|
1
|
Xia M, Li J, Martinez Aguilar LM, Wang J, Trillos Almanza MC, Li Y, Buist-Homan M, Moshage H. Arctigenin Attenuates Hepatic Stellate Cell Activation via Endoplasmic Reticulum-Associated Degradation (ERAD)-Mediated Restoration of Lipid Homeostasis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025. [PMID: 40415275 DOI: 10.1021/acs.jafc.5c01366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2025]
Abstract
Arctigenin, a natural lignan from Arctium lappa L., exhibits potent antifibrotic activity, yet its molecular mechanisms remain unclear. Endoplasmic reticulum (ER) stress is known to promote hepatic stellate cell (HSC) activation and liver fibrosis. This study investigates the therapeutic potential of arctigenin in HSC activation through ER stress modulation. Primary rat HSCs were activated (3-7 days) and treated with tunicamycin (ER stress inducer) or 4-PBA (ER stress inhibitor). Arctigenin attenuated ER stress markers (e.g., GRP78) and suppressed the expression of fibrotic marker α-SMA in ER stress-challenged activating (day 3) and activated (day 7) HSCs. Arctigenin restored lipid homeostasis by modulation of both lipogenesis (via Dgat2 and Ppar-γ upregulation) and lipolysis (suppression via ATGL inhibition). ER stress activated ER-associated degradation (ERAD), triggering the formation of small lipid droplets (LD). Arctigenin normalized the ERAD activity, thereby rescuing LD integrity and suppressing HSC activation. Our findings demonstrate that arctigenin mitigates HSC activation by suppressing ER stress and restoring lipid homeostasis via modulating ERAD-mediated lipid dysregulation. As a dietary and medicinal compound, arctigenin emerges as a promising therapeutic candidate for liver fibrosis.
Collapse
Affiliation(s)
- Mengmeng Xia
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands
| | - Jia Li
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands
| | - Lizbeth Magnolia Martinez Aguilar
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands
| | - Junyu Wang
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands
| | - Maria Camila Trillos Almanza
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands
| | - Yakun Li
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands
| | - Manon Buist-Homan
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands
| | - Han Moshage
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands
| |
Collapse
|
|
2
|
Wang T, Xia G, Li X, Gong M, Lv X. Endoplasmic reticulum stress in liver fibrosis: Mechanisms and therapeutic potential. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167695. [PMID: 39864668 DOI: 10.1016/j.bbadis.2025.167695] [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: 09/29/2024] [Revised: 01/07/2025] [Accepted: 01/22/2025] [Indexed: 01/28/2025]
Abstract
This paper reviews the important role of endoplasmic reticulum stress in the patho mechanism of liver fibrosis and its potential as a potential target for the treatment of liver fibrosis. Liver fibrosis is the result of sustained inflammation and injury to the liver due to a variety of factors, triggering excessive deposition of extracellular matrix and fibrous scar formation, which in turn leads to loss of liver function and a variety of related complications. Endoplasmic reticulum stress is one of the characteristics of chronic liver disease and is closely related to the pathological process of chronic liver disease, including alcohol-related liver disease, viral hepatitis, and liver fibrosis. The unfolded protein response is one of the important response mechanisms to endoplasmic reticulum stress. It is associated with several pathological aspects of liver fibrosis and the maintenance of endoplasmic reticulum homeostasis. Interventions targeting endoplasmic reticulum stress for the treatment of liver fibrosis have potential research and application value. An in-depth understanding of the biological basis of endoplasmic reticulum stress is also needed in the treatment of liver fibrosis, as well as the development of more effective drugs and interventions to accurately regulate the endoplasmic reticulum signaling network, to achieve the restoration and maintenance of endoplasmic reticulum homeostasis at the cellular and organ levels, and to further promote the reversal of the pathological process of liver fibrosis.
Collapse
Affiliation(s)
- Tiantian Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Guoqing Xia
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Xue Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Mingxu Gong
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Xiongwen Lv
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
| |
Collapse
|
|
3
|
Sun Y, Yuan X, Hu Z, Li Y. Harnessing nuclear receptors to modulate hepatic stellate cell activation for liver fibrosis resolution. Biochem Pharmacol 2025; 232:116730. [PMID: 39710274 DOI: 10.1016/j.bcp.2024.116730] [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: 12/04/2024] [Accepted: 12/19/2024] [Indexed: 12/24/2024]
Abstract
With the recent approval of Resmetirom as the first drug targeting nuclear receptors for metabolic dysfunction-associated steatohepatitis (MASH), there is promising way to treat MASH-associated liver fibrosis. However, liver fibrosis can arise from various pathogenic factors, and effective treatments for fibrosis due to other causes remain elusive. The activation of hepatic stellate cells (HSCs) represents a central link in the pathogenesis of hepatic fibrosis. Therefore, harnessing nuclear receptors to modulate HSC activation may be an effective approach to resolving the complex liver fibrosis caused by various factors. In this comprehensive review, we systematically explore the structure and physiological functions of nuclear receptors, shedding light on their multifaceted roles in HSC activation. Recent advancements in drug development targeting nuclear receptors are discussed, providing insights into their potential as rational and effective therapeutic targets for modulating HSC activation in the context of liver fibrosis. By elucidating the intricate interplay between nuclear receptors and HSC activation, this review contributes to the discovery of new nuclear receptor targets in HSCs for resolving hepatic fibrosis.
Collapse
Affiliation(s)
- Yaxin Sun
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; University of Chinese Academy of Sciences, Beijing, China
| | - Xiaoyan Yuan
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; University of Chinese Academy of Sciences, Beijing, China
| | - Zhenhua Hu
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; Department of Health and Nursing, Nanfang College of Sun Yat-sen University, Guangzhou, China.
| | - Yuanyuan Li
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; University of Chinese Academy of Sciences, Beijing, China.
| |
Collapse
|
|
4
|
Khan J, Kim ND, Bromhead C, Truman P, Kruger MC, Mallard BL. Hepatotoxicity of titanium dioxide nanoparticles. J Appl Toxicol 2025; 45:23-46. [PMID: 38740968 PMCID: PMC11634566 DOI: 10.1002/jat.4626] [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: 02/22/2024] [Revised: 04/21/2024] [Accepted: 04/25/2024] [Indexed: 05/16/2024]
Abstract
The food additive E171 (titanium dioxide, TiO2), is widely used in foods, pharmaceuticals and cosmetics. It is a fine white powder, with at least one third of its particles sized in the nanoparticulate (˂100 nm range, TiO2 NPs). The use of E171 is controversial as its relevant risk assessment has never been satisfactorily accomplished. In vitro and in vivo studies have shown dose-dependent toxicity in various organs including the liver. TiO2 NPs have been shown to induce inflammation, cell death and structural and functional changes within the liver. The toxicity of TiO2 NPs in experimental models varies between organs and according to their physiochemical characteristics and parameters such as dosage and route of administration. Among these factors, ingestion is the most significant exposure route, and the liver is a key target organ. The aim of this review is to highlight the reported adverse effects of orally administered TiO2 NPs on the liver and to discuss the controversial state of its toxicity.
Collapse
Affiliation(s)
- Jangrez Khan
- School of Health SciencesMassey UniversityPO Box 756Wellington6021New Zealand
| | - Nicholas D. Kim
- School of Health SciencesMassey UniversityPO Box 756Wellington6021New Zealand
| | - Collette Bromhead
- School of Health SciencesMassey UniversityPO Box 756Wellington6021New Zealand
| | - Penelope Truman
- School of Health SciencesMassey UniversityPO Box 756Wellington6021New Zealand
| | - Marlena C. Kruger
- School of Health SciencesMassey UniversityPO Box 756Wellington6021New Zealand
| | - Beth L. Mallard
- School of Health SciencesMassey UniversityPO Box 756Wellington6021New Zealand
| |
Collapse
|
|
5
|
Tian Y, Sun D, Liu N, Zhao J, Zhao T, Liu X, Dong X, Dong L, Wang W, Jiao P, Ma J. Biomimetic mesenchymal stem cell membrane-coated nanoparticle delivery of MKP5 inhibits hepatic fibrosis through the IRE/XBP1 pathway. J Nanobiotechnology 2024; 22:741. [PMID: 39609656 PMCID: PMC11606114 DOI: 10.1186/s12951-024-03029-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 11/19/2024] [Indexed: 11/30/2024] Open
Abstract
Hepatic fibrosis is a common disease with high morbidity and mortality rates. The complex and poorly understood mechanisms underlying hepatic fibrosis represent a significant challenge for the development of more effective therapeutic strategies. MKP5 is a potential regulator of multiple fibrotic diseases. However, its precise role and mechanism of action in hepatic fibrosis remains unclear. This study identified a reduction in MKP5 expression in fibrotic liver tissues of mice treated with CCl4 and observed that MKP5 knockout mice exhibited a more pronounced development of hepatic fibrosis. In addition, RNA-seq data indicated activation of protein processing in the endoplasmic reticulum signalling pathway in fibrotic liver tissues of mice lacking MKP5. Mechanistically, MKP5 inhibits the activation of hepatic stellate cells (HSCs) and hepatocyte apoptosis through the regulation of the IRE/XBP1 pathway. Based on these findings, we developed PLGA-MKP5 nanoparticles coated with a mesenchymal stem cell membrane (MSCM). Our results demonstrated that MSCM-PLGA-MKP5 was most effective in attenuating hepatic inflammation and fibrosis in murine models by modulating the IRE/XBP1 axis. This study contributes to the current understanding of the pathogenesis of hepatic fibrosis, suggesting that the targeted delivery of MKP5 via a nano-delivery system may represent a promising therapeutic approach to treat hepatic fibrosis.
Collapse
Affiliation(s)
- Yafei Tian
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Dandan Sun
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Na Liu
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Jianan Zhao
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Tongjian Zhao
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Xiaonan Liu
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Xinzhe Dong
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Li Dong
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Wei Wang
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Ping Jiao
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China.
| | - Jie Ma
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China.
| |
Collapse
|
|
6
|
Jarocki M, Turek K, Saczko J, Tarek M, Kulbacka J. Lipids associated with autophagy: mechanisms and therapeutic targets. Cell Death Discov 2024; 10:460. [PMID: 39477959 PMCID: PMC11525783 DOI: 10.1038/s41420-024-02224-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 10/18/2024] [Accepted: 10/22/2024] [Indexed: 11/02/2024] Open
Abstract
Autophagy is a molecular process essential for maintaining cellular homeostasis, with its impairment or dysregulation linked to the progression of various diseases in mammals. Specific lipids, including phosphoinositides, sphingolipids, and oxysterols, play pivotal roles in inducing and regulating autophagy, highlighting their significance in this intricate process. This review focuses on the critical involvement of these lipids in autophagy and lipophagy, providing a comprehensive overview of the current understanding of their functions. Moreover, we delve into how abnormalities in autophagy, influenced by these lipids, contribute to the pathogenesis of various diseases. These include age-related conditions such as cardiovascular diseases, neurodegenerative disorders, type 2 diabetes, and certain cancers, as well as inflammatory and liver diseases, skeletal muscle pathologies and age-related macular degeneration (AMD). This review aims to highlight function of lipids and their potential as therapeutic targets in treating diverse human pathologies by elucidating the specific roles of phosphoinositides, sphingolipids, and oxysterols in autophagy.
Collapse
Affiliation(s)
- Michał Jarocki
- University Clinical Hospital, Wroclaw Medical University, Wroclaw, Poland
| | | | - Jolanta Saczko
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland
| | - Mounir Tarek
- Université de Lorraine, CNRS, LPCT, Nancy, France
| | - Julita Kulbacka
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland.
- Department of Immunology and Bioelectrochemistry, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
| |
Collapse
|
|
7
|
Yue Z, Jiang Z, Qian L, Li L, Qi X, Hu K. Associations of dietary sources of antioxidant intake and NAFLD: NHANES 2017-2020 and Mendelian randomization. Front Nutr 2024; 11:1447524. [PMID: 39555193 PMCID: PMC11565937 DOI: 10.3389/fnut.2024.1447524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 10/21/2024] [Indexed: 11/19/2024] Open
Abstract
Purpose To determine the association between dietary antioxidant sources and non-alcoholic fatty liver disease (NAFLD). Methods In this observational study, we utilized NHANES 2017-2020 data to identify the factors associated with NAFLD in dietary antioxidant sources via weighted multivariate logistic regression models. Then, Mendelian randomization (MR) was applied to investigate the effect of dietary antioxidant sources on NAFLD at the genetic level. Results Of the six dietary sources of antioxidants, only vitamin E (Vit E) was significantly associated with NAFLD (OR = 0.98; 95% CI: 0.97-0.99; p = 0.001). Upon adjusting for all covariates, it was determined that the highest quartile of dietary Vit E intake was associated with a decreased NAFLD occurrence compared with the lowest quartile of dietary Vit E intake (p < 0.001). The results of IVW-MR analysis revealed an association between Vit E and NAFLD (OR = 0.028; p = 0.039). Conclusion Our research indicates a negative and linear relationship between daily vitamin E intake and NAFLD.
Collapse
Affiliation(s)
- Zilong Yue
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- General Surgery Department, Guoyang Branch of Anhui Provincial Hospital, Bozhou, Anhui, China
| | - Ziming Jiang
- Department of Urology, Shanghai 10th People’s Hospital Affiliated to Tongji University, Shanghai, China
| | - Long Qian
- General Surgery Department, Wuhu Hospital of Traditional Chinese Medicine, Wuhu, Anhui, China
| | - Lele Li
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Xianliang Qi
- General Surgery Department, Guoyang Branch of Anhui Provincial Hospital, Bozhou, Anhui, China
| | - Kaifeng Hu
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
| |
Collapse
|
|
8
|
Kuang B, Wang M, Yan H, Jiang Q, Wang Z, Ni H, Hou S, Peng X, Gu S, Zhao Y, Ou T, Gong N. Genetic and pharmacological targeting of XBP1 alleviates hepatic ischemia reperfusion injury by enhancing FoxO1-dependent mitophagy. Transl Res 2024; 272:162-176. [PMID: 38494125 DOI: 10.1016/j.trsl.2024.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 02/10/2024] [Accepted: 03/14/2024] [Indexed: 03/19/2024]
Abstract
Hepatic ischemia reperfusion (I/R) injury is a common clinical complication. X-box binding protein 1 (XBP1), as a critical regulator of the endoplasmic reticulum stress, has been implicated in a variety of diseases. In this study, we aimed to investigate the effects and the underlying mechanism of XBP1 in the progression of hepatic I/R injury. Hepatocyte-specific XBP1 knockout mice, multiple viral delivery systems and specific pharmacological inhibitors were applied in vivo in a partial hepatic I/R injury mouse model and in vitro in a cell model of hypoxia-reoxygenation (H/R) injury. Mitophagy and autophagic flux were evaluated and fluorescence resonance energy transfer (FRET) as well as immunoprecipitation were performed. The results demonstrated that reperfusion for 6 h represented a critical timepoint in hepatic I/R injury and resulted in significant intracellular mitochondrial dysfunction; led to the breakdown of hepatocytes accompanied by the highest expression levels of XBP1. Hepatocyte-specific XBP1 knockout alleviated hepatic I/R injury via enhanced mitophagy, as demonstrated by the reduction in hepatocellular damage/necrosis and increased expression of mitophagy markers. Mechanistically, XBP1 interacted with FoxO1 directly and catalyzed the ubiquitination of FoxO1 for proteasomal degradation. Targeting XBP1 by genetic or pharmacological techniques potentiated the protein levels of FoxO1, further promoting the activity of the PINK1/Parkin signaling pathway, thus augmenting mitophagy and exerting hepatoprotective effects upon I/R injury. In conclusion, the inhibition of XBP1 potentiated FoxO1-mediated mitophagy in hepatic I/R injury. Specific genetic and pharmacological treatment targeting XBP1 in the perioperative 6 h prior to reperfusion exerted beneficial effects, thus providing a novel therapeutic approach.
Collapse
Affiliation(s)
- Baicheng Kuang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei China
| | - Mengqin Wang
- Department of Cardiothoracic surgery, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei China
| | - Hao Yan
- Department of Urology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Qin Jiang
- Department of Gastroenterology, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei China
| | - Zhiheng Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei China
| | - Haiqiang Ni
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei China
| | - Shuaiheng Hou
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei China
| | - Xuan Peng
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei China
| | - Shiqi Gu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei China
| | - Yuanyuan Zhao
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei China
| | - Tongwen Ou
- Department of Urology, Xuanwu Hospital, Capital Medical University, Beijing, China.
| | - Nianqiao Gong
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei China.
| |
Collapse
|
|
9
|
Guo M, Liu R, Zhang F, Qu J, Yang Y, Li X. A new perspective on liver diseases: Focusing on the mitochondria-associated endoplasmic reticulum membranes. Pharmacol Res 2024; 208:107409. [PMID: 39284429 DOI: 10.1016/j.phrs.2024.107409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 08/29/2024] [Accepted: 09/10/2024] [Indexed: 09/19/2024]
Abstract
The pathogenesis of liver diseases is multifaceted and intricate, posing a persistent global public health challenge with limited therapeutic options. Therefore, further research into liver diseases is imperative for better comprehension and advancement in treatment strategies. Numerous studies have confirmed the endoplasmic reticulum (ER) and mitochondria as key organelles driving liver diseases. Notably, the mitochondrial-associated ER membranes (MAMs) establish a physical and functional connection between the ER and mitochondria, highlighting the importance of inter-organelle communication in maintaining their functional homeostasis. This review delves into the intricate architecture and regulative mechanism of the integrated MAM that facilitate the physiological transfer of signals and substances between organelles. Additionally, we also provide a detailed overview regarding the varied pathogenic roles of malfunctioning MAM in liver diseases, focusing on its involvement in the progression of ER stress and mitochondrial dysfunction, the regulation of mitochondrial dynamics and Ca2+ transfer, as well as the disruption of lipid and glucose homeostasis. Furthermore, the current challenges and prospects associated with MAM in liver disease research are thoroughly discussed. In conclusion, elucidating the specific structure and function of MAM in different liver diseases may pave the way for novel therapeutic strategies.
Collapse
Affiliation(s)
- Mengyu Guo
- School of Life Sciences, Beijing University of Chinese Medicine, 100029, China
| | - Runping Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, 100029, China
| | - Fukun Zhang
- School of Life Sciences, Beijing University of Chinese Medicine, 100029, China
| | - Jiaorong Qu
- School of Life Sciences, Beijing University of Chinese Medicine, 100029, China
| | - Yun Yang
- School of Life Sciences, Beijing University of Chinese Medicine, 100029, China
| | - Xiaojiaoyang Li
- School of Life Sciences, Beijing University of Chinese Medicine, 100029, China.
| |
Collapse
|
|
10
|
Duan Y, Yang Y, Zhao S, Bai Y, Yao W, Gao X, Yin J. Crosstalk in extrahepatic and hepatic system in NAFLD/NASH. Liver Int 2024; 44:1856-1871. [PMID: 38717072 DOI: 10.1111/liv.15967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 02/28/2024] [Accepted: 04/26/2024] [Indexed: 07/17/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disease globally. Non-alcoholic steatohepatitis (NASH) represents an extremely progressive form of NAFLD, which, without timely intervention, may progress to cirrhosis or hepatocellular carcinoma. Presently, a definitive comprehension of the pathogenesis of NAFLD/NASH eludes us, and pharmacological interventions targeting NASH specifically remain constrained. The aetiology of NAFLD encompasses a myriad of external factors including environmental influences, dietary habits and gender disparities. More significantly, inter-organ and cellular interactions within the human body play a role in the development or regression of the disease. In this review, we categorize the influences affecting NAFLD both intra- and extrahepatically, elaborating meticulously on the mechanisms governing the onset and progression of NAFLD/NASH. This exploration delves into progress in aetiology and promising therapeutic targets. As a metabolic disorder, the development of NAFLD involves complexities related to nutrient metabolism, liver-gut axis interactions and insulin resistance, among other regulatory functions of extraneous organs. It further encompasses intra-hepatic interactions among hepatic cells, Kupffer cells (KCs) and hepatic stellate cells (HSCs). A comprehensive understanding of the pathogenesis of NAFLD/NASH from a macroscopic standpoint is instrumental in the formulation of future therapies for NASH.
Collapse
Affiliation(s)
- Yiliang Duan
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Yan Yang
- The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China
| | - Shuqiang Zhao
- Jiangsu Institute for Food and Drug Control, NMPA Key Laboratory for Impurity Profile of Chemical Drugs, Nanjing, Jiangsu, China
| | - Yuesong Bai
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Wenbing Yao
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Xiangdong Gao
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Jun Yin
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| |
Collapse
|
|
11
|
Wilhelmsen I, Combriat T, Dalmao-Fernandez A, Stokowiec J, Wang C, Olsen PA, Wik JA, Boichuk Y, Aizenshtadt A, Krauss S. The effects of TGF-β-induced activation and starvation of vitamin A and palmitic acid on human stem cell-derived hepatic stellate cells. Stem Cell Res Ther 2024; 15:223. [PMID: 39044210 PMCID: PMC11267759 DOI: 10.1186/s13287-024-03852-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 07/14/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND Hepatic stellate cells (HSC) have numerous critical roles in liver function and homeostasis, while they are also known for their importance during liver injury and fibrosis. There is therefore a need for relevant in vitro human HSC models to fill current knowledge gaps. In particular, the roles of vitamin A (VA), lipid droplets (LDs), and energy metabolism in human HSC activation are poorly understood. METHODS In this study, human pluripotent stem cell-derived HSCs (scHSCs), benchmarked to human primary HSC, were exposed to 48-hour starvation of retinol (ROL) and palmitic acid (PA) in the presence or absence of the potent HSC activator TGF-β. The interventions were studied by an extensive set of phenotypic and functional analyses, including transcriptomic analysis, measurement of activation-related proteins and cytokines, VA- and LD storage, and cell energy metabolism. RESULTS The results show that though the starvation of ROL and PA alone did not induce scHSC activation, the starvation amplified the TGF-β-induced activation-related transcriptome. However, TGF-β-induced activation alone did not lead to a reduction in VA or LD stores. Additionally, reduced glycolysis and increased mitochondrial fission were observed in response to TGF-β. CONCLUSIONS scHSCs are robust models for activation studies. The loss of VA and LDs is not sufficient for scHSC activation in vitro, but may amplify the TGF-β-induced activation response. Collectively, our work provides an extensive framework for studying human HSCs in healthy and diseased conditions.
Collapse
Affiliation(s)
- Ingrid Wilhelmsen
- Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, Oslo, 0424, Norway.
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway.
| | - Thomas Combriat
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
| | - Andrea Dalmao-Fernandez
- Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, Oslo, 0424, Norway
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, Oslo, 0316, Norway
| | - Justyna Stokowiec
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
| | - Chencheng Wang
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
- Department of Transplantation Medicine, Institute for Surgical Research, Oslo University Hospital, P.O. Box 4950, Nydalen, Oslo, 0424, Norway
| | - Petter Angell Olsen
- Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, Oslo, 0424, Norway
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
| | - Jonas Aakre Wik
- Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, Oslo, 0424, Norway
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
| | - Yuliia Boichuk
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
| | - Aleksandra Aizenshtadt
- Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, Oslo, 0424, Norway
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
| | - Stefan Krauss
- Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, Oslo, 0424, Norway
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
| |
Collapse
|
|
12
|
Akkız H, Gieseler RK, Canbay A. Liver Fibrosis: From Basic Science towards Clinical Progress, Focusing on the Central Role of Hepatic Stellate Cells. Int J Mol Sci 2024; 25:7873. [PMID: 39063116 PMCID: PMC11277292 DOI: 10.3390/ijms25147873] [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: 05/23/2024] [Revised: 06/28/2024] [Accepted: 06/29/2024] [Indexed: 07/28/2024] Open
Abstract
The burden of chronic liver disease is globally increasing at an alarming rate. Chronic liver injury leads to liver inflammation and fibrosis (LF) as critical determinants of long-term outcomes such as cirrhosis, liver cancer, and mortality. LF is a wound-healing process characterized by excessive deposition of extracellular matrix (ECM) proteins due to the activation of hepatic stellate cells (HSCs). In the healthy liver, quiescent HSCs metabolize and store retinoids. Upon fibrogenic activation, quiescent HSCs transdifferentiate into myofibroblasts; lose their vitamin A; upregulate α-smooth muscle actin; and produce proinflammatory soluble mediators, collagens, and inhibitors of ECM degradation. Activated HSCs are the main effector cells during hepatic fibrogenesis. In addition, the accumulation and activation of profibrogenic macrophages in response to hepatocyte death play a critical role in the initiation of HSC activation and survival. The main source of myofibroblasts is resident HSCs. Activated HSCs migrate to the site of active fibrogenesis to initiate the formation of a fibrous scar. Single-cell technologies revealed that quiescent HSCs are highly homogenous, while activated HSCs/myofibroblasts are much more heterogeneous. The complex process of inflammation results from the response of various hepatic cells to hepatocellular death and inflammatory signals related to intrahepatic injury pathways or extrahepatic mediators. Inflammatory processes modulate fibrogenesis by activating HSCs and, in turn, drive immune mechanisms via cytokines and chemokines. Increasing evidence also suggests that cellular stress responses contribute to fibrogenesis. Recent data demonstrated that LF can revert even at advanced stages of cirrhosis if the underlying cause is eliminated, which inhibits the inflammatory and profibrogenic cells. However, despite numerous clinical studies on plausible drug candidates, an approved antifibrotic therapy still remains elusive. This state-of-the-art review presents cellular and molecular mechanisms involved in hepatic fibrogenesis and its resolution, as well as comprehensively discusses the drivers linking liver injury to chronic liver inflammation and LF.
Collapse
Affiliation(s)
- Hikmet Akkız
- Department of Gastroenterology and Hepatology, University of Bahçeşehir, Beşiktaş, Istanbul 34353, Turkey
| | - Robert K. Gieseler
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, In der Schornau 23–25, 44892 Bochum, Germany; (R.K.G.); (A.C.)
| | - Ali Canbay
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, In der Schornau 23–25, 44892 Bochum, Germany; (R.K.G.); (A.C.)
| |
Collapse
|
|
13
|
Horn P, Tacke F. Metabolic reprogramming in liver fibrosis. Cell Metab 2024; 36:1439-1455. [PMID: 38823393 DOI: 10.1016/j.cmet.2024.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 04/30/2024] [Accepted: 05/06/2024] [Indexed: 06/03/2024]
Abstract
Chronic liver diseases, primarily metabolic dysfunction-associated steatotic liver disease (MASLD), harmful use of alcohol, or viral hepatitis, may result in liver fibrosis, cirrhosis, and cancer. Hepatic fibrogenesis is a complex process with interactions between different resident and non-resident heterogeneous liver cell populations, ultimately leading to deposition of extracellular matrix and organ failure. Shifts in cell phenotypes and functions involve pronounced transcriptional and protein synthesis changes that require metabolic adaptations in cellular substrate metabolism, including glucose and lipid metabolism, resembling changes associated with the Warburg effect in cancer cells. Cell activation and metabolic changes are regulated by metabolic stress responses, including the unfolded protein response, endoplasmic reticulum stress, autophagy, ferroptosis, and nuclear receptor signaling. These metabolic adaptations are crucial for inflammatory and fibrogenic activation of macrophages, lymphoid cells, and hepatic stellate cells. Modulation of these pathways, therefore, offers opportunities for novel therapeutic approaches to halt or even reverse liver fibrosis progression.
Collapse
Affiliation(s)
- Paul Horn
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Digital Clinician Scientist Program, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
| |
Collapse
|
|
14
|
Hazari Y, Chevet E, Bailly-Maitre B, Hetz C. ER stress signaling at the interphase between MASH and HCC. Hepatology 2024:01515467-990000000-00844. [PMID: 38626349 DOI: 10.1097/hep.0000000000000893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 03/28/2024] [Indexed: 04/18/2024]
Abstract
HCC is the most frequent primary liver cancer with an extremely poor prognosis and often develops on preset of chronic liver diseases. Major risk factors for HCC include metabolic dysfunction-associated steatohepatitis, a complex multifactorial condition associated with abnormal endoplasmic reticulum (ER) proteostasis. To cope with ER stress, the unfolded protein response engages adaptive reactions to restore the secretory capacity of the cell. Recent advances revealed that ER stress signaling plays a critical role in HCC progression. Here, we propose that chronic ER stress is a common transversal factor contributing to the transition from liver disease (risk factor) to HCC. Interventional strategies to target the unfolded protein response in HCC, such as cancer therapy, are also discussed.
Collapse
Affiliation(s)
- Younis Hazari
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
- Faculty of Medicine, Biomedical Neuroscience Institute (BNI), University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile
- Department of Biotechnology, University of Kashmir, Srinagar, India
| | - Eric Chevet
- Inserm U1242, University of Rennes, Rennes, France
- Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
| | - Béatrice Bailly-Maitre
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1065, Université Côte d'Azur (UCA), Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Team "Metainflammation and Hematometabolism", Metabolism Department, France
- Université Côte d'Azur, INSERM, U1065, C3M, 06200 Nice, France
| | - Claudio Hetz
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
- Faculty of Medicine, Biomedical Neuroscience Institute (BNI), University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile
- Buck Institute for Research on Aging, Novato, California, USA
| |
Collapse
|
|
15
|
Ren Q, Sun Q, Fu J. Dysfunction of autophagy in high-fat diet-induced non-alcoholic fatty liver disease. Autophagy 2024; 20:221-241. [PMID: 37700498 PMCID: PMC10813589 DOI: 10.1080/15548627.2023.2254191] [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: 05/01/2023] [Accepted: 08/24/2023] [Indexed: 09/14/2023] Open
Abstract
ABBREVIATIONS ACOX1: acyl-CoA oxidase 1; ADH5: alcohol dehydrogenase 5 (class III), chi polypeptide; ADIPOQ: adiponectin, C1Q and collagen domain containing; ATG: autophagy related; BECN1: beclin 1; CRTC2: CREB regulated transcription coactivator 2; ER: endoplasmic reticulum; F2RL1: F2R like trypsin receptor 1; FA: fatty acid; FOXO1: forkhead box O1; GLP1R: glucagon like peptide 1 receptor; GRK2: G protein-coupled receptor kinase 2; GTPase: guanosine triphosphatase; HFD: high-fat diet; HSCs: hepatic stellate cells; HTRA2: HtrA serine peptidase 2; IRGM: immunity related GTPase M; KD: knockdown; KDM6B: lysine demethylase 6B; KO: knockout; LAMP2: lysosomal associated membrane protein 2; LAP: LC3-associated phagocytosis; LDs: lipid droplets; Li KO: liver-specific knockout; LSECs: liver sinusoidal endothelial cells; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP3K5: mitogen-activated protein kinase kinase kinase 5; MED1: mediator complex subunit 1; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin complex 1; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; NFE2L2: NFE2 like bZIP transcription factor 2; NOS3: nitric oxide synthase 3; NR1H3: nuclear receptor subfamily 1 group H member 3; OA: oleic acid; OE: overexpression; OSBPL8: oxysterol binding protein like 8; PA: palmitic acid; RUBCNL: rubicon like autophagy enhancer; PLIN2: perilipin 2; PLIN3: perilipin 3; PPARA: peroxisome proliferator activated receptor alpha; PRKAA2/AMPK: protein kinase AMP-activated catalytic subunit alpha 2; RAB: member RAS oncogene family; RPTOR: regulatory associated protein of MTOR complex 1; SCD: stearoyl-CoA desaturase; SIRT1: sirtuin 1; SIRT3: sirtuin 3; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1;SREBF2: sterol regulatory element binding transcription factor 2; STING1: stimulator of interferon response cGAMP interactor 1; STX17: syntaxin 17; TAGs: triacylglycerols; TFEB: transcription factor EB; TP53/p53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; VMP1: vacuole membrane protein 1.
Collapse
Affiliation(s)
- Qiannan Ren
- Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Qiming Sun
- International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China
- Department of Biochemistry, and Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Junfen Fu
- Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| |
Collapse
|
|
16
|
Bellanti F, Mangieri D, Vendemiale G. Redox Biology and Liver Fibrosis. Int J Mol Sci 2023; 25:410. [PMID: 38203581 PMCID: PMC10778611 DOI: 10.3390/ijms25010410] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 12/21/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
Hepatic fibrosis is a complex process that develops in chronic liver diseases. Even though the initiation and progression of fibrosis rely on the underlying etiology, mutual mechanisms can be recognized and targeted for therapeutic purposes. Irrespective of the primary cause of liver disease, persistent damage to parenchymal cells triggers the overproduction of reactive species, with the consequent disruption of redox balance. Reactive species are important mediators for the homeostasis of both hepatocytes and non-parenchymal liver cells. Indeed, other than acting as cytotoxic agents, reactive species are able to modulate specific signaling pathways that may be relevant to hepatic fibrogenesis. After a brief introduction to redox biology and the mechanisms of fibrogenesis, this review aims to summarize the current evidence of the involvement of redox-dependent pathways in liver fibrosis and focuses on possible therapeutic targets.
Collapse
Affiliation(s)
- Francesco Bellanti
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy;
| | - Domenica Mangieri
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy;
| | - Gianluigi Vendemiale
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy;
| |
Collapse
|
|
17
|
Le TV, Truong NH, Holterman AXL. Autophagy modulates physiologic and adaptive response in the liver. LIVER RESEARCH (BEIJING, CHINA) 2023; 7:304-320. [PMID: 39958781 PMCID: PMC11792069 DOI: 10.1016/j.livres.2023.12.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 07/20/2023] [Accepted: 11/14/2023] [Indexed: 01/03/2025]
Abstract
Autophagy is a physiological process that is ubiquitous and essential to the disposal or recycling of damaged cellular organelles and misfolded proteins to maintain organ homeostasis and survival. Its importance in the regulation of liver function in normal and pathological conditions is increasingly recognized. This review summarizes how autophagy regulates epithelial cell- and non-epithelial cell-specific function in the liver and how it differentially participates in hepatic homeostasis, hepatic injury response to stress-induced liver damage such as cholestasis, sepsis, non-alcoholic and alcohol-associated liver disease, viral hepatitis, hepatic fibrosis, hepatocellular and cholangiocellular carcinoma, and aging. Autophagy-based interventional studies for liver diseases that are currently registered in clinicatrials.gov are summarized. Given the broad and multidirectional autophagy response in the liver, a more refined understanding of the liver cell-specific autophagy activities in a context-dependent manner is necessary.
Collapse
Affiliation(s)
- Trinh Van Le
- Laboratory of Stem Cell Research and Application, University of Science-VNUHCM, Ho Chi Minh City, Vietnam
- Vietnam National University, Ho Chi Minh City, Vietnam
| | - Nhung Hai Truong
- Faculty of Biology and Biotechnology, University of Science-VNUHCM, Ho Chi Minh City, Vietnam
| | - Ai Xuan L. Holterman
- Department of Pediatrics and Surgery, University of Illinois College of Medicine, Chicago and Peoria, IL, USA
| |
Collapse
|
|
18
|
Wang S, Friedman SL. Found in translation-Fibrosis in metabolic dysfunction-associated steatohepatitis (MASH). Sci Transl Med 2023; 15:eadi0759. [PMID: 37792957 PMCID: PMC10671253 DOI: 10.1126/scitranslmed.adi0759] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 09/15/2023] [Indexed: 10/06/2023]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a severe form of liver disease that poses a global health threat because of its potential to progress to advanced fibrosis, leading to cirrhosis and liver cancer. Recent advances in single-cell methodologies, refined disease models, and genetic and epigenetic insights have provided a nuanced understanding of MASH fibrogenesis, with substantial cellular heterogeneity in MASH livers providing potentially targetable cell-cell interactions and behavior. Unlike fibrogenesis, mechanisms underlying fibrosis regression in MASH are still inadequately understood, although antifibrotic targets have been recently identified. A refined antifibrotic treatment framework could lead to noninvasive assessment and targeted therapies that preserve hepatocellular function and restore the liver's architectural integrity.
Collapse
Affiliation(s)
- Shuang Wang
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Scott L. Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| |
Collapse
|
|
19
|
Hanquier Z, Misra J, Baxter R, Maiers JL. Stress and Liver Fibrogenesis: Understanding the Role and Regulation of Stress Response Pathways in Hepatic Stellate Cells. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1363-1376. [PMID: 37422148 PMCID: PMC10548279 DOI: 10.1016/j.ajpath.2023.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/24/2023] [Accepted: 06/06/2023] [Indexed: 07/10/2023]
Abstract
Stress response pathways are crucial for cells to adapt to physiological and pathologic conditions. Increased transcription and translation in response to stimuli place a strain on the cell, necessitating increased amino acid supply, protein production and folding, and disposal of misfolded proteins. Stress response pathways, such as the unfolded protein response (UPR) and the integrated stress response (ISR), allow cells to adapt to stress and restore homeostasis; however, their role and regulation in pathologic conditions, such as hepatic fibrogenesis, are unclear. Liver injury promotes fibrogenesis through activation of hepatic stellate cells (HSCs), which produce and secrete fibrogenic proteins to promote tissue repair. This process is exacerbated in chronic liver disease, leading to fibrosis and, if unchecked, cirrhosis. Fibrogenic HSCs exhibit activation of both the UPR and ISR, due in part to increased transcriptional and translational demands, and these stress responses play important roles in fibrogenesis. Targeting these pathways to limit fibrogenesis or promote HSC apoptosis is a potential antifibrotic strategy, but it is limited by our lack of mechanistic understanding of how the UPR and ISR regulate HSC activation and fibrogenesis. This article explores the role of the UPR and ISR in the progression of fibrogenesis, and highlights areas that require further investigation to better understand how the UPR and ISR can be targeted to limit hepatic fibrosis progression.
Collapse
Affiliation(s)
- Zachary Hanquier
- Department of Molecular and Medical Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Jagannath Misra
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Reese Baxter
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Jessica L Maiers
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
| |
Collapse
|
|
20
|
Sharma S, Le Guillou D, Chen JY. Cellular stress in the pathogenesis of nonalcoholic steatohepatitis and liver fibrosis. Nat Rev Gastroenterol Hepatol 2023; 20:662-678. [PMID: 37679454 DOI: 10.1038/s41575-023-00832-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/26/2023] [Indexed: 09/09/2023]
Abstract
The burden of chronic liver disease is rising substantially worldwide. Fibrosis, characterized by excessive deposition of extracellular matrix proteins, is the common pathway leading to cirrhosis, and limited treatment options are available. There is increasing evidence suggesting the role of cellular stress responses contributing to fibrogenesis. This Review provides an overview of studies that analyse the role of cellular stress in different cell types involved in fibrogenesis, including hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells and macrophages.
Collapse
Affiliation(s)
- Sachin Sharma
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- The Liver Center, University of California, San Francisco, San Francisco, CA, USA
| | - Dounia Le Guillou
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- The Liver Center, University of California, San Francisco, San Francisco, CA, USA
| | - Jennifer Y Chen
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
- The Liver Center, University of California, San Francisco, San Francisco, CA, USA.
| |
Collapse
|
|
21
|
Chen Y, Lei Y, Wang H, Wang L, Xu J, Wang S, Yu M, Peng Z, Xiao F, Tian D, Liu M. Sophoricoside attenuates autoimmune‑mediated liver injury through the regulation of oxidative stress and the NF‑κB signaling pathway. Int J Mol Med 2023; 52:78. [PMID: 37477163 PMCID: PMC10555480 DOI: 10.3892/ijmm.2023.5281] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/04/2023] [Indexed: 07/22/2023] Open
Abstract
The prevalence of autoimmune hepatitis (AIH) is increasing, yet specific pharmacotherapies remain to be explored. The present study aimed to investigate the effects of sophoricoside (SOP), a bioactive component of medical herbs, on AIH and to elucidate the underlying mechanisms. Bioinformatic approaches were used to predict the potential targets and underlying regulatory mechanisms of SOP on AIH. The effects of SOP on AIH were evaluated by determining the expression levels of inflammatory cytokines, histological liver injury and hepatic fibrosis in an improved chronic cytochrome P450 2D6 (CYP2D6)‑AIH mouse model and in a model of concanavalin‑A (ConA)‑induced acute immune‑mediated liver injury. The antioxidant activity of SOP was detected in in vivo and in vitro experiments. The selected signal targeted by SOP in AIH was further confirmed using western blot analysis and immunofluorescence staining. The results of bioinformatic analysis revealed that the targets of SOP in AIH were related to oxidative stress and the NF‑κB gene set. The NF‑κB transcription factor family is a key player that controls both innate and adaptive immunity. The activation of the NF‑κB signaling pathway is often associated with autoimmune disorders. In the animal experiments, SOP attenuated CYP2D6/ConA‑induced AIH, as evidenced by a significant reduction in the levels of hepatic enzymes in serum, inflammatory cytokine expression and histological lesions in the liver. The oxidative response in AIH was also significantly inhibited by SOP, as evidenced by a decrease in the levels of hepatic malondialdehyde, and elevations in the total antioxidant capacity and glutathione peroxidase levels. The results of the in vivo and in vitro experiments revealed that SOP significantly reduced the enhanced expression and nuclear translocation of phosphorylated p65 NF‑κB in the livers of mice with AIH and in lipopolysaccharide‑stimulated AML12 cells. On the whole, the present study demonstrates the protective role of SOP in AIH, which may be mediated by limiting the oxidative response and the activation of the NF‑κB signaling pathway in hepatocytes.
Collapse
Affiliation(s)
- Yu Chen
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Yu Lei
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Han Wang
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Lijia Wang
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Jiaxin Xu
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Shuhui Wang
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Meiping Yu
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Zhangqi Peng
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Fang Xiao
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Mei Liu
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| |
Collapse
|
|
22
|
Tao H, Liu Q, Zeng A, Song L. Unlocking the potential of Mesenchymal stem cells in liver Fibrosis: Insights into the impact of autophagy and aging. Int Immunopharmacol 2023; 121:110497. [PMID: 37329808 DOI: 10.1016/j.intimp.2023.110497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 05/30/2023] [Accepted: 06/11/2023] [Indexed: 06/19/2023]
Abstract
Liver fibrosis is a chronic liver disease characterized by extracellular matrix protein accumulation, potentially leading to cirrhosis or hepatocellular carcinoma. Liver cell damage, inflammatory responses, and apoptosis due to various reasons induce liver fibrosis. Although several treatments, such as antiviral drugs and immunosuppressive therapies, are available for liver fibrosis, they only provide limited efficacy. Mesenchymal stem cells (MSCs) have become a promising therapeutic option for liver fibrosis, because they can modulate the immune response, promote liver regeneration, and inhibit the activation of hepatic stellate cells that contribute to disease development. Recent studies have suggested that the mechanisms through which MSCs gain their antifibrotic properties involve autophagy and senescence. Autophagy, a vital cellular self-degradation process, is critical for maintaining homeostasis and protecting against nutritional, metabolic, and infection-mediated stress. The therapeutic effects of MSCs depend on appropriate autophagy levels, which can improve the fibrotic process. Nonetheless, aging-related autophagic damage is associated with a decline in MSC number and function, which play a crucial role in liver fibrosis development. This review summarizes the recent advancements in the understanding of autophagy and senescence in MSC-based liver fibrosis treatment, presenting the key findings from relevant studies.
Collapse
Affiliation(s)
- Hongxia Tao
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China
| | - Qianglin Liu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China
| | - Anqi Zeng
- Institute of Translational Pharmacology and Clinical Application, Sichuan Academy of Chinese Medical Science, Chengdu, Sichuan 610041, PR China.
| | - Linjiang Song
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China.
| |
Collapse
|
|
23
|
Salete-Granado D, Carbonell C, Puertas-Miranda D, Vega-Rodríguez VJ, García-Macia M, Herrero AB, Marcos M. Autophagy, Oxidative Stress, and Alcoholic Liver Disease: A Systematic Review and Potential Clinical Applications. Antioxidants (Basel) 2023; 12:1425. [PMID: 37507963 PMCID: PMC10376811 DOI: 10.3390/antiox12071425] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 07/06/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Ethanol consumption triggers oxidative stress by generating reactive oxygen species (ROS) through its metabolites. This process leads to steatosis and liver inflammation, which are critical for the development of alcoholic liver disease (ALD). Autophagy is a regulated dynamic process that sequesters damaged and excess cytoplasmic organelles for lysosomal degradation and may counteract the harmful effects of ROS-induced oxidative stress. These effects include hepatotoxicity, mitochondrial damage, steatosis, endoplasmic reticulum stress, inflammation, and iron overload. In liver diseases, particularly ALD, macroautophagy has been implicated as a protective mechanism in hepatocytes, although it does not appear to play the same role in stellate cells. Beyond the liver, autophagy may also mitigate the harmful effects of alcohol on other organs, thereby providing an additional layer of protection against ALD. This protective potential is further supported by studies showing that drugs that interact with autophagy, such as rapamycin, can prevent ALD development in animal models. This systematic review presents a comprehensive analysis of the literature, focusing on the role of autophagy in oxidative stress regulation, its involvement in organ-organ crosstalk relevant to ALD, and the potential of autophagy-targeting therapeutic strategies.
Collapse
Affiliation(s)
- Daniel Salete-Granado
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
| | - Cristina Carbonell
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| | - David Puertas-Miranda
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
| | - Víctor-José Vega-Rodríguez
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
| | - Marina García-Macia
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Instituto de Biología Funcional y Genómica (IBFG), Universidad de Salamanca, 37007 Salamanca, Spain
| | - Ana Belén Herrero
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Miguel Marcos
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| |
Collapse
|
|
24
|
Li ZB, Jiang L, Ni JD, Xu YH, Liu F, Liu WM, Wang SG, Liu ZQ, Wang CY. Salvianolic acid B suppresses hepatic fibrosis by inhibiting ceramide glucosyltransferase in hepatic stellate cells. Acta Pharmacol Sin 2023; 44:1191-1205. [PMID: 36627345 PMCID: PMC10203340 DOI: 10.1038/s41401-022-01044-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 12/14/2022] [Indexed: 01/11/2023]
Abstract
UDP-glucose ceramide glucosyltransferase (UGCG) is the first key enzyme in glycosphingolipid (GSL) metabolism that produces glucosylceramide (GlcCer). Increased UGCG synthesis is associated with cell proliferation, invasion and multidrug resistance in human cancers. In this study we investigated the role of UGCG in the pathogenesis of hepatic fibrosis. We first found that UGCG was over-expressed in fibrotic livers and activated hepatic stellate cells (HSCs). In human HSC-LX2 cells, inhibition of UGCG with PDMP or knockdown of UGCG suppressed the expression of the biomarkers of HSC activation (α-SMA and collagen I). Furthermore, pretreatment with PDMP (40 μM) impaired lysosomal homeostasis and blocked the process of autophagy, leading to activation of retinoic acid signaling pathway and accumulation of lipid droplets. After exploring the structure and key catalytic residues of UGCG in the activation of HSCs, we conducted virtual screening, molecular interaction and molecular docking experiments, and demonstrated salvianolic acid B (SAB) from the traditional Chinese medicine Salvia miltiorrhiza as an UGCG inhibitor with an IC50 value of 159 μM. In CCl4-induced mouse liver fibrosis, intraperitoneal administration of SAB (30 mg · kg-1 · d-1, for 4 weeks) significantly alleviated hepatic fibrogenesis by inhibiting the activation of HSCs and collagen deposition. In addition, SAB displayed better anti-inflammatory effects in CCl4-induced liver fibrosis. These results suggest that UGCG may represent a therapeutic target for liver fibrosis; SAB could act as an inhibitor of UGCG, which is expected to be a candidate drug for the treatment of liver fibrosis.
Collapse
Affiliation(s)
- Zi-Bo Li
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Lin Jiang
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Jia-Dong Ni
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Yuan-Hang Xu
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Fang Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Wen-Ming Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Shao-Gui Wang
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
| | - Zhong-Qiu Liu
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
| | - Cai-Yan Wang
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
| |
Collapse
|
|
25
|
Le TV, Phan-Thi HT, Huynh-Thi MX, Dang TM, Holterman AXL, Grassi G, Nguyen-Luu TU, Truong NH. Autophagy Inhibitor Chloroquine Downmodulates Hepatic Stellate Cell Activation and Liver Damage in Bile-Duct-Ligated Mice. Cells 2023; 12:1025. [PMID: 37048098 PMCID: PMC10092998 DOI: 10.3390/cells12071025] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/15/2023] [Accepted: 03/23/2023] [Indexed: 03/30/2023] Open
Abstract
Hepatic stellate cell (HSC) activation via the autophagy pathway is a critical factor in liver fibrogenesis. This study tests the hypothesis that chloroquine (CQ) treatment can prevent autophagy and HSC activation in vitro and in vivo in bile-duct-ligated (BDL) mice. Sham-operated and BDL mice were treated with either PBS or CQ in two 60 mg/kg doses the day (D) before and after surgery. On day 2 (2D), HSCs were isolated, and their biological activities were evaluated by measuring intracellular lipid content, α-sma/collagen, and expression of autophagy lc3, sqstm1/p62 markers. The treatment efficacy on liver function was evaluated with serum albumin, transaminases (AST/ALT), and hepatic histology. Primary HSCs were treated in vitro for 24 h with CQ at 0, 2.5, 5, 10, 30, and 50 µM. Autophagy and HSC activation were assessed after 2D of treatment. CQ treatment improved serum AST/ALT, albumin, and bile duct proliferation in 2D BDL mice. This is associated with a suppression of HSC activation, shown by higher HSC lipid content and collagen I staining, along with the blockage of HSC autophagy indicated by an increase in p62 level and reduction in lc3 staining. CQ 5 µM inhibited autophagy in primary HSCs in vitro by increasing p62 and lc3 accumulation, thereby suppressing their in vitro activation. The autophagy inhibitor CQ reduced HSC activation in vitro and in vivo. CQ improved liver function and reduced liver injury in BDL mice.
Collapse
Affiliation(s)
- Trinh Van Le
- Laboratory of Stem Cell Research and Application, University of Science, Ho Chi Minh City 700000, Vietnam; (T.V.L.)
- Viet Nam National University, Ho Chi Minh City 700000, Vietnam
| | - Hong-Thuy Phan-Thi
- Laboratory of Stem Cell Research and Application, University of Science, Ho Chi Minh City 700000, Vietnam; (T.V.L.)
- Viet Nam National University, Ho Chi Minh City 700000, Vietnam
| | - My-Xuan Huynh-Thi
- Laboratory of Stem Cell Research and Application, University of Science, Ho Chi Minh City 700000, Vietnam; (T.V.L.)
- Viet Nam National University, Ho Chi Minh City 700000, Vietnam
| | - Thanh Minh Dang
- Laboratory of Stem Cell Research and Application, University of Science, Ho Chi Minh City 700000, Vietnam; (T.V.L.)
- Viet Nam National University, Ho Chi Minh City 700000, Vietnam
| | - Ai Xuan Le Holterman
- Department of Pediatrics and Surgery, University of Illinois College of Medicine, Chicago, IL 60607, USA
| | - Gabriele Grassi
- Department of Life Sciences, University Hospital of Cattinara, University of Trieste, 34100 Trieste, Italy
| | - Thao-Uyen Nguyen-Luu
- Laboratory of Stem Cell Research and Application, University of Science, Ho Chi Minh City 700000, Vietnam; (T.V.L.)
- Viet Nam National University, Ho Chi Minh City 700000, Vietnam
| | - Nhung Hai Truong
- Viet Nam National University, Ho Chi Minh City 700000, Vietnam
- Faculty of Biology and Biotechnology, University of Science, Ho Chi Minh City 700000, Vietnam
| |
Collapse
|
|
26
|
Shi B, Wang W, Ye M, Liang M, Yu Z, Zhang Y, Liu Z, Liang X, Ao J, Xu F, Xu G, Jiang X, Zhou X, Liu L. Spermidine suppresses the activation of hepatic stellate cells to cure liver fibrosis through autophagy activator MAP1S. Liver Int 2023; 43:1307-1319. [PMID: 36892418 DOI: 10.1111/liv.15558] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 03/01/2023] [Accepted: 03/04/2023] [Indexed: 03/10/2023]
Abstract
BACKGROUND AND AIMS Liver diseases present a wide range of fibrosis, from fatty liver with no inflammation to steatohepatitis with varying degrees of fibrosis, to established cirrhosis leading to HCC. In a multivariate analysis, serum levels of spermidine were chosen as the top metabolite from 237 metabolites and its levels were drastically reduced along with progression to advanced steatohepatitis. Our previous studies that showed spermidine supplementation helps mice prevent liver fibrosis through MAP1S have prompted us to explore the possibility that spermidine can alleviate or cure already developed liver fibrosis. METHODS We collected tissue samples from patients with liver fibrosis to measure the levels of MAP1S. We treated wild-type and MAP1S knockout mice with CCl4 -induced liver fibrosis with spermidine and isolated HSCs in culture to test the effects of spermidine on HSC activation and liver fibrosis. RESULTS Patients with increasing degrees of liver fibrosis had reduced levels of MAP1S. Supplementing spermidine in mice that had already developed liver fibrosis after 1 month of CCl4 induction for an additional 3 months resulted in significant reductions in levels of ECM proteins and a remarkable improvement in liver fibrosis through MAP1S. Spermidine also suppressed HSC activation by reducing ECM proteins at both the mRNA and protein levels, and increasing the number of lipid droplets in stellate cells. CONCLUSIONS Spermidine supplementation is a potentially clinically meaningful approach to treating and curing liver fibrosis, preventing cirrhosis and HCC in patients.
Collapse
Affiliation(s)
- Boyun Shi
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.,Department of Pediatric Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Wei Wang
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Mengting Ye
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Min Liang
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.,Department of Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ziyu Yu
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yingying Zhang
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Zhaoyu Liu
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Xue Liang
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jian Ao
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.,Department of General Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Fengfeng Xu
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.,Department of General Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Guibin Xu
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.,Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Xianhan Jiang
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.,Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Xinke Zhou
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.,Department of Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Leyuan Liu
- The Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| |
Collapse
|
|
27
|
Wiering L, Subramanian P, Hammerich L. Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease. Cell Mol Gastroenterol Hepatol 2023; 15:1277-1292. [PMID: 36828280 PMCID: PMC10148161 DOI: 10.1016/j.jcmgh.2023.02.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 02/15/2023] [Accepted: 02/15/2023] [Indexed: 02/26/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a fast growing, chronic liver disease affecting ∼25% of the global population. Nonalcoholic fatty liver disease severity ranges from the less severe simple hepatic steatosis to the more advanced nonalcoholic steatohepatitis (NASH). The presence of NASH predisposes individuals to liver fibrosis, which can further progress to cirrhosis and hepatocellular carcinoma. This makes hepatic fibrosis an important indicator of clinical outcomes in patients with NASH. Hepatic stellate cell activation dictates fibrosis development during NASH. Here, we discuss recent advances in the analysis of the profibrogenic pathways and mediators of hepatic stellate cell activation and inactivation, which ultimately determine the course of disease in nonalcoholic fatty liver disease/NASH.
Collapse
Affiliation(s)
- Leke Wiering
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Berlin, Germany
| | - Pallavi Subramanian
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Linda Hammerich
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
| |
Collapse
|
|
28
|
Choi J, Cho Y, Choi H, Lee S, Han H, Lee J, Kwon J. Thymosin Beta 4 Inhibits LPS and ATP-Induced Hepatic Stellate Cells via the Regulation of Multiple Signaling Pathways. Int J Mol Sci 2023; 24:ijms24043439. [PMID: 36834849 PMCID: PMC9959661 DOI: 10.3390/ijms24043439] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 12/29/2022] [Accepted: 01/11/2023] [Indexed: 02/11/2023] Open
Abstract
Risk signals are characteristic of many common inflammatory diseases and can function to activate nucleotide-binding oligomerization (NLR) family pyrin domain-containing 3 (NLRP3), the innate immune signal receptor in cytoplasm. The NLRP3 inflammasome plays an important role in the development of liver fibrosis. Activated NLRP3 nucleates the assembly of inflammasomes, leading to the secretion of interleukin (IL)-1β and IL-18, the activation of caspase-1, and the initiation of the inflammatory process. Therefore, it is essential to inhibit the activation of the NLRP3 inflammasome, which plays a vital role in the immune response and in initiating inflammation. RAW 264.7 and LX-2 cells were primed with lipopolysaccharide (LPS) for 4 h and subsequently stimulated for 30 min with 5 mM of adenosine 5'-triphosphate (ATP) to activate the NLRP3 inflammasome. Thymosin beta 4 (Tβ4) was supplemented to RAW264.7 and LX-2 cells 30 min before ATP was added. As a result, we investigated the effects of Tβ4 on the NLRP3 inflammasome. Tβ4 prevented LPS-induced NLRP3 priming by inhibiting NF-kB and JNK/p38 MAPK expression and the LPS and ATP-induced production of reactive oxygen species. Moreover, Tβ4 induced autophagy by controlling autophagy markers (LC3A/B and p62) through the inhibition of the PI3K/AKT/mTOR pathway. LPS combined with ATP significantly increased thee protein expression of inflammatory mediators and NLRP3 inflammasome markers. These events were remarkably suppressed by Tβ4. In conclusion, Tβ4 attenuated NLRP3 inflammasomes by inhibiting NLRP3 inflammasome-related proteins (NLRP3, ASC, IL-1β, and caspase-1). Our results indicate that Tβ4 attenuated the NLRP3 inflammasome through multiple signaling pathway regulations in macrophage and hepatic stellate cells. Therefore, based on the above findings, it is hypothesized that Tβ4 could be a potential inflammatory therapeutic agent targeting the NLRP3 inflammasome in hepatic fibrosis regulation.
Collapse
|
|
29
|
Role of ER Stress in Xenobiotic-Induced Liver Diseases and Hepatotoxicity. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4640161. [PMID: 36388166 PMCID: PMC9652065 DOI: 10.1155/2022/4640161] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 10/12/2022] [Accepted: 10/25/2022] [Indexed: 11/06/2022]
Abstract
The liver is a highly metabolic organ and plays a crucial role in the transportation, storage, and/or detoxication of xenobiotics. Liver damage induced by xenobiotics (e.g., heavy metal, endocrine disrupting chemicals, Chinese herbal medicine, or nanoparticles) has become a pivotal reason for liver diseases, leading to great clinical challenge and much attention for the past decades. Given that endoplasmic reticulum (ER) is the prominent organelle involved in hepatic metabolism, ER dysfunction, namely, ER stress, is clearly observed in various liver diseases. In response to ER stress, a conserved adaptive signaling pathway known as unfolded protein response (UPR) is activated to restore ER homeostasis. However, the prolonged ER stress with UPR eventually leads to the death of hepatocytes, which is a pathogenic event in many hepatic diseases. Therefore, analyzing the perturbation in the activation or inhibition of ER stress and the UPR signaling pathway is likely an effective marker for investigating the molecular mechanisms behind the toxic effects of xenobiotics on the liver. We review the role of ER stress in hepatic diseases and xenobiotic-induced hepatotoxicity, which not only provides a theoretical basis for further understanding the pathogenesis of liver diseases and the mechanisms of hepatotoxicity induced by xenobiotics but also presents a potential target for the prevention and treatment of xenobiotic-related liver diseases.
Collapse
|
|
30
|
Wang Q, Bu Q, Liu M, Zhang R, Gu J, Li L, Zhou J, Liang Y, Su W, Liu Z, Wang M, Lian Z, Lu L, Zhou H. XBP1-mediated activation of the STING signalling pathway in macrophages contributes to liver fibrosis progression. JHEP Rep 2022; 4:100555. [PMID: 36185574 PMCID: PMC9520276 DOI: 10.1016/j.jhepr.2022.100555] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND & AIMS XBP1 modulates the macrophage proinflammatory response, but its function in macrophage stimulator of interferon genes (STING) activation and liver fibrosis is unknown. X-box binding protein 1 (XBP1) has been shown to promote macrophage nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) activation in steatohepatitis. Herein, we aimed to explore the underlying mechanism of XBP1 in the regulation of STING signalling and the subsequent NLRP3 activation during liver fibrosis. METHODS XBP1 expression was measured in the human fibrotic liver tissue samples. Liver fibrosis was induced in myeloid-specific Xbp1-, STING-, and Nlrp3-deficient mice by carbon tetrachloride injection, bile duct ligation, or a methionine/choline-deficient diet. RESULTS Although increased XBP1 expression was observed in the fibrotic liver macrophages of mice and clinical patients, myeloid-specific Xbp1 deficiency or pharmacological inhibition of XBP1 protected the liver against fibrosis. Furthermore, it inhibited macrophage NLPR3 activation in a STING/IRF3-dependent manner. Oxidative mitochondrial injury facilitated cytosolic leakage of macrophage self-mtDNA and cGAS/STING/NLRP3 signalling activation to promote liver fibrosis. Mechanistically, RNA sequencing analysis indicated a decreased mtDNA expression and an increased BCL2/adenovirus E1B interacting protein 3 (BNIP3)-mediated mitophagy activation in Xbp1-deficient macrophages. Chromatin immunoprecipitation (ChIP) assays further suggested that spliced XBP1 bound directly to the Bnip3 promoter and inhibited the transcription of Bnip3 in macrophages. Xbp1 deficiency decreased the mtDNA cytosolic release and STING/NLRP3 activation by promoting BNIP3-mediated mitophagy activation in macrophages, which was abrogated by Bnip3 knockdown. Moreover, macrophage XBP1/STING signalling contributed to the activation of hepatic stellate cells. CONCLUSIONS Our findings demonstrate that XBP1 controls macrophage cGAS/STING/NLRP3 activation by regulating macrophage self-mtDNA cytosolic leakage via BNIP3-mediated mitophagy modulation, thus providing a novel target against liver fibrosis. LAY SUMMARY Liver fibrosis is a typical progressive process of chronic liver disease, driven by inflammatory and immune responses, and is characterised by an excess of extracellular matrix in the liver. Currently, there is no effective therapeutic strategy for the treatment of liver fibrosis, resulting in high mortality worldwide. In this study, we found that myeloid-specific Xbp1 deficiency protected the liver against fibrosis in mice, while XBP1 inhibition ameliorated liver fibrosis in mice. This study concluded that targeting XBP1 signalling in macrophages may provide a novel strategy for protecting the liver against fibrosis.
Collapse
Key Words
- Acta2/α-SMA, actin, alpha 2, smooth muscle, aorta
- BDL, bile duct ligation
- BMDMs, bone marrow-derived macrophages
- BNIP3
- BNIP3, BCL2/adenovirus E1B interacting protein 3
- CCl4, carbon tetrachloride
- CM, conditional media
- ChIP, chromatin immunoprecipitation
- Col1a1, collagen, type I, alpha 1
- DMXAA, 5,6-dimethylxanthenone-4-acetic acid
- ER, endoplasmic reticulum
- EtBr, ethidium bromide
- HSC, hepatic stellate cell
- IRE1α, inositol-requiring enzyme-1α
- IRF3, interferon regulatory factor 3
- KEGG, Kyoto Encyclopedia of Genes and Genomes
- LC3B, microtubule-associated protein 1 light chain 3 beta
- LPS, lipopolysaccharide
- Liver fibrosis
- MCD, methionine/choline-deficient diet
- Macrophage
- Mitophagy
- MnSOD, manganese superoxide dismutase
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- NLRP3, nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3
- PBMCs, peripheral blood mononuclear cells
- ROS, reactive oxygen species
- STING
- STING, stimulator of interferon genes
- TBK1, TANK binding kinase 1
- TGF-β1, transforming growth factor beta 1
- TLR, Toll-like receptor
- TNF-α, tumour necrosis factor alpha
- Timp1, tissue inhibitor of matrix metalloproteinase 1
- WT, wild-type
- XBP1
- XBP1, X-box binding protein 1
- cGAS, cyclic GMP-AMP synthase
- mtDNA
- mtDNA, mitochondrial DNA
- p62, sequestosome 1
- sXBP1, spliced XBP1
- shRNAs, short hairpin RNAs
- uXBP1, unspliced XBP1
Collapse
Affiliation(s)
- Qi Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- School of Medicine, Southeast University, Nanjing, China
| | - Qingfa Bu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Mu Liu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Rui Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Jian Gu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Lei Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Jinren Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Yuan Liang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Wantong Su
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Zheng Liu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Mingming Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Zhexiong Lian
- Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Ling Lu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- School of Medicine, Southeast University, Nanjing, China
- Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Haoming Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Liver Transplantation, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| |
Collapse
|
|
31
|
Pavlović N, Heindryckx F. Targeting ER stress in the hepatic tumor microenvironment. FEBS J 2022; 289:7163-7176. [PMID: 34331743 DOI: 10.1111/febs.16145] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/13/2021] [Accepted: 07/30/2021] [Indexed: 01/13/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. It currently ranks as one of the most aggressive and deadly cancers worldwide, with an increasing mortality rate and limited treatment options. An important hallmark of liver pathologies, such as liver fibrosis and HCC, is the accumulation of misfolded and unfolded proteins in the lumen of the endoplasmic reticulum (ER), which induces ER stress and leads to the activation of the unfolded protein response (UPR). Upon accumulation of misfolded proteins, ER stress is sensed through three transmembrane proteins, IRE1α, PERK, and ATF6, which trigger the UPR to either alleviate ER stress or induce apoptosis. Increased expression of ER stress markers has been widely shown to correlate with fibrosis, inflammation, drug resistance, and overall HCC aggressiveness, as well as poor patient prognosis. While preclinical in vivo cancer models and in vitro approaches have shown promising results by pharmacologically targeting ER stress mediators, the major challenge of this therapeutic strategy lies in specifically and effectively targeting ER stress in HCC. Furthermore, both ER stress inducers and inhibitors have been shown to ameliorate HCC progression, adding to the complexity of targeting ER stress players as an anticancer strategy. More studies are needed to better understand the dual role and molecular background of ER stress in HCC, as well as its therapeutic potential for patients with liver cancer.
Collapse
Affiliation(s)
- Nataša Pavlović
- Department of Medical Cell Biology, Uppsala University, Sweden
| | | |
Collapse
|
|
32
|
Ramani K, Mavila N, Abeynayake A, Tomasi ML, Wang J, Matsuda M, Seki E. Targeting A-kinase anchoring protein 12 phosphorylation in hepatic stellate cells regulates liver injury and fibrosis in mouse models. eLife 2022; 11:e78430. [PMID: 36193675 PMCID: PMC9531947 DOI: 10.7554/elife.78430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 08/03/2022] [Indexed: 12/24/2022] Open
Abstract
Trans-differentiation of hepatic stellate cells (HSCs) to activated state potentiates liver fibrosis through release of extracellular matrix (ECM) components, distorting the liver architecture. Since limited antifibrotics are available, pharmacological intervention targeting activated HSCs may be considered for therapy. A-kinase anchoring protein 12 (AKAP12) is a scaffolding protein that directs protein kinases A/C (PKA/PKC) and cyclins to specific locations spatiotemporally controlling their biological effects. It has been shown that AKAP12's scaffolding functions are altered by phosphorylation. In previously published work, observed an association between AKAP12 phosphorylation and HSC activation. In this work, we demonstrate that AKAP12's scaffolding activity toward the endoplasmic reticulum (ER)-resident collagen chaperone, heat-shock protein 47 (HSP47) is strongly inhibited by AKAP12's site-specific phosphorylation in activated HSCs. CRISPR-directed gene editing of AKAP12's phospho-sites restores its scaffolding toward HSP47, inhibiting HSP47's collagen maturation functions, and HSC activation. AKAP12 phospho-editing dramatically inhibits fibrosis, ER stress response, HSC inflammatory signaling, and liver injury in mice. Our overall findings suggest a pro-fibrogenic role of AKAP12 phosphorylation that may be targeted for therapeutic intervention in liver fibrosis.
Collapse
Affiliation(s)
- Komal Ramani
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical CenterLos AngelesUnited States
- Applied Cell Biology Division, Department of Biomedical Sciences, Cedars-Sinai Medical CenterLos AngelesUnited States
| | - Nirmala Mavila
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical CenterLos AngelesUnited States
- Applied Cell Biology Division, Department of Biomedical Sciences, Cedars-Sinai Medical CenterLos AngelesUnited States
| | - Aushinie Abeynayake
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical CenterLos AngelesUnited States
| | - Maria Lauda Tomasi
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical CenterLos AngelesUnited States
- Applied Cell Biology Division, Department of Biomedical Sciences, Cedars-Sinai Medical CenterLos AngelesUnited States
| | - Jiaohong Wang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical CenterLos AngelesUnited States
| | - Michitaka Matsuda
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical CenterLos AngelesUnited States
| | - Eki Seki
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical CenterLos AngelesUnited States
- Applied Cell Biology Division, Department of Biomedical Sciences, Cedars-Sinai Medical CenterLos AngelesUnited States
| |
Collapse
|
|
33
|
Zhou L, Shen H, Li X, Wang H. Endoplasmic reticulum stress in innate immune cells - a significant contribution to non-alcoholic fatty liver disease. Front Immunol 2022; 13:951406. [PMID: 35958574 PMCID: PMC9361020 DOI: 10.3389/fimmu.2022.951406] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 06/28/2022] [Indexed: 12/12/2022] Open
Abstract
Liver disease and its complications affect millions of people worldwide. NAFLD (non-alcoholic fatty liver disease) is the liver disease associated with metabolic dysfunction and consists of four stages: steatosis with or without mild inflammation (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. With increased necroinflammation and progression of liver fibrosis, NAFLD may progress to cirrhosis or even hepatocellular carcinoma. Although the underlying mechanisms have not been clearly elucidated in detail, what is clear is that complex immune responses are involved in the pathogenesis of NASH, activation of the innate immune system is critically involved in triggering and amplifying hepatic inflammation and fibrosis in NAFLD/NASH. Additionally, disruption of endoplasmic reticulum (ER) homeostasis in cells, also known as ER stress, triggers the unfolded protein response (UPR) which has been shown to be involved to inflammation and apoptosis. To further develop the prevention and treatment of NAFLD/NASH, it is imperative to clarify the relationship between NAFLD/NASH and innate immune cells and ER stress. As such, this review focuses on innate immune cells and their ER stress in the occurrence of NAFLD and the progression of cirrhosis.
Collapse
Affiliation(s)
- Liangliang Zhou
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Haiyuan Shen
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Xiaofeng Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
- Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
- *Correspondence: Hua Wang,
| |
Collapse
|
|
34
|
Hepatic Myofibroblasts: A Heterogeneous and Redox-Modulated Cell Population in Liver Fibrogenesis. Antioxidants (Basel) 2022; 11:antiox11071278. [PMID: 35883770 PMCID: PMC9311931 DOI: 10.3390/antiox11071278] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/22/2022] [Accepted: 06/24/2022] [Indexed: 12/19/2022] Open
Abstract
During chronic liver disease (CLD) progression, hepatic myofibroblasts (MFs) represent a unique cellular phenotype that plays a critical role in driving liver fibrogenesis and then fibrosis. Although they could originate from different cell types, MFs exhibit a rather common pattern of pro-fibrogenic phenotypic responses, which are mostly elicited or sustained both by oxidative stress and reactive oxygen species (ROS) and several mediators (including growth factors, cytokines, chemokines, and others) that often operate through the up-regulation of the intracellular generation of ROS. In the present review, we will offer an overview of the role of MFs in the fibrogenic progression of CLD from different etiologies by focusing our attention on the direct or indirect role of ROS and, more generally, oxidative stress in regulating MF-related phenotypic responses. Moreover, this review has the purpose of illustrating the real complexity of the ROS modulation during CLD progression. The reader will have to keep in mind that a number of issues are able to affect the behavior of the cells involved: a) the different concentrations of reactive species, b) the intrinsic state of the target cells, as well as c) the presence of different growth factors, cytokines, and other mediators in the extracellular microenvironment or of other cellular sources of ROS.
Collapse
|
|
35
|
Hou LS, Zhang YW, Li H, Wang W, Huan ML, Zhou SY, Zhang BL. The regulatory role and mechanism of autophagy in energy metabolism-related hepatic fibrosis. Pharmacol Ther 2022; 234:108117. [PMID: 35077761 DOI: 10.1016/j.pharmthera.2022.108117] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/13/2022] [Accepted: 01/18/2022] [Indexed: 02/06/2023]
Abstract
Hepatic fibrosis is a key pathological process of chronic liver diseases, caused by alcohol, toxic and aberrant energy metabolism. It progresses to cirrhosis or even hepatic carcinoma without effective treatment. Studies have shown that autophagy has important regulatory effects on hepatic stellate cells (HSCs) energy metabolism, and then affect the activation state of HSCs. Autophagy maintains hepatic energy homeostasis, and the dysregulation of autophagy can lead to the activation of HSCs and the occurrence and development of hepatic fibrosis. It is necessary to explore the mechanism of autophagy in energy metabolism-related hepatic fibrosis. Herein, the current study summarizes the regulating mechanisms of autophagy through different targets and signal pathways in energy metabolism-related hepatic fibrosis, and discusses the regulatory effect of autophagy by natural plant-derived, endogenous and synthetic compounds for the treatment of hepatic fibrosis. A better comprehension of autophagy in hepatic stellate cells energy metabolism-related hepatic fibrosis may provide effective intervention of hepatic fibrosis, explore the potential clinical strategies and promote the drug treatment of hepatic fibrosis.
Collapse
Affiliation(s)
- Li-Shuang Hou
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Yao-Wen Zhang
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Hua Li
- Key Laboratory of Pharmacology of the State Administration of Traditional Chinese Medicine, Fourth Military Medical University, Xi'an 710032, China; Department of Natural Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Wei Wang
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Meng-Lei Huan
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China; Key Laboratory of Pharmacology of the State Administration of Traditional Chinese Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Si-Yuan Zhou
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China; Key Laboratory of Pharmacology of the State Administration of Traditional Chinese Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Bang-Le Zhang
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China; Key Laboratory of Pharmacology of the State Administration of Traditional Chinese Medicine, Fourth Military Medical University, Xi'an 710032, China.
| |
Collapse
|
|
36
|
Liu Z, Wang M, Wang X, Bu Q, Wang Q, Su W, Li L, Zhou H, Lu L. XBP1 deficiency promotes hepatocyte pyroptosis by impairing mitophagy to activate mtDNA-cGAS-STING signaling in macrophages during acute liver injury. Redox Biol 2022; 52:102305. [PMID: 35367811 PMCID: PMC8971356 DOI: 10.1016/j.redox.2022.102305] [Citation(s) in RCA: 188] [Impact Index Per Article: 62.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/13/2022] [Accepted: 03/25/2022] [Indexed: 12/23/2022] Open
Abstract
Hepatocellular cell death and macrophage proinflammatory activation contribute to the pathology of various liver diseases, during which XBP1 plays an important role. However, the function and mechanism of XBP1 in thioacetamide (TAA)-induced acute liver injury (ALI) remains unknown. Here, we investigated the effects of XBP1 inhibition on promoting hepatocellular pyroptosis to activate macrophage STING signaling during ALI. While both TAA- and LPS-induced ALI triggered XBP1 activation in hepatocytes, hepatocyte-specific XBP1 knockout mice exhibited exacerbated ALI with increased hepatocellular pyroptosis and enhanced macrophage STING activation. Mechanistically, mtDNA released from TAA-stressed hepatocytes could be engulfed by macrophages, further inducing macrophage STING activation in a cGAS- and dose-dependent manner. XBP1 deficiency increased ROS production to promote hepatocellular pyroptosis by activating NLRP3/caspase-1/GSDMD signaling, which facilitated the extracellular release of mtDNA. Moreover, impaired mitophagy was found in XBP1 deficient hepatocytes, which was reversed by PINK1 overexpression. Mitophagy restoration also inhibited macrophage STING activation and ALI in XBP1 deficient mice. Activation of XBP1-mediated hepatocellular mitophagy and pyroptosis and macrophage STING signaling pathway were observed in human livers with ALI. Collectively, these findings demonstrate that XBP1 deficiency promotes hepatocyte pyroptosis by impairing mitophagy to activate mtDNA/cGAS/STING signaling of macrophages, providing potential therapeutic targets for ALI.
Collapse
Affiliation(s)
- Zheng Liu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Mingming Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Xun Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Qingfa Bu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Qi Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; School of Medicine, Southeast University, Nanjing, China
| | - Wantong Su
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Lei Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Haoming Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
| | - Ling Lu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
| |
Collapse
|
|
37
|
Leonurine Protects Bone Mesenchymal Stem Cells from Oxidative Stress by Activating Mitophagy through PI3K/Akt/mTOR Pathway. Cells 2022; 11:cells11111724. [PMID: 35681421 PMCID: PMC9179429 DOI: 10.3390/cells11111724] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 05/08/2022] [Accepted: 05/20/2022] [Indexed: 02/06/2023] Open
Abstract
Osteoporosis bears an imbalance between bone formation and resorption, which is strongly related to oxidative stress. The function of leonurine on bone marrow-derived mesenchymal stem cells (BMSCs) under oxidative stress is still unclear. Therefore, this study was aimed at identifying the protective effect of leonurine on H2O2 stimulated rat BMSCs. We found that leonurine can alleviate cell apoptosis and promote the differentiation ability of rat BMSCs induced by oxidative stress at an appropriate concentration at 10 μM. Meanwhile, the intracellular ROS level and the level of the COX2 and NOX4 mRNA decreased after leonurine treatment in vitro. The ATP level and mitochondrial membrane potential were upregulated after leonurine treatment. The protein level of PINK1 and Parkin showed the same trend. The mitophage in rat BMSCs blocked by 3-MA was partially rescued by leonurine. Bioinformatics analysis and leonurine-protein coupling provides a strong direct combination between leonurine and the PI3K protein at the position of Asp841, Glu880, Val882. In conclusion, leonurine protects the proliferation and differentiation of BMSCs from oxidative stress by activating mitophagy, which depends on the PI3K/Akt/mTOR pathway. The results showed that leonurine may have potential usage in osteoporosis and bone defect repair in osteoporosis patients.
Collapse
|
|
38
|
Flessa C, Kyrou I, Nasiri‐Ansari N, Kaltsas G, Kassi E, Randeva HS. Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD). J Cell Biochem 2022; 123:1585-1606. [PMID: 35490371 DOI: 10.1002/jcb.30247] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/09/2022] [Accepted: 03/28/2022] [Indexed: 02/06/2023]
Affiliation(s)
- Christina‐Maria Flessa
- Department of Biological Chemistry, Medical School National and Kapodistrian University of Athens Athens Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) University Hospitals Coventry and Warwickshire NHS Trust Coventry UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) University Hospitals Coventry and Warwickshire NHS Trust Coventry UK
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School University of Warwick Coventry UK
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing Coventry University Coventry UK
- Aston Medical School, College of Health and Life Sciences Aston University Birmingham UK
- Department of Food Science & Human Nutrition Agricultural University of Athens Athens Greece
| | - Narjes Nasiri‐Ansari
- Department of Biological Chemistry, Medical School National and Kapodistrian University of Athens Athens Greece
| | - Gregory Kaltsas
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital National and Kapodistrian University of Athens Athens Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School National and Kapodistrian University of Athens Athens Greece
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital National and Kapodistrian University of Athens Athens Greece
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) University Hospitals Coventry and Warwickshire NHS Trust Coventry UK
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School University of Warwick Coventry UK
| |
Collapse
|
|
39
|
Yu X, Elfimova N, Müller M, Bachurski D, Koitzsch U, Drebber U, Mahabir E, Hansen HP, Friedman SL, Klein S, Dienes HP, Hösel M, Buettner R, Trebicka J, Kondylis V, Mannaerts I, Odenthal M. Autophagy-Related Activation of Hepatic Stellate Cells Reduces Cellular miR-29a by Promoting Its Vesicular Secretion. Cell Mol Gastroenterol Hepatol 2022; 13:1701-1716. [PMID: 35219894 PMCID: PMC9046234 DOI: 10.1016/j.jcmgh.2022.02.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 02/16/2022] [Accepted: 02/17/2022] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Liver fibrosis arises from long-term chronic liver injury, accompanied by an accelerated wound healing response with interstitial accumulation of extracellular matrix (ECM). Activated hepatic stellate cells (HSC) are the main source for ECM production. MicroRNA29a (miR-29a) is a crucial antifibrotic miRNA that is repressed during fibrosis, resulting in up-regulation of collagen synthesis. METHODS Intracellular and extracellular miRNA levels of primary and immortalized myofibroblastic HSC in response to profibrogenic stimulation by transforming growth factor β (TGFβ) or platelet-derived growth factor-BB (PDGF-BB) or upon inhibition of vesicular transport and autophagy processes were determined by quantitative polymerase chain reaction. Autophagy flux was studied by electron microscopy, flow cytometry, immunoblotting, and immunocytochemistry. Hepatic and serum miR-29a levels were quantified by using both liver tissue and serum samples from a cohort of chronic hepatitis C virus patients and a murine CCl4 induced liver fibrosis model. RESULTS In our study, we show that TGFβ and PDGF-BB resulted in decrease of intracellular miR-29a and a pronounced increase of vesicular miR-29a release into the supernatant. Strikingly, miR-29a vesicular release was accompanied by enhanced autophagic activity and up-regulation of the autophagy marker protein LC3. Moreover, autophagy inhibition strongly prevented miR-29a secretion and repressed its targets' expression such as Col1A1. Consistently, hepatic miR-29a loss and increased LC3 expression in myofibroblastic HSC were associated with increased serum miR-29a levels in CCl4-treated murine liver fibrosis and specimens of hepatitis C virus patients with chronic liver disease. CONCLUSIONS We provide evidence that activation-associated autophagy in HSC induces release of miR-29a, whereas inhibition of autophagy represses fibrogenic gene expression in part through attenuated miR-29a secretion.
Collapse
Affiliation(s)
- Xiaojie Yu
- Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Natalia Elfimova
- Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Marion Müller
- Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Daniel Bachurski
- Department I of Internal Medicine, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Ulrike Koitzsch
- Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Uta Drebber
- Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center of Integrative Oncology, University Clinic of Cologne and Bonn, Germany
| | - Esther Mahabir
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Hinrich P Hansen
- Department I of Internal Medicine, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center of Integrative Oncology, University Clinic of Cologne and Bonn, Germany
| | - Scott L Friedman
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Sabine Klein
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany
| | - Hans Peter Dienes
- Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Marianna Hösel
- Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Reinhard Buettner
- Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Center of Integrative Oncology, University Clinic of Cologne and Bonn, Germany
| | - Jonel Trebicka
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany; European Foundation for the Study of Chronic Liver Failure - EF CLIF, Barcelona, Spain
| | - Vangelis Kondylis
- Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Inge Mannaerts
- Liver Cell Biology Research Group, Vrije Universiteit Brussel, Brussel, Belgium.
| | - Margarete Odenthal
- Institute for Pathology, Medical Faculty and University Hospital of Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Center of Integrative Oncology, University Clinic of Cologne and Bonn, Germany.
| |
Collapse
|
|
40
|
Li Y, Mi P, Wu J, Tang Y, Liu X, Cheng J, Huang Y, Qin W, Cheng CY, Sun F. High Throughput scRNA-Seq Provides Insights Into Leydig Cell Senescence Induced by Experimental Autoimmune Orchitis: A Prominent Role of Interstitial Fibrosis and Complement Activation. Front Immunol 2022; 12:771373. [PMID: 35111154 PMCID: PMC8801941 DOI: 10.3389/fimmu.2021.771373] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 12/16/2021] [Indexed: 12/28/2022] Open
Abstract
Leydig cells (Lc), located in the interstitial space of the testis between seminiferous tubules, produce 95% of testosterone in male individuals, which is pivotal for male sexual differentiation, spermatogenesis, and maintenance of the male secondary sex characteristics. Lc are prone to senescence in aging testes, resulting in compromised androgen synthesis capability upon aging. However, little is known about whether Lc undergo senescence in a chronic inflammatory environment. To investigate this question, mouse models of experimental autoimmune orchitis (EAO) were used, and Lc were analyzed by high throughput scRNA-Seq. Data were screened and analyzed by correlating signaling pathways with senescence, apoptosis, androgen synthesis, and cytokine/chemokine signaling pathways. EAO did induce Lc senescence, and Lc senescence in turn antagonized androgen synthesis. Based on the correlation screening of pathways inducing Lc senescence, a plethora of pathways were found to play potential roles in triggering Lc senescence during EAO, among which the Arf6 and angiopoietin receptor pathways were highly correlated with senescence signature. Notably, complement and interstitial fibrosis activated by EAO worsened Lc senescence and strongly antagonized androgen synthesis. Furthermore, most proinflammatory cytokines enhanced both senescence and apoptosis in Lc and spermatogonia (Sg) during EAO, and proinflammatory cytokine antagonism of the glutathione metabolism pathway may be key in inducing cellular senescence during EAO.
Collapse
Affiliation(s)
- Yinchuan Li
- Institute of Reproductive Medicine, Medical School of Nantong University, Nantong, China.,NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, China
| | - Panpan Mi
- Institute of Reproductive Medicine, Medical School of Nantong University, Nantong, China
| | - Jiabao Wu
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, China
| | - Yunge Tang
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, China
| | - Xiaohua Liu
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, China
| | - Jinmei Cheng
- Institute of Reproductive Medicine, Medical School of Nantong University, Nantong, China
| | - Yingying Huang
- Institute of Reproductive Medicine, Medical School of Nantong University, Nantong, China
| | - Weibing Qin
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, China
| | - C Yan Cheng
- The Mary M. Wohlford Laboratory for Male Contraceptive Research, Center for Biomedical Research, Population Council, New York, NY, United States
| | - Fei Sun
- Institute of Reproductive Medicine, Medical School of Nantong University, Nantong, China
| |
Collapse
|
|
41
|
Zhou JC, Wang JL, Ren HZ, Shi XL. Autophagy plays a double-edged sword role in liver diseases. J Physiol Biochem 2022; 78:9-17. [PMID: 34657993 PMCID: PMC8873123 DOI: 10.1007/s13105-021-00844-7] [Citation(s) in RCA: 9] [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: 06/01/2021] [Accepted: 09/07/2021] [Indexed: 12/12/2022]
Abstract
As a highly evolutionarily conserved process, autophagy can be found in all types of eukaryotic cells. Such a constitutive process maintains cellular homeostasis in a wide variety of cell types through the encapsulation of damaged proteins or organelles into double-membrane vesicles. Autophagy not only simply eliminates materials but also serves as a dynamic recycling system that produces new building blocks and energy for cellular renovation and homeostasis. Previous studies have primarily recognized the role of autophagy in the degradation of dysfunctional proteins and unwanted organelles. However, there are findings of autophagy in physiological and pathological processes. In hepatocytes, autophagy is not only essential for homeostatic functions but also implicated in some diseases, such as viral hepatitis, alcoholic hepatitis, and hepatic failure. In the present review, we summarized the molecular mechanisms of autophagy and its role in several liver diseases and put forward several new strategies for the treatment of liver disease.
Collapse
Affiliation(s)
- Jing-Chao Zhou
- Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jing-Lin Wang
- Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Hao-Zhen Ren
- Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
| | - Xiao-Lei Shi
- Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
- Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
| |
Collapse
|
|
42
|
Zhang X, Huang C, Yuan Y, Jin S, Zhao J, Zhang W, Liang H, Chen X, Zhang B. FOXM1-mediated activation of phospholipase D1 promotes lipid droplet accumulation and reduces ROS to support paclitaxel resistance in metastatic cancer cells. Free Radic Biol Med 2022; 179:213-228. [PMID: 34808333 DOI: 10.1016/j.freeradbiomed.2021.11.024] [Citation(s) in RCA: 9] [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: 10/09/2021] [Revised: 11/16/2021] [Accepted: 11/17/2021] [Indexed: 12/25/2022]
Abstract
Chemoresistance is a major challenge for the treatment of cancer with metastasis. We investigated the mechanisms of lipid metabolites involved in drug resistance. Here, metastatic cancer cells isolated from mouse models were resistant to paclitaxel treatment in vitro and in vivo when compared with parental cancer cells. FOXM1, an oncogenic transcriptional factor, was highly expressed in metastatic cancer cells, and overexpression of FOXM1 conferred parental cancer cells resistance to paclitaxel. Lipidomic analysis showed that FOXM1 increased unsaturated triglyceride (TG) and phosphatidylcholine (PC) abundance, which are the main components of lipid droplet (LD). Inhibition of LD formation sensitized cells to paclitaxel. Mechanistically, the enzyme phospholipase D1 (PLD1) was identified as a potential effector target of FOXM1. PLD1 promoted LD accumulation, which reduced the level of reactive oxygen species (ROS) and maintained endoplasmic reticulum (ER) homeostasis in resistant cells with the treatment of paclitaxel. Moreover, inhibition of PLD1 reversed FOXM1-conferred paclitaxel resistance in vitro and in vivo. This study, for the first time, reveals the role of FOXM1-mediated PLD1 in LD accumulation and paclitaxel resistance. Targeting PLD1 or LD formation may help reverse chemoresistance in metastatic cancer cells. Generally, our results identified FOXM1 as a driver of paclitaxel resistance via activation of PLD1 to promote of LD accumulation, which contributes to the maintenace of ER homeostasis when metastatic cancer cells are confronted with ROS induced by paclitaxel.
Collapse
Affiliation(s)
- Xin Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Chao Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yue Yuan
- Division of Gastroenterology, Department of Internal Medicine at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Sanshan Jin
- Department of Traditional Chinese Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, China
| | - Jianping Zhao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Hepato-Pancreato-Biliary Disease, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, 430030, China.
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Hepato-Pancreato-Biliary Disease, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, 430030, China.
| |
Collapse
|
|
43
|
Duwaerts CC, Maiers JL. ER Disposal Pathways in Chronic Liver Disease: Protective, Pathogenic, and Potential Therapeutic Targets. Front Mol Biosci 2022; 8:804097. [PMID: 35174209 PMCID: PMC8841999 DOI: 10.3389/fmolb.2021.804097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 11/18/2021] [Indexed: 11/13/2022] Open
Abstract
The endoplasmic reticulum is a central player in liver pathophysiology. Chronic injury to the ER through increased lipid content, alcohol metabolism, or accumulation of misfolded proteins causes ER stress, dysregulated hepatocyte function, inflammation, and worsened disease pathogenesis. A key adaptation of the ER to resolve stress is the removal of excess or misfolded proteins. Degradation of intra-luminal or ER membrane proteins occurs through distinct mechanisms that include ER-associated Degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD), which includes macro-ER-phagy, micro-ER-phagy, and Atg8/LC-3-dependent vesicular delivery. All three of these processes are critical for removing misfolded or unfolded protein aggregates, and re-establishing ER homeostasis following expansion/stress, which is critical for liver function and adaptation to injury. Despite playing a key role in resolving ER stress, the contribution of these degradative processes to liver physiology and pathophysiology is understudied. Analysis of publicly available datasets from diseased livers revealed that numerous genes involved in ER-related degradative pathways are dysregulated; however, their roles and regulation in disease progression are not well defined. Here we discuss the dynamic regulation of ER-related protein disposal pathways in chronic liver disease and cell-type specific roles, as well as potentially targetable mechanisms for treatment of chronic liver disease.
Collapse
Affiliation(s)
- Caroline C. Duwaerts
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Jessica L. Maiers
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
| |
Collapse
|
|
44
|
Solhi R, Lotfi AS, Lotfinia M, Farzaneh Z, Piryaei A, Najimi M, Vosough M. Hepatic stellate cell activation by TGFβ induces hedgehog signaling and endoplasmic reticulum stress simultaneously. Toxicol In Vitro 2022; 80:105315. [PMID: 35051607 DOI: 10.1016/j.tiv.2022.105315] [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: 11/30/2021] [Revised: 01/07/2022] [Accepted: 01/11/2022] [Indexed: 12/11/2022]
Abstract
Activation of hepatic stellates (HSCs) is known as the major cause of initiation and progression of liver fibrosis. A wide array of events occurs during HSC activation including induction of hedgehog (Hh) signaling and endoplasmic reticulum (ER) stress. Targeting HSC activation may provide promising insights into liver fibrosis treatment. In this regard, establishing in vitro models which can mimic the molecular pathways of interest is very important. We aimed to activate HSC in which Hh signaling and ER stress are stimulated simultaneously. We used 5 ng/ml TGFβ to activate LX-2 cells, HSC cell line. Gene expression analysis using qRT-PCR, immunostaining and immunoblotting were performed to show HSC activation associated markers. Furthermore, the migration capacity of the TGFβ treated cells is evaluated. The results demonstrated that major fibrogenic markers including collagen1a, lysyl oxidase, and tissue inhibitor of matrix metalloproteinase 1 genes are up-regulated significantly. In addition, our immunofluorescence and immunoblotting results showed that protein levels of GLI-2 and XBP1, were enhanced. Moreover, we found that TGFβ treatment reduced the migration of LX-2 cells. Our results are compatible with high throughput data analysis with respect to differentially expressed genes of activated HSC compared to the quiescent ones. Moreover, our findings suggest that quercetin can reduce fibrogenic markers of activated HSCs as well as osteopontin expression, a target gene of hedgehog signaling.
Collapse
Affiliation(s)
- Roya Solhi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Abbas Sahebghadam Lotfi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Majid Lotfinia
- Physiology Research Center, Basic Sciences Research Institute, Kashan University of Medical Sciences, Kashan, Iran; Core Research Lab, Kashan University of Medical Sciences, Kashan, Iran
| | - Zahra Farzaneh
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 1665659911, Iran
| | - Abbas Piryaei
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 1665659911, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
| | - Massoud Vosough
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 1665659911, Iran; Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran.
| |
Collapse
|
|
45
|
Gu L, Zhang F, Wu J, Zhuge Y. Nanotechnology in Drug Delivery for Liver Fibrosis. Front Mol Biosci 2022; 8:804396. [PMID: 35087870 PMCID: PMC8787125 DOI: 10.3389/fmolb.2021.804396] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 12/17/2021] [Indexed: 12/15/2022] Open
Abstract
Liver fibrosis is a reversible disease course caused by various liver injury etiologies, and it can lead to severe complications, such as liver cirrhosis, liver failure, and even liver cancer. Traditional pharmacotherapy has several limitations, such as inadequate therapeutic effect and side effects. Nanotechnology in drug delivery for liver fibrosis has exhibited great potential. Nanomedicine improves the internalization and penetration, which facilitates targeted drug delivery, combination therapy, and theranostics. Here, we focus on new targets and new mechanisms in liver fibrosis, as well as recent designs and development work of nanotechnology in delivery systems for liver fibrosis treatment.
Collapse
Affiliation(s)
- Lihong Gu
- Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Feng Zhang
- Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jinhui Wu
- State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center, Medical School of Nanjing University, Nanjing, China
- Jiangsu Key Laboratory for Nano Technology, Nanjing University, Nanjing, China
| | - Yuzheng Zhuge
- Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| |
Collapse
|
|
46
|
Alegre F, Martí-Rodrigo A, Polo M, Ortiz-Masiá D, Bañuls C, Pinti M, Álvarez Á, Apostolova N, Esplugues JV, Blas-García A. Macrophages Modulate Hepatic Injury Involving NLRP3 Inflammasome: The Example of Efavirenz. Biomedicines 2022; 10:biomedicines10010109. [PMID: 35052789 PMCID: PMC8772956 DOI: 10.3390/biomedicines10010109] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/22/2021] [Accepted: 12/30/2021] [Indexed: 02/04/2023] Open
Abstract
Drug-induced liver injury (DILI) constitutes a clinical challenge due to the incomplete characterization of the mechanisms involved and potential risk factors. Efavirenz, an anti-HIV drug, induces deleterious actions in hepatocytes that could underlie induction of the NLRP3 inflammasome, an important regulator of inflammatory responses during liver injury. We assessed the potential of efavirenz to modulate the inflammatory and fibrogenic responses of major liver cell types involved in DILI. The effects of efavirenz were evaluated both in vitro and in vivo. Efavirenz triggered inflammation in hepatocytes, in a process that involved NF-κB and the NLRP3 inflammasome, and activated hepatic stellate cells (HSCs), thereby enhancing expression of inflammatory and fibrogenic markers. The NLRP3 inflammasome was not altered in efavirenz-treated macrophages, but these cells polarized towards the anti-inflammatory M2 phenotype and displayed upregulated anti-inflammatory mediators. Conversely, no evidence of damage was observed in efavirenz-treated animals, except when macrophages were depleted, which resulted in the in vivo manifestation of the deleterious effects detected in hepatocytes and HSCs. Efavirenz elicits a cell-specific activation of the NLRP3 inflammasome in hepatocytes and HSCs, but macrophages appear to counteract efavirenz-induced liver injury. Our results highlight the dynamic nature of the interaction among liver cell populations and emphasize the potential of targeting macrophage polarization as a strategy to treat NLRP3 inflammasome-induced liver injury.
Collapse
Affiliation(s)
- Fernando Alegre
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
- Servicio de Endocrinología, FISABIO-Hospital Universitario Dr. Peset, 46017 Valencia, Spain
| | - Alberto Martí-Rodrigo
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
| | - Miriam Polo
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
- Servicio de Endocrinología, FISABIO-Hospital Universitario Dr. Peset, 46017 Valencia, Spain
| | - Dolores Ortiz-Masiá
- Departamento de Medicina, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), 46010 Valencia, Spain
| | - Celia Bañuls
- Servicio de Endocrinología, FISABIO-Hospital Universitario Dr. Peset, 46017 Valencia, Spain
| | - Marcello Pinti
- Department of Life Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Ángeles Álvarez
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), 46010 Valencia, Spain
| | - Nadezda Apostolova
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
- Servicio de Endocrinología, FISABIO-Hospital Universitario Dr. Peset, 46017 Valencia, Spain
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), 46010 Valencia, Spain
| | - Juan V Esplugues
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
- Servicio de Endocrinología, FISABIO-Hospital Universitario Dr. Peset, 46017 Valencia, Spain
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), 46010 Valencia, Spain
| | - Ana Blas-García
- Servicio de Endocrinología, FISABIO-Hospital Universitario Dr. Peset, 46017 Valencia, Spain
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), 46010 Valencia, Spain
- Departamento de Fisiología, Universidad de Valencia, 46010 Valencia, Spain
| |
Collapse
|
|
47
|
Li M, Yang L. Autophagy in the liver. AUTOPHAGY IN HEALTH AND DISEASE 2022:161-179. [DOI: 10.1016/b978-0-12-822003-0.00014-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
48
|
Xiong Y, Hu J, Xuan C, Tian J, Tan K, Chen Z, Luo Y, Du X, Cheng J, Zhang L, Cao W. Transcriptome analysis reveals the molecular mechanism of Yiqi Rougan decoction in reducing CCl 4-induced liver fibrosis in rats. Chin Med 2021; 16:142. [PMID: 34952623 PMCID: PMC8709947 DOI: 10.1186/s13020-021-00552-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 12/09/2021] [Indexed: 12/13/2022] Open
Abstract
Background Liver fibrosis develops from various chronic liver diseases, and there is currently a lack of specific treatment strategies. Yiqi Rougan decoction (YQRG) is a traditional Chinese medicine that has shown durative effects in the treatment of liver fibrosis; however, the mechanism associated with YQRG-related improvements in liver fibrosis remains to be experimentally determined. This study evaluated the therapeutic effect of YQRG on carbon tetrachloride (CCl4)-induced liver fibrosis in rats and its molecular mechanism. Methods We used low-, medium-, and high-dose YQRG to treat CCl4-induced liver fibrosis in rats, followed by assessment of liver injury and fibrosis according to liver appearance, body weight, liver mass index, histopathologic examination, and serum testing. Additionally, we performed transcriptome analysis using RNA-sequencing (RNA-seq) technology, including cluster, Gene Ontology (GO), and pathway analyses, to identify differentially expressed genes (DEGs), and protein and gene expression were detected by immunofluorescence (IFC), western blot and real-time quantitative PCR. Results The results showed that YQRG effectively alleviated CCl4-induced liver injury and fibrosis in rats, including observations of improved liver function, decreased activity of hepatic stellate cells (HSCs), and decreased extracellular matrix (ECM) deposition. Moreover, we identified downregulated and upregulated DEGs in the model group relative to the control and YQRG-treated groups, with GO analysis revealing their enrichment in biological processes, such as endoplasmic reticulum stress (ERS), apoptosis, and autophagy. Furthermore, pathway analysis showed that YQRG treatment downregulated the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/Akt (PI3K/AKT) signalling pathways and upregulated other signalling pathways, including those related to peroxisome proliferator-activated receptors(PPAR) and AMP-activated protein kinase(AMPK), with these findings subsequently verified experimentally. Conclusion These findings showed that YQRG improved CCl4-induced liver fibrosis through multiple mechanisms and pathways, offering critical insight into the YQRG-related therapeutic mechanism and promoting further research into its potential application. Supplementary Information The online version contains supplementary material available at 10.1186/s13020-021-00552-w.
Collapse
Affiliation(s)
- Yu Xiong
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Jinyuan Hu
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Chen Xuan
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Jiayu Tian
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Kaiyue Tan
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Zhiwei Chen
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Yan Luo
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China.,Department of Kidney Disease, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400021, China
| | - Xuqin Du
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Junxiong Cheng
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Lanyue Zhang
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China.,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China
| | - Wenfu Cao
- College of Traditional Chinese Medicine, Chongqing Medical University, No. 1 Medical College Road, Yuzhong District, Chongqing, 400016, China. .,Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing, 400016, China. .,Department of Combination of Chinese and Western Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
| |
Collapse
|
|
49
|
Fan C, Ma Y, Chen S, Zhou Q, Jiang H, Zhang J, Wu F. Comprehensive Analysis of the Transcriptome-Wide m6A Methylation Modification Difference in Liver Fibrosis Mice by High-Throughput m6A Sequencing. Front Cell Dev Biol 2021; 9:767051. [PMID: 34869362 PMCID: PMC8635166 DOI: 10.3389/fcell.2021.767051] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/01/2021] [Indexed: 01/01/2023] Open
Abstract
N6-Methyladenosine (m6A), a unique and common mRNA modification method in eukaryotes, is involved in the occurrence and development of many diseases. Liver fibrosis (LF) is a common response to chronic liver injury and may lead to cirrhosis and even liver cancer. However, the involvement of m6A methylation in the development of LF is still unknown. In this study, we performed a systematic evaluation of hepatic genome-wide m6A modification and mRNA expression by m6A-seq and RNA-seq using LF mice. There were 3,315 genes with significant differential m6A levels, of which 2,498 were hypermethylated and 817 hypomethylated. GO and KEGG analyses illustrated that differentially expressed m6A genes were closely correlated with processes such as the endoplasmic reticulum stress response, PPAR signaling pathway and TGF-β signaling pathway. Moreover, a total of 90 genes had both a significant change in the m6A level and mRNA expression shown by joint analysis of m6A-seq and RNA-seq. Hence, the critical elements of m6A modification, including methyltransferase WTAP, demethylases ALKBH5 and binding proteins YTHDF1 were confirmed by RT-qPCR and Western blot. In an additional cell experiment, we also observed that the decreased expression of WTAP induced the development of LF as a result of promoting hepatic stellate cell (HSC) activation. Therefore, this study revealed unique differential m6A methylation patterns in LF mice and suggested that m6A methylation was associated with the occurrence and course of LF to some extent.
Collapse
Affiliation(s)
- Chang Fan
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.,School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
| | - Yanzhen Ma
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.,School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
| | - Sen Chen
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.,School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
| | - Qiumei Zhou
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Hui Jiang
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.,School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.,Key Laboratory of Xin'an Medicine of the Ministry of Education, Anhui University of Chinese Medicine, Hefei, China
| | - Jiafu Zhang
- Department of Pharmacy, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Furong Wu
- Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| |
Collapse
|
|
50
|
Shu S, Wang H, Zhu J, Liu Z, Yang D, Wu W, Cai J, Chen A, Tang C, Dong Z. Reciprocal regulation between ER stress and autophagy in renal tubular fibrosis and apoptosis. Cell Death Dis 2021; 12:1016. [PMID: 34716302 PMCID: PMC8556380 DOI: 10.1038/s41419-021-04274-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 10/01/2021] [Accepted: 10/05/2021] [Indexed: 02/07/2023]
Abstract
Both endoplasmic reticulum (ER) stress and autophagy have been implicated in chronic kidney injury and renal fibrosis. However, the relationship and regulatory mechanisms between ER stress and autophagy under this condition remain largely unknown. In this study, we first established a mouse model of ER stress-induced chronic kidney injury by 2 weekly injections of a low dose of tunicamycin (TM), a classical ER stress inducer. This model showed the induction of ER stress, autophagy, fibrosis and apoptosis in kidney tissues. In vitro, TM also induced ER stress, autophagy, fibrosis and apoptosis in HK-2 human kidney proximal tubular cells and BUMPT-306 mouse kidney proximal tubular cells. In these cells, autophagy inhibitor suppressed TM-induced fibrotic changes and apoptosis, suggesting an involvement of autophagy in ER stress-associated chronic kidney injury. PERK inhibitor ameliorated autophagy, fibrotic protein expression and apoptosis in TM-treated cells, indicating a role of the PERK/eIF2α pathway in autophagy activation during ER stress. Similar results were shown in TGF-β1-treated HK-2 cells. Interestingly, in both TM- or TGF-β1-treated kidney proximal tubular cells, inhibition of autophagy exaggerated ER stress, suggesting that autophagy induced by ER stress provides a negative feedback mechanism to reduce the stress. Together, these results unveil a reciprocal regulation between ER stress and autophagy in chronic kidney injury and fibrosis.
Collapse
Affiliation(s)
- Shaoqun Shu
- grid.452708.c0000 0004 1803 0208Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011 China
| | - Hui Wang
- grid.452708.c0000 0004 1803 0208Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011 China
| | - Jiefu Zhu
- grid.452708.c0000 0004 1803 0208Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011 China
| | - Zhiwen Liu
- grid.452708.c0000 0004 1803 0208Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011 China
| | - Danyi Yang
- grid.452708.c0000 0004 1803 0208Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011 China
| | - Wenwen Wu
- grid.452708.c0000 0004 1803 0208Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011 China
| | - Juan Cai
- grid.452708.c0000 0004 1803 0208Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011 China
| | - Anqun Chen
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011, China.
| | - Chengyuan Tang
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011, China.
| | - Zheng Dong
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011, China. .,Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA.
| |
Collapse
|