reduced liver damage, steatosis, and inflammation in HFD mice. Digoxin attenuated hypoxia-inducible factor (HIF)-1α axis-sustained inflammasome activity in macrophages and hepatic oxidative stress response in hepatocytes via the regulation of PKM2-HIF-1α axis pathway activation. Oral digoxin may have significant clinical applicability in human NASH.
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Affiliation(s)
- Peng Zhao
- 1Section of Digestive Diseases, Yale University School of medicine, New Haven, Connecticut,5Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Collaborative Innovation Center for Respiratory Disease Diagnosis and Treatment and Chinese Medicine Development of Henan Province, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Sheng-Na Han
- 1Section of Digestive Diseases, Yale University School of medicine, New Haven, Connecticut,6Department of Pharmacology, Basic Medical College, Zhengzhou University, Zhengzhou, China
| | - Suyavaran Arumugam
- 1Section of Digestive Diseases, Yale University School of medicine, New Haven, Connecticut
| | - Muhammad Nadeem Yousaf
- 1Section of Digestive Diseases, Yale University School of medicine, New Haven, Connecticut
| | - Yanqin Qin
- 1Section of Digestive Diseases, Yale University School of medicine, New Haven, Connecticut,5Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Collaborative Innovation Center for Respiratory Disease Diagnosis and Treatment and Chinese Medicine Development of Henan Province, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Joy X. Jiang
- 2Department of Internal Medicine, University of California, Davis, Sacramento, California
| | - Natalie Julia Torok
- 3Department of Gastroenterology and Hepatology, Stanford University and Veterans Affairs, Palo Alto, Stanford, California
| | - Yonglin Chen
- 1Section of Digestive Diseases, Yale University School of medicine, New Haven, Connecticut
| | - Mohd Salah Mankash
- 1Section of Digestive Diseases, Yale University School of medicine, New Haven, Connecticut
| | - Junbao Liu
- 4The People’s Hospital of Henan Province, Zhengzhou, China
| | - Jiansheng Li
- 5Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Collaborative Innovation Center for Respiratory Disease Diagnosis and Treatment and Chinese Medicine Development of Henan Province, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yasuko Iwakiri
- 1Section of Digestive Diseases, Yale University School of medicine, New Haven, Connecticut
| | - Xinshou Ouyang
- 1Section of Digestive Diseases, Yale University School of medicine, New Haven, Connecticut
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Elchaninov AV, Fatkhudinov TK, Vishnyakova PA, Lokhonina AV, Sukhikh GT. Phenotypical and Functional Polymorphism of Liver Resident Macrophages. Cells 2019; 8:1032. [PMID: 31491903 PMCID: PMC6769646 DOI: 10.3390/cells8091032] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Revised: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 02/07/2023] Open
Abstract
Liver diseases are one of the main causes of mortality. In this regard, the development of new ways of reparative processes stimulation is relevant. Macrophages play a leading role in the regulation of liver homeostasis in physiological conditions and in pathology. In this regard, the development of new liver treatment methods is impossible without taking into account this cell population. Resident macrophages of the liver, Kupffer cells, represent a unique cell population, first of all, due to their development. Most of the liver macrophages belong to the self-sustaining macrophage cell population, whose origin is not bone marrow. In addition, Kupffer cells are involved in such processes as regulation of hepatocyte proliferation and apoptosis, remodeling of the intercellular matrix, lipid metabolism, protective function, etc. Such a broad spectrum of liver macrophage functions indicates their high functional plasticity. The review summarizes recent data on the development, phenotypic and functional plasticity, and participation in the reparative processes of liver macrophages: resident macrophages (Kupffer cells) and bone marrow-derived macrophages.
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Affiliation(s)
- Andrey V Elchaninov
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow 117997, Russia.
- Histology, Embryology and Cytology Department, Ministry of Healthcare of The Russian Federation, Pirogov Russian National Research Medical University, 1 Ostrovitianov Street, Moscow 117997, Russia.
| | - Timur Kh Fatkhudinov
- Histology, Embryology and Cytology Department, Peoples' Friendship University of Russia, 6 Miklukho-Maklaya Street, Moscow 117198, Russia.
- Scientific Research Institute of Human Morphology, 3 Tsurupa Street, Moscow 117418, Russia.
| | - Polina A Vishnyakova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow 117997, Russia.
| | - Anastasia V Lokhonina
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow 117997, Russia.
- Histology, Embryology and Cytology Department, Peoples' Friendship University of Russia, 6 Miklukho-Maklaya Street, Moscow 117198, Russia.
| | - Gennady T Sukhikh
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow 117997, Russia.
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Leng W, Wu M, Pan H, Lei X, Chen L, Wu Q, Ouyang X, Liang Z. The SGLT2 inhibitor dapagliflozin attenuates the activity of ROS-NLRP3 inflammasome axis in steatohepatitis with diabetes mellitus. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:429. [PMID: 31700865 DOI: 10.21037/atm.2019.09.03] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background Diabetes mellitus (DM) is considered as a risk factor for the progress of liver diseases. After tissue damage, there is the highest amplitude of ubiquitously sterile inflammatory response in the liver, resulting in a major clinical consequence concerning a high prevalence of steatohepatitis in DM patients. This study aimed to investigate the inhibitory efficacy of dapagliflozin (DAPA), a sodium glucose cotransporter-2 (SGLT2) inhibitor, on experimental steatohepatitis with DM. Methods DM-steatohepatitis model was established by dual intraperitoneal injection of streptozotocin (STZ) and feeding with the high-fat diet (HFD) in apolipoprotein E-deficient (ApoE-/-) mice (n=40). The mice were concurrently treated with DAPA (1 mg/kg/d) by gavage for 12 weeks. Results In ApoE-/- mice, dual HFD/STZ dramatically induced hepatic damage and inflammation as compared with HFD alone. DAPA treatment was effective to protect from hepatic damage and inflammation in dual HFD/STZ treated ApoE-/- mice. DAPA also significantly the probability decreased the blood glucose, hepatic lipid accumulation, liver steatosis, and fibrotic response in dual HFD/STZ treated ApoE-/- mice. Further mechanistic investigations indicated that the protection of DAPA on diabetic liver injury was associated with the suppressed production of hepatic reactive oxygen species (ROS) and malondialdehyde (MDA) and the inhibited activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Conclusions These data demonstrate the efficacy of DAPA for protecting liver damage, inflammation and steatosis from experimental steatohepatitis with DM, and indicate a possible involvement of the inhibited activity of ROS-NLRP3 inflammasome.
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Affiliation(s)
- Weiling Leng
- Department of Endocrinology, Southwest Hospital, the Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Mingxia Wu
- Health Management Center, Southwest Hospital, the Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Hang Pan
- Department of Endocrinology, Southwest Hospital, the Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Xiaotian Lei
- Department of Endocrinology, Southwest Hospital, the Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Liu Chen
- Department of Endocrinology, Southwest Hospital, the Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Qinan Wu
- Department of Endocrine Nephropathy, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing 400038, China
| | - Xinshou Ouyang
- Section of Digestive Diseases, Yale University of Medicine, New Haven, CT, USA
| | - Ziwen Liang
- Department of Endocrinology, Southwest Hospital, the Third Military Medical University (Army Medical University), Chongqing 400038, China
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JASIRWAN COM, LESMANA CRA, HASAN I, SULAIMAN AS, GANI RA. The role of gut microbiota in non-alcoholic fatty liver disease: pathways of mechanisms. BIOSCIENCE OF MICROBIOTA, FOOD AND HEALTH 2019; 38:81-88. [PMID: 31384519 PMCID: PMC6663510 DOI: 10.12938/bmfh.18-032] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 04/15/2019] [Indexed: 12/20/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Its prevalence increases with increasing rates of obesity, insulin resistance, and diabetes mellitus. The pathogenesis of NAFLD involves many factors, including the gastrointestinal microbiota. However, there is still debate about the impact of gut dysbiosis in the NAFLD disease progression. Therefore, this paper aims to review the relationship between gut microbiota and other risk factors for NAFLD and how gut dysbiosis plays a role in the pathogenesis of NAFLD. Hopefully, this paper can make an appropriate contribution to the development of NAFLD research in the future.
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Affiliation(s)
- Chyntia Olivia Maurine JASIRWAN
- Department of Internal Medicine, Hepatobiliary Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Pangeran Diponegoro Road No. 71st, Central Jakarta 10430, Indonesia
| | - Cosmas Rinaldi Adithya LESMANA
- Department of Internal Medicine, Hepatobiliary Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Pangeran Diponegoro Road No. 71st, Central Jakarta 10430, Indonesia
| | - Irsan HASAN
- Department of Internal Medicine, Hepatobiliary Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Pangeran Diponegoro Road No. 71st, Central Jakarta 10430, Indonesia
| | - Andri Sanityosos SULAIMAN
- Department of Internal Medicine, Hepatobiliary Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Pangeran Diponegoro Road No. 71st, Central Jakarta 10430, Indonesia
| | - Rino Alvani GANI
- Department of Internal Medicine, Hepatobiliary Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Pangeran Diponegoro Road No. 71st, Central Jakarta 10430, Indonesia
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Mohamaden WI, Zhen-fen Z, Hegab IM, Shang-li S. Experimental infection in mice with Erwinia persicina. Microb Pathog 2019; 130:38-43. [DOI: 10.1016/j.micpath.2019.01.050] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 01/31/2019] [Accepted: 01/31/2019] [Indexed: 12/01/2022]
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Shen N, Cheng A, Qiu M, Zang G. Allicin Improves Lung Injury Induced by Sepsis via Regulation of the Toll-Like Receptor 4 (TLR4)/Myeloid Differentiation Primary Response 88 (MYD88)/Nuclear Factor kappa B (NF-κB) Pathway. Med Sci Monit 2019; 25:2567-2576. [PMID: 30957795 PMCID: PMC6467176 DOI: 10.12659/msm.914114] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Background The aim of this study was to assess the effects and mechanisms of allicin in a sepsis-induced lung injury in vivo study. Material/Methods The rats (n=54) were divided into 6 groups: Normal, DMSO, LPS, LPS+LD, LPS+MD, and LPS+HD groups. After being treated by different methods, we collected the lung tissues of different groups and evaluated the pathology by HE staining and positive apoptosis cells by TUNEL. We assessed the W/D ratio, inflammatory cytokines (TNF-α, IL-6 and IL-1β), and relative protein expressions (TLR4, MyD88, NF-κB, caspase-3, and caspase-9) by IHC assay. Results Compared with LPS group, the lung injury and positive cell number of allicin treated groups were significantly improved with dose-dependent (P<0.05, respectively) and the W/D ratio and TNF-α, IL-6 and IL-1β concentration were significantly down-regulation compared with those of LPS group with dose-dependent (P<0.05, respectively). By IHC, the TLR4, MyD88, NF-κB, caspase-3 and caspase-9 protein activities of allicin treated groups were significantly suppressed compared with those of LPS group (P<0.05, respectively) in lung tissues. Conclusions This in vivo study shows that allicin improved sepsis-induced lung injury by regulation of TLR4/MyD88/NF-κB.
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Affiliation(s)
- Ning Shen
- Department of Respiratory Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China (mainland)
| | - Ailing Cheng
- Department of Geriatrics, Jinan Hospital, Jinan, Shandong, China (mainland)
| | - Mengru Qiu
- Department of Respiratory Medicine, Shandong Academy of Occupational Health and Occupational Medicine, Jinan, Shandong, China (mainland)
| | - Guodong Zang
- Department of Respiratory Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China (mainland)
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Fernández Rodríguez CM, Aller R, Gutiérrez García ML, Ampuero J, Gómez-Camarero J, Martín-Mateos RMª, Burgos-Santamaría D, Rosales JM, Aspichueta P, Buque X, Latorre M, Andrade RJ, Hernández-Guerra M, Romero-Gómez M. Higher levels of serum uric acid influences hepatic damage in patients with non-alcoholic fatty liver disease (NAFLD). REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2019; 111:264-269. [PMID: 30810330 DOI: 10.17235/reed.2019.5965/2018] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND recent evidence suggests a causal link between serum uric acid and the metabolic syndrome, diabetes mellitus, arterial hypertension, and renal and cardiac disease. Uric acid is an endogenous danger signal and activator of the inflammasome, and has been independently associated with an increased risk of cirrhosis. AIM AND METHODS six hundred and thirty-four patients from the nation-wide HEPAMET registry with biopsy-proven NAFLD (53% NASH) were analyzed to determine whether hyperuricemia is related with advanced liver damage in patients with non-alcoholic fatty liver disease (NAFLD). Patients were divided into three groups according to the tertile levels of serum uric acid and gender. RESULTS the cohort was composed of 50% females, with a mean age of 49 years (range 19-80). Patients in the top third of serum uric acid levels were older (p = 0.017); they had a higher body mass index (p < 0.01), arterial blood pressure (p = 0.05), triglyceridemia (p = 0.012), serum creatinine (p < 0.001) and total cholesterol (p = 0.016) and lower HDL-cholesterol (p = 0.004). According to the univariate analysis, the variables associated with patients in the top third were more advanced steatosis (p = 0.02), liver fibrosis (F2-F4 vs F0-1; p = 0.011), NASH (p = 0.002) and NAS score (p = 0.05). According to the multivariate logistic regression analysis, the top third of uric acid level was independently associated with steatosis (adjusted hazard ratio 1.7; CI 95%: 1.05-2.8) and NASH (adjusted hazard ratio 1.8; CI 95%: 1.08-3.0) but not with advanced fibrosis (F2-F4) (adjusted hazard ratio 1.09; CI 95%: 0.63-1.87). CONCLUSION higher levels of serum uric acid were independently associated with hepatocellular steatosis and NASH in a cohort of patients with NAFLD. Serum uric acid levels warrants further evaluation as a component of the current non-invasive NAFLD scores of histopathological damage.
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Affiliation(s)
| | - Rocío Aller
- Digestivo, Hospital Clínico Universitario de Valladolid, España
| | | | - Javier Ampuero
- UNIT for the clinical Management of Digestive Dise, Virgen del Rocio University Hospital CIBEReh
| | | | - Rosa M ª Martín-Mateos
- Gastroenterologia, Hospital Universitario Ramon y Cajal. Universidad de ALcala de Henares. CIBERehd
| | - Diego Burgos-Santamaría
- Gastroenterologia, Hospital Universitario Ramon y Cajal. Universidad de ALcala de Henares. CIBERehd, España
| | | | - Patricia Aspichueta
- Biocruces Health Research Institute, University of Basque Country UPV/EHU, Bizkaia, Spain
| | - Xabier Buque
- Biocruces Health Research Institute, University of Basque Country UPV/EHU, Bizkaia, Spain
| | - Mercedes Latorre
- Unidad de hepatología, Consorcio Hospital General Universitario de Valencia
| | - Raúl J Andrade
- Unidad Aparato Digestivo. Complejo Hospitalario de Especialidades Virgen de la Victoria, Málaga
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Li Z, Feng H, Wang Y, Shen B, Tian Y, Wu L, Zhang Q, Jin M, Liu G. Rosmarinic acid protects mice from lipopolysaccharide/d-galactosamine-induced acute liver injury by inhibiting MAPKs/NF-κB and activating Nrf2/HO-1 signaling pathways. Int Immunopharmacol 2019; 67:465-472. [PMID: 30597292 DOI: 10.1016/j.intimp.2018.12.052] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 11/23/2018] [Accepted: 12/24/2018] [Indexed: 10/27/2022]
Abstract
Rosmarinic acid (RA) has antioxidation, anticancer, antibacterial, anti-inflammatory and various biological functions. In our study, we aim to evaluate effects of RA on acute liver injury caused by LPS and d-galactosamine (d-GalN) and its underlying molecular mechanism in mice. Our findings showed that RA could protect C57BL/6 mice from LPS/d-GalN-induced acute liver injury, which not only reflected on declining aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of the serum, but also restrained the phosphorylation of nuclear factor-kappa B (NF-κB), extracellular signal-regulated kinase (ERK1/2) and p38 protein expression and the content of tissue myeloperoxidase (MPO) elevation. Moreover, RA could enhance the level of glutathione-dependent peroxidase (GSH-PX). Furthermore, RA promoted that nuclear factor erythroid-2-related factor 2 (Nrf2) transported into nucleus, and then up-regulated heme oxygenase 1 (HO-1), glutamate-cysteine ligase catalytic (GCLC), glutamate cysteine ligase modifier (GCLM) and quinone oxidoreductase (NQO1). These results indicated that RA could protect the mice from acute liver injury induced by LPS/d-GalN.
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Affiliation(s)
- Zheng Li
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, PR China
| | - Haihua Feng
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, PR China
| | - Yue Wang
- Department of Paediatric Hematology, The First Hospital of Jilin University, Changchun, Jilin 130021, PR China
| | - Bingyu Shen
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, PR China
| | - Ye Tian
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, PR China
| | - Lin Wu
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, PR China
| | - Qiaoling Zhang
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, PR China
| | - Meiyu Jin
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, PR China
| | - Guowen Liu
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, PR China.
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Protective effects of Kangxian ruangan capsule against nonalcoholic fatty liver disease fibrosis in rats induced by MCD diet. Biomed Pharmacother 2018; 108:424-434. [PMID: 30236852 DOI: 10.1016/j.biopha.2018.06.134] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 06/25/2018] [Accepted: 06/25/2018] [Indexed: 12/19/2022] Open
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Bruzzì S, Sutti S, Giudici G, Burlone ME, Ramavath NN, Toscani A, Bozzola C, Schneider P, Morello E, Parola M, Pirisi M, Albano E. B2-Lymphocyte responses to oxidative stress-derived antigens contribute to the evolution of nonalcoholic fatty liver disease (NAFLD). Free Radic Biol Med 2018; 124:249-259. [PMID: 29920340 DOI: 10.1016/j.freeradbiomed.2018.06.015] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 06/11/2018] [Accepted: 06/13/2018] [Indexed: 01/04/2023]
Abstract
Recent evidence implicates adaptive immunity as a key player in the mechanisms supporting hepatic inflammation during the progression of nonalcoholic fatty liver disease (NAFLD). In these settings, patients with NAFLD often show an increase in the circulating levels of antibodies against oxidative stress-derived epitopes (OSE). Nonetheless, the actual role of humoral immunity in NAFLD is still unclear. This study investigates the contribution of B-lymphocytes to NAFLD evolution. B-lymphocyte immunostaining of liver biopsies from NAFLD patients showed that B-cells were evident within cell aggregates rich in T-lymphocytes. In these subjects, B/T-lymphocyte infiltration positively correlated with both circulating IgG targeting oxidative stress-derived epitopes (OSE) and interferon-γ (IFN-γ) levels. Furthermore, high prevalence of lymphocyte aggregates identified patients with more severe lobular inflammation and fibrosis. In mouse models of NAFLD, the onset of steatohepatitis was characterized by hepatic B2-lymphocytes maturation to plasma cells and by an elevation in circulating anti-OSE IgG titers. B-cell responses preceded T-cell activation and were accompanied by the up-regulation in the hepatic expression of B-cell Activating Factor (BAFF). Selective B2-cell depletion in mice over-expressing a soluble form of the BAFF/APRIL receptor Transmembrane Activator and Cyclophilin Ligand Interactor (TACI-Ig) prevented plasma cell maturation and Th-1 activation of liver CD4+ T-lymphocytes. Furthermore, TACI-Ig mice showed milder steatohepatitis and a decreased progression to fibrosis. Similarly, mice treatment with the BAFF-neutralizing monoclonal antibody Sandy-2 prevented hepatic B2-cell responses and ameliorated steatohepatitis. From these data we conclude that B2-lymphocyte activation is an early event in NAFLD evolution and contributes to the disease progression through the interaction with T-cells. Furthermore, combined clinical and experimental data suggest that elevated circulating anti-OSE IgG can identify a subset of NAFLD patients in whom adaptive immunity has a relevant role in the disease evolution toward fibrosis.
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Affiliation(s)
- Stefania Bruzzì
- Dept. of Health Sciences, Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Novara, Italy
| | - Salvatore Sutti
- Dept. of Health Sciences, Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Novara, Italy
| | - Gabriele Giudici
- Dept. of Health Sciences, Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Novara, Italy
| | - Michela E Burlone
- Dept. of Translational Medicine, Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Novara, Italy
| | - Naresh Naik Ramavath
- Dept. of Health Sciences, Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Novara, Italy
| | - Alberto Toscani
- Dept. of Health Sciences, Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Novara, Italy
| | - Cristina Bozzola
- Dept. of Health Sciences, Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Novara, Italy
| | - Pascal Schneider
- Dept. of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Elisabetta Morello
- Dept. of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Turin, Turin, Italy
| | - Maurizio Parola
- Dept. of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Turin, Turin, Italy
| | - Mario Pirisi
- Dept. of Translational Medicine, Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Novara, Italy
| | - Emanuele Albano
- Dept. of Health Sciences, Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Novara, Italy.
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Wu Z, Yang F, Jiang S, Sun X, Xu J. Induction of Liver Steatosis in BAP31-Deficient Mice Burdened with Tunicamycin-Induced Endoplasmic Reticulum Stress. Int J Mol Sci 2018; 19:ijms19082291. [PMID: 30081561 PMCID: PMC6121476 DOI: 10.3390/ijms19082291] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 07/24/2018] [Accepted: 08/02/2018] [Indexed: 12/12/2022] Open
Abstract
Endoplasmic reticulum (ER) stress is highly associated with liver steatosis. B-cell receptor-associated protein 31 (BAP31) has been reported to be involved in ER homeostasis, and plays key roles in hepatic lipid metabolism in high-fat diet-induced obese mice. However, whether BAP31 modulates hepatic lipid metabolism via regulating ER stress is still uncertain. In this study, wild-type and liver-specific BAP31-depleted mice were administrated with ER stress activator of Tunicamycin, the markers of ER stress, liver steatosis, and the underlying molecular mechanisms were determined. BAP31 deficiency increased Tunicamycin-induced hepatic lipid accumulation, aggravated liver dysfunction, and increased the mRNA levels of ER stress markers, including glucose-regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), inositol-requiring protein-1α (IRE1α) and C/EBP homologous protein (CHOP), thus promoting ER stress in vivo and in vitro. Hepatic lipid export via very low-density lipoprotein (VLDL) secretion was impaired in BAP31-depleted mice, accompanied by reduced Apolipoprotein B (APOB) and microsomal triglyceride transfer protein (MTTP) expression. Exogenous lipid clearance was also inhibited, along with impaired gene expression related to fatty acid transportation and fatty acid β-oxidation. Finally, BAP31 deficiency increased Tunicamycin-induced hepatic inflammatory response. These results demonstrate that BAP31 deficiency increased Tunicamycin-induced ER stress, impaired VLDL secretion and exogenous lipid clearance, and reduced fatty acid β-oxidation, which eventually resulted in liver steatosis.
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Affiliation(s)
- Zhenhua Wu
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang 110169, China.
| | - Fan Yang
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang 110169, China.
| | - Shan Jiang
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang 110169, China.
| | - Xiaoyu Sun
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang 110169, China.
| | - Jialin Xu
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang 110169, China.
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Han LP, Sun B, Li CJ, Xie Y, Chen LM. Effect of celastrol on toll‑like receptor 4‑mediated inflammatory response in free fatty acid‑induced HepG2 cells. Int J Mol Med 2018; 42:2053-2061. [PMID: 30015859 PMCID: PMC6108865 DOI: 10.3892/ijmm.2018.3775] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 07/10/2018] [Indexed: 01/11/2023] Open
Abstract
Toll-like receptor 4 (TLR4)-mediated immune and inflammatory signaling serves a pivotal role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Our previous study demonstrated that celastrol treatment was able to improve hepatic steatosis and inhibit the TLR4 signaling cascade pathway in type 2 diabetic rats. The present study aimed to investigate the effects of celastrol on triglyceride accumulation and inflammation in steatotic HepG2 cells, and the possible mechanisms responsible for the regulation of cellular responses following TLR4 gene knockdown by small interfering RNA (siRNA) in vitro. A cell model of hepatic steatosis was prepared by exposing the HepG2 cells to free fatty acid (FFA) in the absence or presence of celastrol. Intracellular triglycerides were visualized by Oil red O staining, and the TLR4/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) signaling cascade pathway were investigated. To directly elucidate whether TLR4 was the blocking target of celastrol upon FFA exposure, the cellular response to inflammation was determined upon transfection with TLR4 siRNA. The results revealed that celastrol significantly reduced triglyceride accumulation in the steatotic HepG2 cells, and downregulated the expression levels of TLR4, MyD88 and phospho-NF-κBp65, as well as of the downstream inflammatory cytokines interleukin-1β and tumor necrosis factor α. Knockdown of TLR4 also alleviated FFA-induced inflammatory response. In addition, co-treatment with TLR4 siRNA and celastrol further attenuated the expression of inflammatory mediators. These results suggest that celastrol exerts its protective effect partly via inhibiting the TLR4-mediated immune and inflammatory response in steatotic HepG2 cells.
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Affiliation(s)
- Li-Ping Han
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Bei Sun
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Chun-Jun Li
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Yun Xie
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Li-Ming Chen
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, P.R. China
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Li M, Song K, Huang X, Fu S, Zeng Q. GDF‑15 prevents LPS and D‑galactosamine‑induced inflammation and acute liver injury in mice. Int J Mol Med 2018; 42:1756-1764. [PMID: 29956733 DOI: 10.3892/ijmm.2018.3747] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 06/22/2018] [Indexed: 11/06/2022] Open
Abstract
Growth differentiation factor‑15 (GDF‑15) is a transforming growth factor (TGF)‑β superfamily member with a poorly characterized biological activity, speculated to be implicated in several diseases. The present study aimed to determine whether GDF‑15 participates in sepsis‑induced acute liver injury in mice. Lipopolysaccharide (LPS) and D‑galactosamine (D‑GalN) were administered to mice to induce acute liver injury. Survival of mice, histological changes in liver tissue, and levels of inflammatory biomarkers in serum and liver tissue were evaluated following treatment with GDF‑15. The underlying mechanism was investigated by western blotting, ELISA, flow cytometry, and reverse transcription‑quantitative polymerase chain reaction using Kupffer cells. The results demonstrated that GDF‑15 prevented LPS/D‑GalN‑induced death, increase in inflammatory cell infiltration and serum alanine aminotransferase and aspartate aminotransferase activities. In addition, GDF‑15 treatment reduced the production of hepatic malondialdehyde and myeloperoxidase, and attenuated the increase of interleukin (IL)‑6, tumor necrosis factor (TNF)‑α, and IL‑1β expression in serum and liver tissue, accompanied by inducible nitric oxide synthase (iNOS) inactivation in the liver. Similar changes in the expression of inflammatory cytokines, IL‑6, TNF‑α and IL‑1β, and iNOS activation were observed in the Kupffer cells. Further mechanistic experiments revealed that GDF‑15 effectively protected against LPS‑induced nuclear factor (NF)‑κB pathway activation by regulating TGFβ‑activated kinase 1 (TAK1) phosphorylation in Kupffer cells. In conclusion, GDF‑15 reduced the activation of pro‑inflammatory factors, and prevented LPS‑induced liver injury, most likely by disrupting TAK1 phosphorylation, and consequently inhibiting the activation of the NF‑κB pathway in the liver.
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Affiliation(s)
- Min Li
- Department of Pediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Kui Song
- Department of Hematology, The First Affiliated Hospital of Jishou University, Jishou, Hunan 416000, P.R. China
| | - Xiaowen Huang
- Department of Pediatrics, Boai Hospital of Zhongshan City, Zhongshan, Guangdong 528400, P.R. China
| | - Simao Fu
- Department of Pediatrics, Boai Hospital of Zhongshan City, Zhongshan, Guangdong 528400, P.R. China
| | - Qiyi Zeng
- Department of Pediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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Mirea AM, Tack CJ, Chavakis T, Joosten LAB, Toonen EJM. IL-1 Family Cytokine Pathways Underlying NAFLD: Towards New Treatment Strategies. Trends Mol Med 2018; 24:458-471. [PMID: 29665983 PMCID: PMC5939989 DOI: 10.1016/j.molmed.2018.03.005] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 03/11/2018] [Accepted: 03/12/2018] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Pathways responsible for the activation of IL-1 family cytokines are key in the development of NAFLD but underlying mechanisms are not fully understood. Many studies have focused on the inflammasome-caspase-1 pathway and have shown that this pathway is an important inducer of inflammation in NAFLD. However, this pathway is not solely responsible for the activation of proinflammatory cytokines. Also, neutrophil serine proteases (NSPs) are capable of activating cytokines and recent studies reported that these proteases also contribute to NAFLD. These studies provided, for the first time, evidence that this inflammasome-independent pathway is involved in NAFLD. In our opinion, these new insights open up new approaches for therapeutic intervention.
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Affiliation(s)
- Andreea-Manuela Mirea
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Cees J Tack
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl-Gustav-Carus, Technische Universität Dresden, Dresden, Germany
| | - Leo A B Joosten
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Erik J M Toonen
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; R&D Department, Hycult Biotech, Uden, The Netherlands.
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Ouyang X, Han SN, Zhang JY, Dioletis E, Nemeth BT, Pacher P, Feng D, Bataller R, Cabezas J, Stärkel P, Caballeria J, Pongratz RL, Cai SY, Schnabl B, Hoque R, Chen Y, Yang WH, Garcia-Martinez I, Wang FS, Gao B, Torok NJ, Kibbey RG, Mehal WZ. Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis. Cell Metab 2018; 27:339-350.e3. [PMID: 29414684 PMCID: PMC5806149 DOI: 10.1016/j.cmet.2018.01.007] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 03/07/2017] [Accepted: 01/15/2018] [Indexed: 12/19/2022]
Abstract
Sterile inflammation after tissue damage is a ubiquitous response, yet it has the highest amplitude in the liver. This has major clinical consequences, for alcoholic and non-alcoholic steatohepatitis (ASH and NASH) account for the majority of liver disease in industrialized countries and both lack therapy. Requirements for sustained sterile inflammation include increased oxidative stress and activation of the HIF-1α signaling pathway. We demonstrate the ability of digoxin, a cardiac glycoside, to protect from liver inflammation and damage in ASH and NASH. Digoxin was effective in maintaining cellular redox homeostasis and suppressing HIF-1α pathway activation. A proteomic screen revealed that digoxin binds pyruvate kinase M2 (PKM2), and independently of PKM2 kinase activity results in chromatin remodeling and downregulation of HIF-1α transactivation. These data identify PKM2 as a mediator and therapeutic target for regulating liver sterile inflammation, and demonstrate a novel role for digoxin that can effectively protect the liver from ASH and NASH.
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Affiliation(s)
- Xinshou Ouyang
- Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA.
| | - Sheng-Na Han
- Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA
| | - Ji-Yuan Zhang
- Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA
| | - Evangelos Dioletis
- Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA
| | - Balazs Tamas Nemeth
- Laboratory of Cardiovascular Physiology and Tissue Injury, NIAAA/NIH, Bethesda, MD 20892, USA
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, NIAAA/NIH, Bethesda, MD 20892, USA
| | - Dechun Feng
- NIAAA, NIH, 5625 Fishers Lane, Bethesda, MD 20892, USA
| | - Ramon Bataller
- Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Joaquin Cabezas
- Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Peter Stärkel
- Department of Gastroenterology, Saint-Luc Academic Hospital and Institute of Clinical Research, Catholic University of Louvain, Brussels, Belgium
| | - Joan Caballeria
- Unidad de Hepatología, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | | | - Shi-Ying Cai
- Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA
| | - Bernd Schnabl
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Rafaz Hoque
- Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA
| | - Yonglin Chen
- Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA
| | - Wei-Hong Yang
- Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA
| | | | - Fu-Sheng Wang
- Institute of Translational Hepatology, Beijing 302 Hospital, Beijing 100039, China
| | - Bin Gao
- NIAAA, NIH, 5625 Fishers Lane, Bethesda, MD 20892, USA
| | - Natalie Julia Torok
- Department of Medicine, Gastroenterology, and Hepatology, University of California, Davis, Sacramento, CA, USA
| | | | - Wajahat Zafar Mehal
- Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA; West Haven Veterans Medical Center, West Haven, CT 06516, USA.
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Reccia I, Kumar J, Akladios C, Virdis F, Pai M, Habib N, Spalding D. Non-alcoholic fatty liver disease: A sign of systemic disease. Metabolism 2017; 72:94-108. [PMID: 28641788 DOI: 10.1016/j.metabol.2017.04.011] [Citation(s) in RCA: 129] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2017] [Revised: 04/11/2017] [Accepted: 04/23/2017] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and leading cause of cirrhosis in the United States and developed countries. NAFLD is closely associated with obesity, insulin resistance and metabolic syndrome, significantly contributing to the exacerbation of the latter. Although NAFLD represents the hepatic component of metabolic syndrome, it can also be found in patients prior to their presentation with other manifestations of the syndrome. The pathogenesis of NAFLD is complex and closely intertwined with insulin resistance and obesity. Several mechanisms are undoubtedly involved in its pathogenesis and progression. In this review, we bring together the current understanding of the pathogenesis that makes NAFLD a systemic disease.
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Affiliation(s)
- Isabella Reccia
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Jayant Kumar
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Cherif Akladios
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Francesco Virdis
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Madhava Pai
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Nagy Habib
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Duncan Spalding
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
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Andrographolide Ameliorates Inflammation and Fibrogenesis and Attenuates Inflammasome Activation in Experimental Non-Alcoholic Steatohepatitis. Sci Rep 2017; 7:3491. [PMID: 28615649 PMCID: PMC5471224 DOI: 10.1038/s41598-017-03675-z] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 05/04/2017] [Indexed: 12/13/2022] Open
Abstract
Therapy for nonalcoholic steatohepatitis (NASH) is limited. Andrographolide (ANDRO), a botanical compound, has a potent anti-inflammatory activity due to its ability to inhibit NF-κB. ANDRO has been also shown to inhibit the NLRP3 inflammasome, a relevant pathway in NASH. Our aim was to evaluate the effects of ANDRO in NASH and its influence on inflammasome activation in this setting. Thus, mice were fed a choline-deficient-amino-acid–defined (CDAA) diet with/without concomitant ANDRO administration (1 mg/kg, 3-times/week). Also, we assessed serum levels of alanine-aminotransferase (ALT), liver histology, hepatic triglyceride content (HTC) and hepatic expression of pro-inflammatory, pro-fibrotic and inflammasome genes. Inflammasome activation was also evaluated in fat-laden HepG2 cells. Our results showed that ANDRO administration decreased HTC and attenuated hepatic inflammation and fibrosis in CDAA-fed mice. ANDRO treatment determined a strong reduction in hepatic macrophage infiltration and reduced hepatic mRNA levels of both pro-inflammatory and pro-fibrotic genes. In addition, mice treated with ANDRO showed reduced expression of inflammasome genes. Finally, ANDRO inhibited LPS-induced interleukin-1β expression through NF-κB inhibition in fat-laden HepG2 cells and inflammasome disassembly. In conclusion, ANDRO administration reduces inflammation and fibrosis in experimental NASH. Inflammasome modulation by a NF-κB-dependent mechanism may be involved in the therapeutic effects of ANDRO.
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Garay-Lugo N, Domínguez-Lopez A, Miliar García A, Aguilar Barrera E, Gómez López M, Gómez Alcalá A, Martínez Godinez MDLA, Lara-Padilla E. n-3 Fatty acids modulate the mRNA expression of the Nlrp3 inflammasome and Mtor in the liver of rats fed with high-fat or high-fat/fructose diets. Immunopharmacol Immunotoxicol 2017; 38:353-63. [PMID: 27367537 DOI: 10.1080/08923973.2016.1208221] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
CONTEXT There is evidence that n-3 polyunsaturated fatty acids (n-3-PUFAs) can inhibit mTORC1, which should potentiate autophagy and eliminate NLRP3 inflammasome activity. OBJECTIVE Evaluate the effect of a high-fat or high-fat/fructose diet with and without n-3-PUFAs on hepatic gene expression. MATERIALS AND METHODS We examined the mRNA expression by RT-PCR of Mtor, Nlrp3, and other 22 genes associated with inflammation in rats livers after a 9-week diet. The dietary regimens were low-fat (control, CD), high-fat (HF), high-fat/fructose (HF-Fr), and also each of these supplemented with n-3-PUFAs (CD-n-3-PUFAs, HF-n-3-PUFAs, and HF-Fr-n-3-PUFAs). These data were processed by GeneMania and STRING databases. RESULTS Compared to the control, the HF group showed a significant increase (between p < 0.05 and p < 0.0001) in 20 of these genes (Il1b, Il18, Rxra, Nlrp3, Casp1, Il33, Tnf, Acaca, Mtor, Eif2s1, Eif2ak4, Nfkb1, Srebf1, Hif1a, Ppara, Ppard, Pparg, Mlxipl, Fasn y Scd1), and a decrease in Sirt1 (p < 0.05). With the HF-Fr diet, a significant increase (between p < 0.05 and p < 0.005) was also found in the expression of 16 evaluated genes (Srebf1, Mlxipl, Rxra, Abca1, Il33, Nfkb1, Hif1a, Pparg, Casp1, Il1b, Il-18, Tnf, Ppard, Acaca, Fasn, Scd1), along with a decrease in the transcription of Mtor and Elovl6 (p < 0.05). Contrarily, many of the genes whose expression increased with the HF and HF-Fr diets did not significantly increase with the HF-n-3-PUFAs or HF-Fr-n-3-PUFAs diet. DISCUSSION AND CONCLUSION We found the interrelation of the genes for the mTORC1 complex, the NLRP3 inflammasome, and other metabolically important proteins, and that these genes respond to n-3-PUFAs.
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Affiliation(s)
- Natalia Garay-Lugo
- a Laboratorio de Biología Molecular , Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis and Salvador Díaz Mirón , México , D.F , México
| | - Aarón Domínguez-Lopez
- a Laboratorio de Biología Molecular , Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis and Salvador Díaz Mirón , México , D.F , México
| | - Angel Miliar García
- a Laboratorio de Biología Molecular , Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis and Salvador Díaz Mirón , México , D.F , México
| | - Eliud Aguilar Barrera
- a Laboratorio de Biología Molecular , Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis and Salvador Díaz Mirón , México , D.F , México
| | - Modesto Gómez López
- a Laboratorio de Biología Molecular , Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis and Salvador Díaz Mirón , México , D.F , México
| | - Alejandro Gómez Alcalá
- a Laboratorio de Biología Molecular , Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis and Salvador Díaz Mirón , México , D.F , México
| | - Maria de Los Angeles Martínez Godinez
- a Laboratorio de Biología Molecular , Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis and Salvador Díaz Mirón , México , D.F , México
| | - Eleazar Lara-Padilla
- b Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis and Díaz Mirón , México , D.F , México
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Manowsky J, Camargo RG, Kipp AP, Henkel J, Püschel GP. Insulin-induced cytokine production in macrophages causes insulin resistance in hepatocytes. Am J Physiol Endocrinol Metab 2016; 310:E938-46. [PMID: 27094035 DOI: 10.1152/ajpendo.00427.2015] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 04/14/2016] [Indexed: 01/09/2023]
Abstract
Overweight and obesity are associated with hyperinsulinemia, insulin resistance, and a low-grade inflammation. Although hyperinsulinemia is generally thought to result from an attempt of the β-cell to compensate for insulin resistance, there is evidence that hyperinsulinaemia itself may contribute to the development of insulin resistance and possibly the low-grade inflammation. To test this hypothesis, U937 macrophages were exposed to insulin. In these cells, insulin induced expression of the proinflammatory cytokines IL-1β, IL-8, CCL2, and OSM. The insulin-elicited induction of IL-1β was independent of the presence of endotoxin and most likely mediated by an insulin-dependent activation of NF-κB. Supernatants of the insulin-treated U937 macrophages rendered primary cultures of rat hepatocytes insulin resistant; they attenuated the insulin-dependent induction of glucokinase by 50%. The cytokines contained in the supernatants of insulin-treated U937 macrophages activated ERK1/2 and IKKβ, resulting in an inhibitory serine phosphorylation of the insulin receptor substrate. In addition, STAT3 was activated and SOCS3 induced, further contributing to the interruption of the insulin receptor signal chain in hepatocytes. These results indicate that hyperinsulinemia per se might contribute to the low-grade inflammation prevailing in overweight and obese patients and thereby promote the development of insulin resistance particularly in the liver, because the insulin concentration in the portal circulation is much higher than in all other tissues.
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Affiliation(s)
- Julia Manowsky
- University of Potsdam, Institute of Nutritional Science, Nutritional Biochemistry, Nuthetal, Germany;
| | - Rodolfo Gonzalez Camargo
- University of Potsdam, Institute of Nutritional Science, Nutritional Biochemistry, Nuthetal, Germany; Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil; and
| | - Anna P Kipp
- German Institute for Human Nutrition, Nuthetal, Germany
| | - Janin Henkel
- University of Potsdam, Institute of Nutritional Science, Nutritional Biochemistry, Nuthetal, Germany
| | - Gerhard P Püschel
- University of Potsdam, Institute of Nutritional Science, Nutritional Biochemistry, Nuthetal, Germany
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Arrese M, Cabrera D, Kalergis AM, Feldstein AE. Innate Immunity and Inflammation in NAFLD/NASH. Dig Dis Sci 2016; 61:1294-303. [PMID: 26841783 PMCID: PMC4948286 DOI: 10.1007/s10620-016-4049-x] [Citation(s) in RCA: 375] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 01/19/2016] [Indexed: 02/06/2023]
Abstract
Inflammation and hepatocyte injury and death are the hallmarks of nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease (NAFLD), which is a currently burgeoning public health problem. Innate immune activation is a key factor in triggering and amplifying hepatic inflammation in NAFLD/NASH. Thus, identification of the underlying mechanisms by which immune cells in the liver recognize cell damage signals or the presence of pathogens or pathogen-derived factors that activate them is relevant from a therapeutic perspective. In this review, we present new insights into the factors promoting the inflammatory response in NASH including sterile cell death processes resulting from lipotoxicity in hepatocytes as well as into the altered gut-liver axis function, which involves translocation of bacterial products into portal circulation as a result of gut leakiness. We further delineate the key immune cell types involved and how they recognize both damage-associated molecular patterns or pathogen-associated molecular patterns through binding of surface-expressed pattern recognition receptors, which initiate signaling cascades leading to injury amplification. The relevance of modulating these inflammatory signaling pathways as potential novel therapeutic strategies for the treatment of NASH is summarized.
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Affiliation(s)
- Marco Arrese
- Departmento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Daniel Cabrera
- Departmento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Ciencias Químicas y Biológicas, Facultad de Salud, Universidad Bernardo O Higgins, Santiago, Chile
| | - Alexis M Kalergis
- Millenium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ariel E Feldstein
- Department of Pediatrics, University of California San Diego (UCSD), San Diego, CA, USA.
- Rady Children's Hospital, San Diego, CA, USA.
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, UCSD, 3020 Children's Way, MC 5030, San Diego, CA, 92103-8450, USA.
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C/EBPβ-Thr217 Phosphorylation Stimulates Macrophage Inflammasome Activation and Liver Injury. Sci Rep 2016; 6:24268. [PMID: 27067260 PMCID: PMC4828658 DOI: 10.1038/srep24268] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Accepted: 03/23/2016] [Indexed: 12/20/2022] Open
Abstract
Amplification of liver injury is mediated by macrophages but the signaling by which the macrophage inflammasome enhances liver injury is not completely understood. The CCAAT/Enhancer Binding Protein-β (C/EBPβ) is a critical signaling molecule for macrophages because expression of a dominant inhibitor of C/EBPβ DNA-binding sites or a targeted deletion of C/EBPβ results in impaired macrophage differentiation. We reported that expression of the phosphorylation-mutant C/EBPβ-Glu217, which mimics phosphorylated C/EBPβ-Thr217, was sufficient to confer macrophage survival to Anthrax lethal toxin. Here, using primary hepatocytes, primary liver macrophages, dominant positive and negative transgenic mice of the C/EBPβ-Thr217 phosphoacceptor, macrophage ablation, and an inhibitory peptide of C/EBPβ-Thr217 phosphorylation, we determined that this phosphorylation is essential for the activation of the inflammasome in liver macrophages and for the hepatocyte apoptosis induced by hepatotoxins that results in liver injury. Similar findings were observed in the livers of patients with acute injury induced by Toxic Oil Syndrome.
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Dattaroy D, Seth RK, Das S, Alhasson F, Chandrashekaran V, Michelotti G, Fan D, Nagarkatti M, Nagarkatti P, Diehl AM, Chatterjee S. Sparstolonin B attenuates early liver inflammation in experimental NASH by modulating TLR4 trafficking in lipid rafts via NADPH oxidase activation. Am J Physiol Gastrointest Liver Physiol 2016; 310:G510-25. [PMID: 26718771 PMCID: PMC4824178 DOI: 10.1152/ajpgi.00259.2015] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 12/28/2015] [Indexed: 01/31/2023]
Abstract
Although significant research data exist on the pathophysiology of nonalcoholic steatohepatitis (NASH), finding an efficient treatment regimen for it remains elusive. The present study used sparstolonin B (SsnB), a novel TLR4 antagonist derived from the Chinese herb Sparganium stoloniferum, as a possible drug to mitigate early inflammation in NASH. This study used an early steatohepatitic injury model in high-fat-fed mice with CYP2E1-mediated oxidative stress as a second hit. SsnB was administered for 1 wk along with bromodichloromethane (BDCM), an inducer of CYP2E1-mediated oxidative stress. Results showed that SsnB administration attenuated inflammatory morphology and decreased elevation of the liver enzyme alanine aminotransferase (ALT). Mice administered SsnB also showed decreased mRNA expression of proinflammatory cytokines TNF-α, IFN-γ, IL-1β, and IL-23, while protein levels of both TNF-α and IL-1β were significantly decreased. SsnB significantly decreased Kupffer cell activation as evidenced by reduction in CD68 and monocyte chemoattractant protein-1 (MCP1) mRNA and protein levels with concomitant inhibition of macrophage infiltration in the injured liver. Mechanistically, SsnB decreased TLR4 trafficking to the lipid rafts, a phenomenon described by the colocalization of TLR4 and lipid raft marker flotillin in tissues and immortalized Kupffer cells. Since we have shown previously that NADPH oxidase drives TLR4 trafficking in NASH, we studied the role of SsnB in modulating this pathway. SsnB prevented NADPH oxidase activation in vivo and in vitro as indicated by decreased peroxynitrite formation. In summary, the present study reports a novel use of the TLR4 antagonist SsnB in mitigating inflammation in NASH and in parallel shows a unique molecular mechanism of decreasing nitrative stress.
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Affiliation(s)
- Diptadip Dattaroy
- 1Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina;
| | - Ratanesh Kumar Seth
- 1Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina;
| | - Suvarthi Das
- 1Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina;
| | - Firas Alhasson
- 1Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina;
| | - Varun Chandrashekaran
- 1Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina;
| | | | - Daping Fan
- 3Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina; and
| | - Mitzi Nagarkatti
- 4Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina
| | - Prakash Nagarkatti
- 4Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina
| | - Anna Mae Diehl
- 2Division of Gastroenterology, Duke University, Durham, North Carolina;
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina;
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Nati M, Haddad D, Birkenfeld AL, Koch CA, Chavakis T, Chatzigeorgiou A. The role of immune cells in metabolism-related liver inflammation and development of non-alcoholic steatohepatitis (NASH). Rev Endocr Metab Disord 2016; 17:29-39. [PMID: 26847547 DOI: 10.1007/s11154-016-9339-2] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The low grade inflammatory state present in obesity promotes the progression of Non-Alcoholic Fatty Liver Disease (NAFLD). In Non-Alcoholic Steatohepatitis (NASH), augmented hepatic steatosis is accompanied by aberrant intrahepatic inflammation and exacerbated hepatocellular injury. NASH is an important disorder and can lead to fibrosis, cirrhosis and even neoplasia. The pathology of NASH involves a complex network of mechanisms, including increased infiltration of different subsets of immune cells, such as monocytes, T-lymphocytes and neutrophils, to the liver, as well as activation and in situ expansion of liver resident cells such as Kupffer cells or stellate cells. In this review, we summarize recent advances regarding understanding the role of the various cells of the innate and adaptive immunity in NASH development and progression, and discuss possible future therapeutic options and tools to interfere with disease progression.
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Affiliation(s)
- Marina Nati
- Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universität Dresden, MTZ, Fiedlerstrasse 42, 01307, Dresden, Germany
| | - David Haddad
- Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universität Dresden, MTZ, Fiedlerstrasse 42, 01307, Dresden, Germany
| | - Andreas L Birkenfeld
- Section of Metabolic Vascular Medicine, Medical Clinic III, Faculty of Medicine, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
- Division of Diabetes and Nutritional Sciences, Rayne Institute, King's College London, London, UK
| | - Christian A Koch
- Division of Endocrinology, Endocrine Tumor Program, Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA
| | - Triantafyllos Chavakis
- Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universität Dresden, MTZ, Fiedlerstrasse 42, 01307, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Antonios Chatzigeorgiou
- Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universität Dresden, MTZ, Fiedlerstrasse 42, 01307, Dresden, Germany.
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany.
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, TU Dresden, Dresden, Germany.
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Han LP, Li CJ, Sun B, Xie Y, Guan Y, Ma ZJ, Chen LM. Protective Effects of Celastrol on Diabetic Liver Injury via TLR4/MyD88/NF-κB Signaling Pathway in Type 2 Diabetic Rats. J Diabetes Res 2016; 2016:2641248. [PMID: 27057550 PMCID: PMC4745324 DOI: 10.1155/2016/2641248] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Revised: 12/05/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
Immune and inflammatory pathways play a central role in the pathogenesis of diabetic liver injury. Celastrol is a potent immunosuppressive and anti-inflammatory agent. So far, there is no evidence regarding the mechanism of innate immune alterations of celastrol on diabetic liver injury in type 2 diabetic animal models. The present study was aimed at investigating protective effects of celastrol on the liver injury in diabetic rats and at elucidating the possible involved mechanisms. We analyzed the liver histopathological and biochemical changes and the expressions of TLR4 mediated signaling pathway. Compared to the normal control group, diabetic rats were found to have obvious steatohepatitis and proinflammatory cytokine activities were significantly upregulated. Celastrol-treated diabetic rats show reduced hepatic inflammation and macrophages infiltration. The expressions of TLR4, MyD88, NF-κB, and downstream inflammatory factors IL-1β and TNFα in the hepatic tissue of treated rats were downregulated in a dose-dependent manner. We firstly found that celastrol treatment could delay the progression of diabetic liver disease in type 2 diabetic rats via inhibition of TLR4/MyD88/NF-κB signaling cascade pathways and its downstream inflammatory effectors.
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Affiliation(s)
- Li-ping Han
- 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development, Ministry of Health, Metabolic Disease Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
| | - Chun-jun Li
- 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development, Ministry of Health, Metabolic Disease Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
| | - Bei Sun
- 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development, Ministry of Health, Metabolic Disease Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
| | - Yun Xie
- 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development, Ministry of Health, Metabolic Disease Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
| | - Yue Guan
- 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development, Ministry of Health, Metabolic Disease Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
| | - Ze-jun Ma
- 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development, Ministry of Health, Metabolic Disease Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
| | - Li-ming Chen
- 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development, Ministry of Health, Metabolic Disease Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China
- *Li-ming Chen:
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Chandrashekaran V, Das S, Seth RK, Dattaroy D, Alhasson F, Michelotti G, Nagarkatti M, Nagarkatti P, Diehl AM, Chatterjee S. Purinergic receptor X7 mediates leptin induced GLUT4 function in stellate cells in nonalcoholic steatohepatitis. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1862:32-45. [PMID: 26474534 PMCID: PMC4988689 DOI: 10.1016/j.bbadis.2015.10.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 10/09/2015] [Accepted: 10/12/2015] [Indexed: 12/19/2022]
Abstract
Metabolic oxidative stress via CYP2E1 can act as a second hit in NASH progression. Our previous studies have shown that oxidative stress in NASH causes higher leptin levels and induces purinergic receptor X7 (P2X7r). We tested the hypothesis that higher circulating leptin due to CYP2E1-mediated oxidative stress induces P2X7r. P2X7r in turn activates stellate cells and causes increased proliferation via modulating Glut4, the glucose transporter, and increased intracellular glucose. Using a high fat diet-fed NAFLD model where bromodichloromethane (BDCM) was administered to induce CYP2E1-mediated oxidative stress, we show that P2X7r expression and protein levels were leptin and CYP2E1 dependent. P2X7r KO mice had significantly decreased stellate cell proliferation. Human NASH livers showed marked increase in P2X7r, and Glut4 in α-SMA positive cells. NASH livers had significant increase in Glut4 protein and phosphorylated AKT, needed for Glut4 translocation while leptin KO and P2X7r KO mice showed marked decrease in Glut4 levels primarily in stellate cells. Mechanistically stellate cells showed increase in phosphorylated AKT, Glut4 protein and localization in the membrane following administration of P2X7r agonist or leptin+P2X7r agonist, while use of P2X7r antagonist or AKT inhibitor attenuated the response suggesting that leptin-P2X7r axis in concert but not leptin alone is responsible for the Glut4 induction and translocation. Finally P2X7r-agonist and leptin caused an increase in intracellular glucose and consumption by increasing the activity of hexokinase. In conclusion, the study shows a novel role of leptin-induced P2X7r in modulating Glut4 induction and translocation in hepatic stellate cells, that are key to NASH progression.
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Affiliation(s)
- Varun Chandrashekaran
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
| | - Suvarthi Das
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
| | - Ratanesh Kumar Seth
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
| | - Diptadip Dattaroy
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
| | - Firas Alhasson
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
| | | | - Mitzi Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA
| | - Prakash Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA
| | - Anna Mae Diehl
- Division of Gastroenterology, Duke University, Durham, NC 27707, USA
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA.
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by excess accumulation of fat in hepatocytes (nonalcoholic fatty liver (NAFL)); in up to 40% of individuals, there are additional findings of portal and lobular inflammation and hepatocyte injury (which characterize nonalcoholic steatohepatitis (NASH)). A subset of patients will develop progressive fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma and cardiovascular complications are life-threatening co-morbidities of both NAFL and NASH. NAFLD is closely associated with insulin resistance; obesity and metabolic syndrome are common underlying factors. As a consequence, the prevalence of NAFLD is estimated to be 10-40% in adults worldwide, and it is the most common liver disease in children and adolescents in developed countries. Mechanistic insights into fat accumulation, subsequent hepatocyte injury, the role of the immune system and fibrosis as well as the role of the gut microbiota are unfolding. Furthermore, genetic and epigenetic factors might explain the considerable interindividual variation in disease phenotype, severity and progression. To date, no effective medical interventions exist that completely reverse the disease other than lifestyle changes, dietary alterations and, possibly, bariatric surgery. However, several strategies that target pathophysiological processes such as an oversupply of fatty acids to the liver, cell injury and inflammation are currently under investigation. Diagnosis of NAFLD can be established by imaging, but detection of the lesions of NASH still depend on the gold-standard but invasive liver biopsy. Several non-invasive strategies are being evaluated to replace or complement biopsies, especially for follow-up monitoring.
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