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Hansen D, Jensen JER, Andersen CAT, Jakobsgaard PR, Havelund J, Lauritsen L, Mandacaru S, Siersbaek M, Shackleton OL, Inoue H, Brewer JR, Schwabe RF, Blagoev B, Færgeman NJ, Salmi M, Ravnskjaer K. Hepatic stellate cells regulate liver fatty acid utilization via plasmalemma vesicle-associated protein. Cell Metab 2025; 37:971-986.e8. [PMID: 40037362 DOI: 10.1016/j.cmet.2025.01.022] [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: 11/26/2024] [Accepted: 01/24/2025] [Indexed: 03/06/2025]
Abstract
The liver is essential for normal fatty acid utilization during fasting. Circulating fatty acids are taken up by hepatocytes and esterified as triacylglycerols for either oxidative metabolization and ketogenesis or export. Whereas the regulation of fatty acid oxidation in hepatocytes is well understood, the uptake and retention of non-esterified fatty acids by hepatocytes is not. Here, we show that murine hepatic stellate cells (HSCs) and their abundantly expressed plasmalemma vesicle-associated protein (PLVAP) control hepatic substrate preference for fasting energy metabolism. HSC-specific ablation of PLVAP in mice elevated hepatic insulin signaling and improved glucose tolerance. Fasted HSC PLVAP knockout mice showed suppressed hepatic fatty acid esterification into di- and triacylglycerols, shifting fasting metabolism from fatty acid oxidation to reliance on carbohydrates. By super-resolution microscopy, we localized HSC PLVAP to caveolae residing along the sinusoidal lumen, supporting a role for HSCs and PLVAP-diaphragmed caveolae in normal fasting metabolism of the liver.
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Affiliation(s)
- Daniel Hansen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Jasmin E R Jensen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Christian A T Andersen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Peter R Jakobsgaard
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Jesper Havelund
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Line Lauritsen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Samuel Mandacaru
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Majken Siersbaek
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Oliver L Shackleton
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Hiroshi Inoue
- Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa 920-8641, Ishikawa, Japan
| | - Jonathan R Brewer
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Robert F Schwabe
- Department of Medicine, Columbia University, New York, NY 10032, USA; Institute of Human Nutrition, Columbia University, New York, NY 10032, USA
| | - Blagoy Blagoev
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark
| | - Nils J Færgeman
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - Marko Salmi
- MediCity Research Laboratory, University of Turku, 20014 Turku, Finland; Institute of Biomedicine, University of Turku, 20014 Turku, Finland; InFLAMES Research Flagship Centre, University of Turku, 20014 Turku, Finland
| | - Kim Ravnskjaer
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), University of Southern Denmark, 5230 Odense M, Denmark.
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Li B, Liu S, Han W, Song P, Sun H, Cao X, Di G, Chen P. Aquaporin five deficiency suppresses fatty acid oxidation and delays liver regeneration through the transcription factor PPAR. J Biol Chem 2025; 301:108303. [PMID: 39947476 PMCID: PMC11930093 DOI: 10.1016/j.jbc.2025.108303] [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: 10/07/2024] [Revised: 02/03/2025] [Accepted: 02/07/2025] [Indexed: 03/09/2025] Open
Abstract
After 70% partial hepatectomy (PHx), the metabolic pathways leading to hepatocyte lipid droplet accumulation during liver regeneration remain unclear. Aquaporin 5 (Aqp5) is an aquaporin that facilitates the transport of both water and hydrogen peroxide (H2O2). In this study, we observed delayed liver regeneration following PHx in Aqp5 knockout (Aqp5-/-) mice. Considering the role of Aqp5 in H2O2 transport, we hypothesized that deficiency in Aqp5 may induce oxidative stress and hepatocyte injury. Through the measurement of reactive oxygen species (ROS) and redox-related indices, we observed significant alterations in ROS levels as well as malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) concentrations in regenerating livers lacking Aqp5 compared to wild-type controls. Oil Red O and 4-hydroxynonenal (4-HNE) staining results indicated that Aqp5 deficiency caused lipid accumulation during liver regeneration. The transcriptome sequencing results showed that the PPAR pathway is inhibited during the liver regeneration process in Aqp5 gene-knockout mice. The administration of the WY-14643 agonist, which targets the PPAR pathway, significantly mitigated delayed liver regeneration by enhancing hepatocyte proliferation and reducing lipid accumulation caused by Aqp5 deficiency. Our findings highlight the crucial role of Aqp5 in regulating H2O2 levels and lipid metabolism through the PPAR pathway during liver regeneration.
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Affiliation(s)
- Bin Li
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China
| | - Shixu Liu
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China
| | - Wenshuo Han
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China
| | - Peirong Song
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China
| | - Hetong Sun
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China
| | - Xin Cao
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China.
| | - Guohu Di
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China; Institute of Stem Cell Regeneration Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China.
| | - Peng Chen
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China; Institute of Stem Cell Regeneration Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China; Department of Ophthalmology, Qingdao Eighth People's Hospital, Qingdao, Shandong Province, China.
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Lund A, Thomsen MT, Kirkegård J, Knudsen AR, Andersen KJ, Meier M, Nyengaard JR, Mortensen FV. Role of Steatosis in Preventing Post-hepatectomy Liver Failure After Major Resection: Findings From an Animal Study. J Clin Exp Hepatol 2025; 15:102453. [PMID: 39703722 PMCID: PMC11652769 DOI: 10.1016/j.jceh.2024.102453] [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: 04/05/2024] [Accepted: 11/05/2024] [Indexed: 12/21/2024] Open
Abstract
Background/Aim Post-hepatectomy liver failure (PHLF) and hepatic steatosis are evident shortly after extensive partial hepatectomy (PH) in rodents. This study aimed to extrapolate the protein expression and biological pathways involved in recovering PHLF (rPHLF) and non-recovering PHLF (nrPHLF). Methods Rats were randomly assigned to 90% PH or sham surgery. rPHLF was distinguished from nrPHLF using a quantitative scoring system. The sham (n = 6), rPHLF (n = 8), and nrPHLF (n = 13) groups were compared 24 h post-PH. Proteomics was used to assess protein variations and to investigate differentially regulated biological pathways. Stereological methods were used to quantify hepatic lipid content. The plasma triglyceride levels were measured. Results rPHLF demonstrated substantial downregulation of proteins involved in lipid metabolism compared to nrPHLF (P < 0.001). Several proteins associated with lipogenesis, beta-oxidation, lipolysis, membrane trafficking, and inhibition of cell proliferation were markedly downregulated in rPHLF.The hepatic lipid proportion was significantly higher for rPHLF (61% of hepatocyte volume, 95% confidence interval [CI]: 48%-82%) than for nrPHLF (32% of hepatocyte volume, 95% CI: 22%-39%). The median lipid volume per hepatocyte in rPHLF was 2815 μm3 (95% CI: 2208-3774 μm3) and 1759 μm3 in nrPHLF (95% CI: 1188-2134 μm3). Lipid droplets were not detected in the sham-operated rats. No significant differences in plasma triglyceride levels were found between the groups (P > 0.08). Conclusion The degree of hepatic steatosis is a promising prognostic indicator for early liver regeneration and nrPHLF onset immediately following extensive PH. Intrahepatic lipid accumulation appears to be linked to the coordinated downregulation of proteins integral to lipid metabolism and cellular transport.
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Affiliation(s)
- Andrea Lund
- Department of Surgery, Section for HPB Surgery, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Mikkel T. Thomsen
- Core Center for Molecular Morphology, Section for Stereology and Microscopy, Aarhus University, Denmark
| | - Jakob Kirkegård
- Department of Surgery, Section for HPB Surgery, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Anders R. Knudsen
- Department of Surgery, Section for HPB Surgery, Aarhus University Hospital, Aarhus, Denmark
| | - Kasper J. Andersen
- Department of Surgery, Section for HPB Surgery, Aarhus University Hospital, Aarhus, Denmark
| | - Michelle Meier
- Department of Surgery, Section for HPB Surgery, Aarhus University Hospital, Aarhus, Denmark
| | - Jens R. Nyengaard
- Core Center for Molecular Morphology, Section for Stereology and Microscopy, Aarhus University, Denmark
- Department of Pathology, Aarhus University Hospital, Denmark
| | - Frank V. Mortensen
- Department of Surgery, Section for HPB Surgery, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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Lund A, Andersen KH, Andersen KJ, Kirkegård J, Nyengaard JR, Mortensen FV. Exploring the dynamics of postoperative steatosis in the regenerating liver: An animal study. Surg Open Sci 2025; 24:66-69. [PMID: 40114677 PMCID: PMC11924926 DOI: 10.1016/j.sopen.2025.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Accepted: 02/18/2025] [Indexed: 03/22/2025] Open
Abstract
Introduction The rat model of 70 % partial hepatectomy (PH) is commonly used to investigate liver regeneration processes. The aim of this study was to explore the dynamics of hepatic lipid accumulation and its correlation with the proliferation response during the entire regeneration phase after 70 % PH in rats. Methods Sixty-four rats underwent 70 % PH and were randomly divided into eight groups for evaluation on post-operative day (POD) 1 to 8. Hepatocyte volume, relative lipid content, and lipid volume per hepatocyte were assessed by stereological analysis.Results: Lipid volume per hepatocyte reached its peak on POD 1 and POD 2, with mean values of 2895 μm3 (95 % CI: 1756-4034 μm3) and 3090 μm3 (95 % CI: 2277-3903 μm3), respectively. A marked decline was observed by POD 4, with a mean of 1323 μm3 (95 % CI: 985-1741 μm3), which continued through POD 5, reaching 619 μm3 (95 % CI: 136-1102 μm3). From POD 5 onwards, lipid volume remained consistently low, with no significant differences detected between POD 5 and POD 8. Conclusion Lipid accumulation and proliferation peak and decline concurrently, suggesting a strong correlation.
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Affiliation(s)
- Andrea Lund
- Department of Surgery, Section for HPB Surgery, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Katrine Holm Andersen
- Department of Surgery, Section for HPB Surgery, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | | | - Jakob Kirkegård
- Department of Surgery, Section for HPB Surgery, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Jens Randel Nyengaard
- Core Center for Molecular Morphology, Section for Stereology and Microscopy, Aarhus University, Denmark
- Department of Pathology, Aarhus University Hospital, Denmark
| | - Frank Viborg Mortensen
- Department of Surgery, Section for HPB Surgery, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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Ma X, Huang T, Chen X, Li Q, Liao M, Fu L, Huang J, Yuan K, Wang Z, Zeng Y. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics. Signal Transduct Target Ther 2025; 10:63. [PMID: 39920130 PMCID: PMC11806117 DOI: 10.1038/s41392-024-02104-8] [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: 11/08/2023] [Revised: 09/02/2024] [Accepted: 12/12/2024] [Indexed: 02/09/2025] Open
Abstract
Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.
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Affiliation(s)
- Xiao Ma
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tengda Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiangzheng Chen
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qian Li
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Mingheng Liao
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Fu
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiwei Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhen Wang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Yong Zeng
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Dong Q, Liu Z, Ma Y, Chen X, Wang X, Tang J, Ma K, Liang C, Wang M, Wu X, Liu Y, Zhou Y, Yang H, Gao M. Adipose tissue deficiency impairs transient lipid accumulation and delays liver regeneration following partial hepatectomy in male Seipin knockout mice. Clin Transl Med 2025; 15:e70238. [PMID: 39980067 PMCID: PMC11842221 DOI: 10.1002/ctm2.70238] [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: 10/08/2024] [Revised: 01/30/2025] [Accepted: 02/11/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND Liver diseases pose significant health challenges, underscoring the importance of understanding liver regeneration mechanisms. Systemic adipose tissue is thought to be a primary source of lipids and energy during this process; however, empirical data on the effects of adipose tissue deficiency are limited. This study investigates the role of adipose tissue in liver regeneration, focusing on transient regeneration-associated steatosis (TRAS) and hepatocyte proliferation using a Seipin knockout mouse model that mimics severe human lipodystrophy. Additionally, the study explores therapeutic strategies through adipose tissue transplantation. METHODS Male Seipin knockout (Seipin-/-) and wild-type (WT) mice underwent 2/3 partial hepatectomy (PHx). Liver and plasma samples were collected at various time points post-surgery. Histological assessments, lipid accumulation analyses and measurements of hepatocyte proliferation markers were conducted. Additionally, normal adipose tissue was transplanted into Seipin-/- mice to evaluate the restoration of liver regeneration. RESULTS Seipin-/- mice exhibited significantly reduced liver regeneration rates and impaired TRAS, as evidenced by histological and lipid measurements. While WT mice demonstrated extensive hepatocyte proliferation at 48 and 72 h post-PHx, characterised by increased mitotic cells, elevated proliferating cell nuclear antigen and Ki67 expression, Seipin-/- mice showed delayed hepatocyte proliferation. Notably, adipose tissue transplantation into Seipin-/- mice restored TRAS and improved liver regeneration and hepatocyte proliferation. Conversely, liver-specific overexpression of Seipin in Seipin-/- mice did not affect TRAS or liver regeneration, indicating that the observed effects are primarily due to adipose tissue deficiency rather than hepatic Seipin itself. CONCLUSIONS Systemic adipose tissue is essential for TRAS and effective liver regeneration following PHx. Its deficiency impairs these processes, while adipose tissue transplantation can restore normal liver function. These findings underscore the critical role of adipose tissue in liver recovery and suggest potential therapeutic strategies for liver diseases associated with lipodystrophies. KEY POINTS Seipin-/- mice, which lack adipose tissue, exhibit significantly impaired TRAS and delayed liver regeneration following partial hepatectomy. Transplantation of normal adipose tissue into Seipin-/- mice restores TRAS and enhances liver regeneration, highlighting the essential role of adipose tissue in these processes. Liver-specific overexpression of Seipin has no effect on TRAS and liver regeneration in Seipin-/- mice.
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Affiliation(s)
- Qianqian Dong
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education, The Key Laboratory of Vascular Biology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical UniversityShijiazhuangHebeiChina
- Department of Clinical LaboratoryThe Second Hospital of Hebei Medical UniversityShijiazhuangHebeiChina
| | - Ziwei Liu
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education, The Key Laboratory of Vascular Biology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical UniversityShijiazhuangHebeiChina
- Department of Clinical LaboratoryBethune International Peace HospitalShijiazhuangHebeiChina
| | - Yidan Ma
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education, The Key Laboratory of Vascular Biology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical UniversityShijiazhuangHebeiChina
| | - Xin Chen
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education, The Key Laboratory of Vascular Biology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical UniversityShijiazhuangHebeiChina
- Department of General SurgeryThe First Hospital of Hebei Medical UniversityShijiazhuangHebeiChina
| | - Xiaowei Wang
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education, The Key Laboratory of Vascular Biology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical UniversityShijiazhuangHebeiChina
| | - Jinye Tang
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education, The Key Laboratory of Vascular Biology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical UniversityShijiazhuangHebeiChina
| | - Kexin Ma
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education, The Key Laboratory of Vascular Biology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical UniversityShijiazhuangHebeiChina
| | - Chenxi Liang
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education, The Key Laboratory of Vascular Biology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical UniversityShijiazhuangHebeiChina
| | - Mengyu Wang
- Department of CardiologyFirst Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Xiaoqin Wu
- Department of Integrative Biology and PharmacologyUniversity of Texas Health Science Center at HoustonHoustonTexasUSA
| | - Yang Liu
- Department of Integrative Biology and PharmacologyUniversity of Texas Health Science Center at HoustonHoustonTexasUSA
| | - Yaru Zhou
- Department of EndocrinologyThe Third Hospital of Hebei Medical UniversityShijiazhuangHebeiChina
| | - Hongyuan Yang
- Department of Integrative Biology and PharmacologyUniversity of Texas Health Science Center at HoustonHoustonTexasUSA
| | - Mingming Gao
- Department of Biochemistry and Molecular BiologyThe Key Laboratory of Neural and Vascular BiologyMinistry of Education, The Key Laboratory of Vascular Biology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical UniversityShijiazhuangHebeiChina
- Department of Integrative Biology and PharmacologyUniversity of Texas Health Science Center at HoustonHoustonTexasUSA
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Li P, Zhou H, Yan R, Yan W, Yang L, Li T, Qin X, Zhou Y, Li L, Bao J, Li J, Li S, Liu Y. Aligned fibrous scaffolds promote directional migration of breast cancer cells via caveolin-1/YAP-mediated mechanosensing. Mater Today Bio 2024; 28:101245. [PMID: 39318372 PMCID: PMC11421348 DOI: 10.1016/j.mtbio.2024.101245] [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: 07/27/2024] [Revised: 09/11/2024] [Accepted: 09/13/2024] [Indexed: 09/26/2024] Open
Abstract
Tumorigenesis and metastasis are highly dependent on the interactions between the tumor and the surrounding microenvironment. In 3D matrix, the fibrous structure of the extracellular matrix (ECM) undergoes dynamic remodeling during tumor progression. In particular, during the late stage of tumor development, the fibers become more aggregated and oriented. However, it remains unclear how cancer cells respond to the organizational change of ECM fibers and exhibit distinct morphology and behavior. Here, we used electrospinning technology to fabricate biomimetic ECM with distinct fiber arrangements, which mimic the structural characteristics of normal or tumor tissues and found that aligned and oriented nanofibers induce cytoskeletal rearrangement to promote directed migration of cancer cells. Mechanistically, caveolin-1(Cav-1)-expressing cancer cells grown on aligned fibers exhibit increased integrin β1 internalization and actin polymerization, which promoted stress fiber formation, focal adhesion dynamics and YAP activity, thereby accelerating the directional cell migration. In general, the linear fibrous structure of the ECM provides convenient tracks on which tumor cells can invade and migrate. Moreover, histological data from both mice and patients with tumors indicates that tumor tissue exhibits a greater abundance of isotropic ECM fibers compared to normal tissue. And Cav-1 downregulation can suppress cancer cells muscle invasion through the inhibition of YAP-dependent mechanotransduction. Taken together, our findings revealed the Cav-1 is indispensable for the cellular response to topological change of ECM, and that the Cav-1/YAP axis is an attractive target for inhibiting cancer cell directional migration which induced by linearization of ECM fibers.
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Affiliation(s)
- Ping Li
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, PR China
| | - Hanying Zhou
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, PR China
| | - Ran Yan
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, PR China
| | - Wei Yan
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, PR China
| | - Lu Yang
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, PR China
| | - Tingting Li
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, PR China
| | - Xiang Qin
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, PR China
| | - Yanyan Zhou
- Department of Pathology, Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, PR China
| | - Li Li
- Department of Pathology, Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, PR China
| | - Ji Bao
- Department of Pathology, Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, PR China
| | - Junjie Li
- Breast Surgery Department, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, PR China
| | - Shun Li
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, PR China
| | - Yiyao Liu
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, PR China
- Traditional Chinese Medicine Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, Sichuan, PR China
- Department of Urology, Deyang People's Hospital, Deyang, 618099, Sichuan, PR China
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Xiong J, Chen S, Liu J. Acute liver steatosis signals the chromatin for regeneration via MIER1. Metabol Open 2024; 23:100258. [PMID: 39351485 PMCID: PMC11440081 DOI: 10.1016/j.metop.2023.100258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 09/21/2023] [Indexed: 10/04/2024] Open
Abstract
During liver regeneration, especially after a hepatectomy, hepatocytes experience significant lipid accumulation. These transiently accumulated lipids are generally believed to provide substrates for energy supply or membrane biomaterials for newly generated hepatocytes. Remarkably, a recent study found that acute lipid accumulation during regeneration can act as a signal for chromatin remodeling to regulate regeneration. Chen, Y.H., et al. identified MIER1 (mesoderm induction early response protein 1) as a crucial inhibitor of liver regeneration through in vivo CRISPR screening. MIER1 binds to and restrains cell cycle genes' expression. During liver regeneration, acute lipid accumulation suppresses MIER1 translation via the EIF2S pathway, resulting in transient down-regulation of MIER1 protein, which promotes cell cycle gene expression and liver regeneration. Interestingly, the researchers also found that the dynamic regulation of MIER1 was impaired in fatty and aging livers with chronic steatosis, while of knockout of MIER1 in these animals improved their regenerative capacity. In conclusion, this study provides valuable insights into the complex mechanisms underlying liver regeneration and highlights the potential therapeutic applications of targeting MIER1 for improving liver regeneration in disease states associated with impaired lipid homeostasis.
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Affiliation(s)
- Jie Xiong
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Suzhen Chen
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junli Liu
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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9
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Qin M, Ou R, He W, Han H, Zhang Y, Huang Y, Chen Z, Pan X, Chi Y, He S, Gao L. Salvianolic acid B enhances tissue repair and regeneration by regulating immune cell migration and Caveolin-1-mediated blastema formation in zebrafish. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 130:155553. [PMID: 38820664 DOI: 10.1016/j.phymed.2024.155553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 02/01/2024] [Accepted: 03/19/2024] [Indexed: 06/02/2024]
Abstract
INTRODUCTION Non-healing wounds resulting from trauma, surgery, and chronic diseases annually affect millions of individuals globally, with limited therapeutic strategies available due to the incomplete understanding of the molecular processes governing tissue repair and regeneration. Salvianolic acid B (Sal B) has shown promising bioactivities in promoting angiogenesis and inhibiting inflammation. However, its regulatory mechanisms in tissue regeneration remain unclear. PURPOSE This study aims to investigate the effects of Sal B on wound healing and regeneration processes, along with its underlying molecular mechanisms, by employing zebrafish as a model organism. METHODS In this study, we employed a multifaceted approach to evaluate the impact of Sal B on zebrafish tail fin regeneration. We utilized whole-fish immunofluorescence, TUNEL staining, mitochondrial membrane potential (MMP), and Acridine Orange (AO) probes to analyze the tissue repair and regenerative under Sal B treatment. Additionally, we utilized transgenic zebrafish strains to investigate the migration of inflammatory cells during different phases of fin regeneration. To validate the importance of Caveolin-1 (Cav1) in tissue regeneration, we delved into its functional role using molecular docking and Morpholino-based gene knockdown techniques. Additionally, we quantified Cav1 expression levels through the application of in situ hybridization. RESULTS Our findings demonstrated that Sal B expedites zebrafish tail fin regeneration through a multifaceted mechanism involving the promotion of cell proliferation, suppression of apoptosis, and enhancement of MMP. Furthermore, Sal B was found to exert regulatory control over the dynamic aggregation and subsequent regression of immune cells during tissue regenerative processes. Importantly, we observed that the knockdown of Cav1 significantly compromised tissue regeneration, leading to an excessive infiltration of immune cells and increased levels of apoptosis. Moreover, the knockdown of Cav1 also affects blastema formation, a critical process influenced by Cav1 in tissue regeneration. CONCLUSION The results of this study showed that Sal B facilitated tissue repair and regeneration through regulating of immune cell migration and Cav1-mediated fibroblast activation, promoting blastema formation and development. This study highlighted the potential pharmacological effects of Sal B in promoting tissue regeneration. These findings contributed to the advancement of regenerative medicine research and the development of novel therapeutic approaches for trauma.
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Affiliation(s)
- Mengchen Qin
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Rouxuan Ou
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Weiyi He
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Haoyang Han
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Yuxue Zhang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Yan Huang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Zhaohan Chen
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Xiaoyan Pan
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Yali Chi
- Department of Obstetrics & Gynecology, Nanfang Hospital, Southern Medical University (SMU), Guangzhou, China.
| | - Songqi He
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
| | - Lei Gao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
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10
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Safi R, Menéndez P, Pol A. Lipid droplets provide metabolic flexibility for cancer progression. FEBS Lett 2024; 598:1301-1327. [PMID: 38325881 DOI: 10.1002/1873-3468.14820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 01/08/2024] [Accepted: 01/10/2024] [Indexed: 02/09/2024]
Abstract
A hallmark of cancer cells is their remarkable ability to efficiently adapt to favorable and hostile environments. Due to a unique metabolic flexibility, tumor cells can grow even in the absence of extracellular nutrients or in stressful scenarios. To achieve this, cancer cells need large amounts of lipids to build membranes, synthesize lipid-derived molecules, and generate metabolic energy in the absence of other nutrients. Tumor cells potentiate strategies to obtain lipids from other cells, metabolic pathways to synthesize new lipids, and mechanisms for efficient storage, mobilization, and utilization of these lipids. Lipid droplets (LDs) are the organelles that collect and supply lipids in eukaryotes and it is increasingly recognized that the accumulation of LDs is a new hallmark of cancer cells. Furthermore, an active role of LD proteins in processes underlying tumorigenesis has been proposed. Here, by focusing on three major classes of LD-resident proteins (perilipins, lipases, and acyl-CoA synthetases), we provide an overview of the contribution of LDs to cancer progression and discuss the role of LD proteins during the proliferation, invasion, metastasis, apoptosis, and stemness of cancer cells.
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Affiliation(s)
- Rémi Safi
- Josep Carreras Leukemia Research Institute, Barcelona, Spain
- Lipid Trafficking and Disease Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
| | - Pablo Menéndez
- Josep Carreras Leukemia Research Institute, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
- Department of Biomedical Sciences, Faculty of Medicine, Universitat de Barcelona, Spain
- Consorcio Investigación Biomédica en Red de Cancer, CIBER-ONC, ISCIII, Barcelona, Spain
- Spanish Network for Advanced Cell Therapies (TERAV), Barcelona, Spain
| | - Albert Pol
- Lipid Trafficking and Disease Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
- Department of Biomedical Sciences, Faculty of Medicine, Universitat de Barcelona, Spain
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11
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Portolés I, Ribera J, Fernandez-Galán E, Lecue E, Casals G, Melgar-Lesmes P, Fernández-Varo G, Boix L, Sanduzzi M, Aishwarya V, Reig M, Jiménez W, Morales-Ruiz M. Identification of Dhx15 as a Major Regulator of Liver Development, Regeneration, and Tumor Growth in Zebrafish and Mice. Int J Mol Sci 2024; 25:3716. [PMID: 38612527 PMCID: PMC11011938 DOI: 10.3390/ijms25073716] [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: 02/26/2024] [Revised: 03/15/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
RNA helicase DHX15 plays a significant role in vasculature development and lung metastasis in vertebrates. In addition, several studies have demonstrated the overexpression of DHX15 in the context of hepatocellular carcinoma. Therefore, we hypothesized that this helicase may play a significant role in liver regeneration, physiology, and pathology. Dhx15 gene deficiency was generated by CRISPR/Cas9 in zebrafish and by TALEN-RNA in mice. AUM Antisense-Oligonucleotides were used to silence Dhx15 in wild-type mice. The hepatocellular carcinoma tumor induction model was generated by subcutaneous injection of Hepa 1-6 cells. Homozygous Dhx15 gene deficiency was lethal in zebrafish and mouse embryos. Dhx15 gene deficiency impaired liver organogenesis in zebrafish embryos and liver regeneration after partial hepatectomy in mice. Also, heterozygous mice presented decreased number and size of liver metastasis after Hepa 1-6 cells injection compared to wild-type mice. Dhx15 gene silencing with AUM Antisense-Oligonucleotides in wild-type mice resulted in 80% reduced expression in the liver and a significant reduction in other major organs. In addition, Dhx15 gene silencing significantly hindered primary tumor growth in the hepatocellular carcinoma experimental model. Regarding the potential use of DHX15 as a diagnostic marker for liver disease, patients with hepatocellular carcinoma showed increased levels of DHX15 in blood samples compared with subjects without hepatic affectation. In conclusion, Dhx15 is a key regulator of liver physiology and organogenesis, is increased in the blood of cirrhotic and hepatocellular carcinoma patients, and plays a key role in controlling hepatocellular carcinoma tumor growth and expansion in experimental models.
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Affiliation(s)
- Irene Portolés
- Biochemistry and Molecular Genetics Department-CDB, Hospital Clínic of Barcelona, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), 170 Villarroel St. Barcelona, 08036 Barcelona, Spain; (I.P.); (J.R.); (E.F.-G.); (E.L.); (G.C.); (P.M.-L.); (G.F.-V.); (W.J.)
| | - Jordi Ribera
- Biochemistry and Molecular Genetics Department-CDB, Hospital Clínic of Barcelona, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), 170 Villarroel St. Barcelona, 08036 Barcelona, Spain; (I.P.); (J.R.); (E.F.-G.); (E.L.); (G.C.); (P.M.-L.); (G.F.-V.); (W.J.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28222 Madrid, Spain; (L.B.); (M.S.); (M.R.)
| | - Esther Fernandez-Galán
- Biochemistry and Molecular Genetics Department-CDB, Hospital Clínic of Barcelona, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), 170 Villarroel St. Barcelona, 08036 Barcelona, Spain; (I.P.); (J.R.); (E.F.-G.); (E.L.); (G.C.); (P.M.-L.); (G.F.-V.); (W.J.)
| | - Elena Lecue
- Biochemistry and Molecular Genetics Department-CDB, Hospital Clínic of Barcelona, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), 170 Villarroel St. Barcelona, 08036 Barcelona, Spain; (I.P.); (J.R.); (E.F.-G.); (E.L.); (G.C.); (P.M.-L.); (G.F.-V.); (W.J.)
| | - Gregori Casals
- Biochemistry and Molecular Genetics Department-CDB, Hospital Clínic of Barcelona, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), 170 Villarroel St. Barcelona, 08036 Barcelona, Spain; (I.P.); (J.R.); (E.F.-G.); (E.L.); (G.C.); (P.M.-L.); (G.F.-V.); (W.J.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28222 Madrid, Spain; (L.B.); (M.S.); (M.R.)
- Commission for the Biochemical Evaluation of the Hepatic Disease-SEQCML, 08036 Barcelona, Spain
| | - Pedro Melgar-Lesmes
- Biochemistry and Molecular Genetics Department-CDB, Hospital Clínic of Barcelona, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), 170 Villarroel St. Barcelona, 08036 Barcelona, Spain; (I.P.); (J.R.); (E.F.-G.); (E.L.); (G.C.); (P.M.-L.); (G.F.-V.); (W.J.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28222 Madrid, Spain; (L.B.); (M.S.); (M.R.)
- Biomedicine Department, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain
| | - Guillermo Fernández-Varo
- Biochemistry and Molecular Genetics Department-CDB, Hospital Clínic of Barcelona, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), 170 Villarroel St. Barcelona, 08036 Barcelona, Spain; (I.P.); (J.R.); (E.F.-G.); (E.L.); (G.C.); (P.M.-L.); (G.F.-V.); (W.J.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28222 Madrid, Spain; (L.B.); (M.S.); (M.R.)
| | - Loreto Boix
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28222 Madrid, Spain; (L.B.); (M.S.); (M.R.)
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clinic, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Marco Sanduzzi
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28222 Madrid, Spain; (L.B.); (M.S.); (M.R.)
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clinic, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Veenu Aishwarya
- AUM LifeTech, Inc., 3675 Market Street, Suite 200, Philadelphia, PA 19104, USA;
| | - Maria Reig
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28222 Madrid, Spain; (L.B.); (M.S.); (M.R.)
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clinic, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Wladimiro Jiménez
- Biochemistry and Molecular Genetics Department-CDB, Hospital Clínic of Barcelona, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), 170 Villarroel St. Barcelona, 08036 Barcelona, Spain; (I.P.); (J.R.); (E.F.-G.); (E.L.); (G.C.); (P.M.-L.); (G.F.-V.); (W.J.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28222 Madrid, Spain; (L.B.); (M.S.); (M.R.)
- Biomedicine Department, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain
| | - Manuel Morales-Ruiz
- Biochemistry and Molecular Genetics Department-CDB, Hospital Clínic of Barcelona, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), 170 Villarroel St. Barcelona, 08036 Barcelona, Spain; (I.P.); (J.R.); (E.F.-G.); (E.L.); (G.C.); (P.M.-L.); (G.F.-V.); (W.J.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28222 Madrid, Spain; (L.B.); (M.S.); (M.R.)
- Commission for the Biochemical Evaluation of the Hepatic Disease-SEQCML, 08036 Barcelona, Spain
- Biomedicine Department, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain
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12
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Banerjee A, Hariharan D. History of liver surgery. Clin Liver Dis (Hoboken) 2024; 23:e0237. [PMID: 38919867 PMCID: PMC11199012 DOI: 10.1097/cld.0000000000000237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 03/29/2024] [Indexed: 06/27/2024] Open
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13
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Hu Y, Wang R, Liu J, Wang Y, Dong J. Lipid droplet deposition in the regenerating liver: A promoter, inhibitor, or bystander? Hepatol Commun 2023; 7:e0267. [PMID: 37708445 PMCID: PMC10503682 DOI: 10.1097/hc9.0000000000000267] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 07/29/2023] [Indexed: 09/16/2023] Open
Abstract
Liver regeneration (LR) is a complex process involving intricate networks of cellular connections, cytokines, and growth factors. During the early stages of LR, hepatocytes accumulate lipids, primarily triacylglycerol, and cholesterol esters, in the lipid droplets. Although it is widely accepted that this phenomenon contributes to LR, the impact of lipid droplet deposition on LR remains a matter of debate. Some studies have suggested that lipid droplet deposition has no effect or may even be detrimental to LR. This review article focuses on transient regeneration-associated steatosis and its relationship with the liver regenerative response.
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Affiliation(s)
- Yuelei Hu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Ruilin Wang
- Department of Cadre’s Wards Ultrasound Diagnostics. Ultrasound Diagnostic Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Juan Liu
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing, China
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing, China
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Yunfang Wang
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing, China
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing, China
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Jiahong Dong
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing, China
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing, China
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14
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Safi R, Sánchez-Álvarez M, Bosch M, Demangel C, Parton RG, Pol A. Defensive-lipid droplets: Cellular organelles designed for antimicrobial immunity. Immunol Rev 2023; 317:113-136. [PMID: 36960679 DOI: 10.1111/imr.13199] [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] [Indexed: 03/25/2023]
Abstract
Microbes have developed many strategies to subvert host organisms, which, in turn, evolved several innate immune responses. As major lipid storage organelles of eukaryotes, lipid droplets (LDs) are an attractive source of nutrients for invaders. Intracellular viruses, bacteria, and protozoan parasites induce and physically interact with LDs, and the current view is that they "hijack" LDs to draw on substrates for host colonization. This dogma has been challenged by the recent demonstration that LDs are endowed with a protein-mediated antibiotic activity, which is upregulated in response to danger signals and sepsis. Dependence on host nutrients could be a generic "Achilles' heel" of intracellular pathogens and LDs a suitable chokepoint harnessed by innate immunity to organize a front-line defense. Here, we will provide a brief overview of the state of the conflict and discuss potential mechanisms driving the formation of the 'defensive-LDs' functioning as hubs of innate immunity.
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Affiliation(s)
- Rémi Safi
- Lipid Trafficking and Disease Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
- Josep Carreras Leukemia Research Institute, Barcelona, Spain
| | - Miguel Sánchez-Álvarez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Instituto de Investigaciones Biomédicas Alberto Sols (IIB), Madrid, Spain
| | - Marta Bosch
- Lipid Trafficking and Disease Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
- Department of Biomedical Sciences, Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain
| | - Caroline Demangel
- Immunobiology and Therapy Unit, Institut Pasteur, Université Paris Cité, INSERM U1224, Paris, France
| | - Robert G Parton
- Institute for Molecular Bioscience (IMB), Brisbane, Queensland, Australia
- Centre for Microscopy and Microanalysis (CMM), University of Queensland, Brisbane, Queensland, Australia
| | - Albert Pol
- Lipid Trafficking and Disease Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
- Department of Biomedical Sciences, Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
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15
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Gautier-Stein A, Chilloux J, Soty M, Thorens B, Place C, Zitoun C, Duchampt A, Da Costa L, Rajas F, Lamaze C, Mithieux G. A caveolin-1 dependent glucose-6-phosphatase trafficking contributes to hepatic glucose production. Mol Metab 2023; 70:101700. [PMID: 36870604 PMCID: PMC10023957 DOI: 10.1016/j.molmet.2023.101700] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 02/15/2023] [Accepted: 02/24/2023] [Indexed: 03/06/2023] Open
Abstract
OBJECTIVE Deregulation of hepatic glucose production is a key driver in the pathogenesis of diabetes, but its short-term regulation is incompletely deciphered. According to textbooks, glucose is produced in the endoplasmic reticulum by glucose-6-phosphatase (G6Pase) and then exported in the blood by the glucose transporter GLUT2. However, in the absence of GLUT2, glucose can be produced by a cholesterol-dependent vesicular pathway, which remains to be deciphered. Interestingly, a similar mechanism relying on vesicle trafficking controls short-term G6Pase activity. We thus investigated whether Caveolin-1 (Cav1), a master regulator of cholesterol trafficking, might be the mechanistic link between glucose production by G6Pase in the ER and glucose export through a vesicular pathway. METHODS Glucose production from fasted mice lacking Cav1, GLUT2 or both proteins was measured in vitro in primary culture of hepatocytes and in vivo by pyruvate tolerance tests. The cellular localization of Cav1 and the catalytic unit of glucose-6-phosphatase (G6PC1) were studied by western blotting from purified membranes, immunofluorescence on primary hepatocytes and fixed liver sections and by in vivo imaging of chimeric constructs overexpressed in cell lines. G6PC1 trafficking to the plasma membrane was inhibited by a broad inhibitor of vesicular pathways or by an anchoring system retaining G6PC1 specifically to the ER membrane. RESULTS Hepatocyte glucose production is reduced at the step catalyzed by G6Pase in the absence of Cav1. In the absence of both GLUT2 and Cav1, gluconeogenesis is nearly abolished, indicating that these pathways can be considered as the two major pathways of de novo glucose production. Mechanistically, Cav1 colocalizes but does not interact with G6PC1 and controls its localization in the Golgi complex and at the plasma membrane. The localization of G6PC1 at the plasma membrane is correlated to glucose production. Accordingly, retaining G6PC1 in the ER reduces glucose production by hepatic cells. CONCLUSIONS Our data evidence a pathway of glucose production that relies on Cav1-dependent trafficking of G6PC1 to the plasma membrane. This reveals a new cellular regulation of G6Pase activity that contributes to hepatic glucose production and glucose homeostasis.
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Affiliation(s)
- Amandine Gautier-Stein
- Université Claude Bernard Lyon 1, Université de Lyon, INSERM UMR-S1213, F-69374, Lyon, France.
| | - Julien Chilloux
- Université Claude Bernard Lyon 1, Université de Lyon, INSERM UMR-S1213, F-69374, Lyon, France
| | - Maud Soty
- Université Claude Bernard Lyon 1, Université de Lyon, INSERM UMR-S1213, F-69374, Lyon, France
| | - Bernard Thorens
- Center for Integrative Genomics, University of Lausanne, Genopode Building, 1015, Lausanne, Switzerland
| | - Christophe Place
- Laboratoire de Physique (UMR CNRS 5672), ENS de Lyon, Université de Lyon, F-69364, Lyon cedex 07, France
| | - Carine Zitoun
- Université Claude Bernard Lyon 1, Université de Lyon, INSERM UMR-S1213, F-69374, Lyon, France
| | - Adeline Duchampt
- Université Claude Bernard Lyon 1, Université de Lyon, INSERM UMR-S1213, F-69374, Lyon, France
| | - Lorine Da Costa
- Université Claude Bernard Lyon 1, Université de Lyon, INSERM UMR-S1213, F-69374, Lyon, France
| | - Fabienne Rajas
- Université Claude Bernard Lyon 1, Université de Lyon, INSERM UMR-S1213, F-69374, Lyon, France
| | - Christophe Lamaze
- Institut Curie, PSL Research University, INSERM U1143, CNRS UMR 3666, Membrane Mechanics and Dynamics of Intracellular Signaling Laboratory, 75005, Paris, France
| | - Gilles Mithieux
- Université Claude Bernard Lyon 1, Université de Lyon, INSERM UMR-S1213, F-69374, Lyon, France
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16
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Chen Y, Chen L, Wu X, Zhao Y, Wang Y, Jiang D, Liu X, Zhou T, Li S, Wei Y, Liu Y, Hu C, Zhou B, Qin J, Ying H, Ding Q. Acute liver steatosis translationally controls the epigenetic regulator MIER1 to promote liver regeneration in a study with male mice. Nat Commun 2023; 14:1521. [PMID: 36934083 PMCID: PMC10024732 DOI: 10.1038/s41467-023-37247-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 03/07/2023] [Indexed: 03/20/2023] Open
Abstract
The early phase lipid accumulation is essential for liver regeneration. However, whether this acute lipid accumulation can serve as signals to direct liver regeneration rather than simply providing building blocks for cell proliferation remains unclear. Through in vivo CRISPR screening, we identify MIER1 (mesoderm induction early response 1) as a key epigenetic regulator that bridges the acute lipid accumulation and cell cycle gene expression during liver regeneration in male animals. Physiologically, liver acute lipid accumulation induces the phosphorylation of EIF2S1(eukaryotic translation initiation factor 2), which consequently attenuated Mier1 translation. MIER1 downregulation in turn promotes cell cycle gene expression and regeneration through chromatin remodeling. Importantly, the lipids-EIF2S1-MIER1 pathway is impaired in animals with chronic liver steatosis; whereas MIER1 depletion significantly improves regeneration in these animals. Taken together, our studies identify an epigenetic mechanism by which the early phase lipid redistribution from adipose tissue to liver during regeneration impacts hepatocyte proliferation, and suggest a potential strategy to boost liver regeneration.
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Affiliation(s)
- Yanhao Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China.
| | - Lanlan Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China
| | - Xiaoshan Wu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China
- School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, P. R. China
| | - Yongxu Zhao
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China
| | - Yuchen Wang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China
| | - Dacheng Jiang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China
| | - Xiaojian Liu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China
| | - Tingting Zhou
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China
| | - Shuang Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China
| | - Yuda Wei
- Department of Clinical Laboratory, Linyi People's Hospital, Xuzhou Medical University, Xuzhou, Shandong, 276000, P. R. China
| | - Yan Liu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China
| | - Cheng Hu
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Ben Zhou
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China
| | - Jun Qin
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China
| | - Hao Ying
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China
| | - Qiurong Ding
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101, Beijing, P. R. China.
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Optical Biomedical Imaging Reveals Criteria for Violated Liver Regenerative Potential. Cells 2023; 12:cells12030479. [PMID: 36766821 PMCID: PMC9914457 DOI: 10.3390/cells12030479] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/12/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
To reduce the risk of post-hepatectomy liver failure in patients with hepatic pathologies, it is necessary to develop an approach to express the intraoperative assessment of the liver's regenerative potential. Traditional clinical methods do not enable the prediction of the function of the liver remnant. Modern label-free bioimaging, using multiphoton microscopy in combination with second harmonic generation (SHG) and fluorescence lifetime imaging microscopy (FLIM), can both expand the possibilities for diagnosing liver pathologies and for assessing the regenerative potential of the liver. Using multiphoton and SHG microscopy, we assessed the structural state of liver tissue at different stages of induced steatosis and fibrosis before and after 70% partial hepatectomy in rats. Using FLIM, we also performed a detailed analysis of the metabolic state of the hepatocytes. We were able to determine criteria that can reveal a lack of regenerative potential in violated liver, such as the presence of zones with reduced NAD(P)H autofluorescence signals. Furthermore, for a liver with pathology, there was an absence of the jump in the fluorescence lifetime contributions of the bound form of NADH and NADPH the 3rd day after hepatectomy that is characteristic of normal liver regeneration. Such results are associated with decreased intensity of oxidative phosphorylation and of biosynthetic processes in pathological liver, which is the reason for the impaired liver recovery. This modern approach offers an effective tool that can be successfully translated into the clinic for express, intraoperative assessment of the regenerative potential of the pathological liver of a patient.
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18
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Chen Z, Wang Z, Liu D, Zhao X, Ning S, Liu X, Wang G, Zhang F, Luo F, Yao J, Tian X. Critical role of caveolin-1 in intestinal ischemia reperfusion by inhibiting protein kinase C βII. Free Radic Biol Med 2023; 194:62-70. [PMID: 36410585 DOI: 10.1016/j.freeradbiomed.2022.11.030] [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: 07/18/2022] [Revised: 10/24/2022] [Accepted: 11/17/2022] [Indexed: 11/19/2022]
Abstract
Intestinal ischemia reperfusion (I/R) is a common clinical pathological process. We previously reported that pharmacological inhibition of protein kinase C (PKC) βII with a specific inhibitor attenuated gut I/R injury. However, the endogenous regulatory mechanism of PKCβII inactivation is still unclear. Here, we explored the critical role of caveolin-1 (Cav1) in protecting against intestinal I/R injury by regulating PKCβII inactivation. PKCβII translocated to caveolae and bound with Cav1 after intestinal I/R. Cav1 was highly expressed in the intestine of mice with I/R and IEC-6 cells stimulated with hypoxia/reoxygenation (H/R). Cav1-knockout (KO) mice suffered from worse intestinal injury after I/R than wild-type (WT) mice and showed extremely low survival due to exacerbated systemic inflammatory response syndrome (SIRS) and remote organ (lung and liver) injury. Cav1 deficiency resulted in excessive PKCβII activation and increased oxidative stress and apoptosis after intestinal I/R. Full-length Cav1 scaffolding domain peptide (CSP) suppressed excessive PKCβII activation and protected the gut against oxidative stress and apoptosis due to I/R injury. In summary, Cav1 could regulate PKCβII endogenous inactivation to alleviate intestinal I/R injury. This finding may represent a novel therapeutic strategy for the prevention and treatment of intestinal I/R injury.
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Affiliation(s)
- Zhao Chen
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China
| | - Zhecheng Wang
- Department of Pharmacology, Dalian Medical University, 116044, Dalian, China
| | - Deshun Liu
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China
| | - Xuzi Zhao
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China
| | - Shili Ning
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China
| | - Xingming Liu
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China
| | - Guangzhi Wang
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China
| | - Feng Zhang
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China
| | - Fuwen Luo
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China
| | - Jihong Yao
- Department of Pharmacology, Dalian Medical University, 116044, Dalian, China
| | - Xiaofeng Tian
- Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, 116023, Dalian, China.
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19
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Song J, Baek IJ, Park S, Oh J, Kim D, Song K, Kim MK, Lee HW, Jang BK, Jin EJ. Deficiency of peroxisomal NUDT7 stimulates de novo lipogenesis in hepatocytes. iScience 2022; 25:105135. [PMID: 36185359 PMCID: PMC9523354 DOI: 10.1016/j.isci.2022.105135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 05/14/2022] [Accepted: 09/09/2022] [Indexed: 12/18/2022] Open
Affiliation(s)
- Jinsoo Song
- Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
- Integrated Omics Institute, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - In-Jeoung Baek
- Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Sujeong Park
- Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Jinjoo Oh
- Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Deokha Kim
- Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Kyung Song
- Department of Pharmacy, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Mi Kyung Kim
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu 42601, Korea
| | - Hye Won Lee
- Department of Pathology, Keimyung University School of Medicine, Daegu 42601, Korea
| | - Byoung Kuk Jang
- Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu 42601, Korea
| | - Eun-Jung Jin
- Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
- Integrated Omics Institute, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
- Corresponding author
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20
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Yan X, Shu Q, Zhao L, Sha B, Zhang Y. The Pivotal Mediating Role of Adenosine Monophosphate-Activated Protein Kinase (AMPK) in Liver Tight Junctions and Liver Regeneration of a Partial-Hepatectomy Mouse Model. Transplant Proc 2022; 54:2374-2380. [PMID: 36182577 DOI: 10.1016/j.transproceed.2022.08.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 08/29/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE This study aims to explore the pivotal mediating role of adenosine monophosphate-activated protein kinase (AMPK) in liver tight junctions and liver regeneration of a partial hepatectomy (PH) mouse model. METHODS A 70% PH mouse model was used. Firstly, mice were randomly divided into sham, 70% PH, AMPK-activated, and AMPK-inhibited groups. Then serum levels of alanine aminotransferase, aspartate transaminase, total bilirubin, direct bilirubin, albumin, and prealbumin were tested on postoperative days 1, 2 and 3. Furthermore, the expression of tight junction proteins like occludin, claudin-3, and ZO-1, together with bile salt export pump (BSEP), which reflects liver function, and AMPK were measured by Western blot and quantitative real-time polymerase chain reaction. Moreover, the expression of tight junction proteins, BSEP, and Ki-67 were examined by immunohistochemistry. RESULTS After 70% PH, without intervention, the changes in expression of hepatic tight junction proteins (occludin, claudin-3, and ZO-1) were consistent with that of BSEP, which could reflect liver function. After treatment with AMPK activator, the high expression status of tight junction proteins occurred in advance and was maintained stably and for a longer time. It was beneficial to liver function and liver regeneration was promoted at early periods and enhanced continuously after PH. CONCLUSIONS Activation of AMPK could effectively enhance the expression of hepatic tight junction proteins after PH. Therefore, it could speed up the recovery of liver function and promote liver regeneration especially early after PH.
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Affiliation(s)
- Xiaopeng Yan
- Department of Hepatopancreatobiliary Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Qinghua Shu
- Department of Hepatopancreatobiliary Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Liang Zhao
- Department of Hepatopancreatobiliary Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Bowen Sha
- Department of Hepatopancreatobiliary Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yufeng Zhang
- Department of Hepatopancreatobiliary Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
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21
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Zhang L, Li Y, Wang Y, Qiu Y, Mou H, Deng Y, Yao J, Xia Z, Zhang W, Zhu D, Qiu Z, Lu Z, Wang J, Yang Z, Mao G, Chen D, Sun L, Liu L, Ju Z. mTORC2 Facilitates Liver Regeneration Through Sphingolipid-Induced PPAR-α-Fatty Acid Oxidation. Cell Mol Gastroenterol Hepatol 2022; 14:1311-1331. [PMID: 35931382 PMCID: PMC9703135 DOI: 10.1016/j.jcmgh.2022.07.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND & AIMS During liver regeneration after partial hepatectomy, the function and metabolic pathways governing transient lipid droplet accumulation in hepatocytes remain obscure. Mammalian target of rapamycin 2 (mTORC2) facilitates de novo synthesis of hepatic lipids. Under normal conditions and in tumorigenesis, decreased levels of triglyceride (TG) and fatty acids (FAs) are observed in the mTORC2-deficient liver. However, during liver regeneration, their levels increase in the absence of mTORC2. METHODS Rictor liver-specific knockout and control mice underwent partial hepatectomy, followed by measurement of TG and FA contents during liver regeneration. FA metabolism was evaluated by analyzing the expression of FA metabolism-related genes and proteins. Intraperitoneal injection of the peroxisome proliferator-activated receptor α (PPAR-α) agonist, p53 inhibitor, and protein kinase B (AKT) activator was performed to verify the regulatory pathways involved. Lipid mass spectrometry was performed to identify the potential PPAR-α activators. RESULTS The expression of FA metabolism-related genes and proteins suggested that FAs are mainly transported into hepatocytes during liver regeneration. The PPAR-α pathway is down-regulated significantly in the mTORC2-deficient liver, resulting in the accumulation of TGs. The PPAR-α agonist WY-14643 rescued deficient liver regeneration and survival in mTORC2-deficient mice. Furthermore, lipidomic analysis suggested that mTORC2 deficiency substantially reduced glucosylceramide (GluCer) content. GluCer activated PPAR-α. GluCer treatment in vivo restored the regenerative ability and survival rates in the mTORC2-deficient group. CONCLUSIONS Our data suggest that FAs are mainly transported into hepatocytes during liver regeneration, and their metabolism is facilitated by mTORC2 through the GluCer-PPAR-α pathway, thereby establishing a novel role for mTORC2 in lipid metabolism.
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Affiliation(s)
- Lingling Zhang
- International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China,Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China,Correspondence Address correspondence to: Lingling Zhang, MD, PhD, International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China.
| | - Yanqiu Li
- Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Ying Wang
- International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Yugang Qiu
- School of Rehabilitation Medicine, Weifang Medical University, Weifang, Shandong, China
| | - Hanchuan Mou
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China
| | - Yuanyao Deng
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China
| | - Jiyuan Yao
- Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Zhiqing Xia
- International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Wenzhe Zhang
- International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Di Zhu
- International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Zeyu Qiu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
| | - Zhongjie Lu
- Department of Thoracic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jirong Wang
- Zhejiang Provincial Key Lab of Geriatrics and Geriatrics Institute of Zhejiang Province, Department of Geriatrics, Zhejiang Hospital, Hangzhou, Zhejiang, China
| | - Zhouxin Yang
- Zhejiang Provincial Key Lab of Geriatrics and Geriatrics Institute of Zhejiang Province, Department of Geriatrics, Zhejiang Hospital, Hangzhou, Zhejiang, China
| | - GenXiang Mao
- Zhejiang Provincial Key Lab of Geriatrics and Geriatrics Institute of Zhejiang Province, Department of Geriatrics, Zhejiang Hospital, Hangzhou, Zhejiang, China
| | - Dan Chen
- International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Leimin Sun
- International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Leiming Liu
- International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China,Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China,Leiming Liu, PhD, International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China.
| | - Zhenyu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China,Zhenyu Ju, MD, PhD, Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China.
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22
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Morimoto Y, Saitoh S, Takayama Y. Growth conditions inducing G1 cell cycle arrest enhance lipid production in the oleaginous yeast Lipomyces starkeyi. J Cell Sci 2022; 135:276362. [PMID: 35833504 DOI: 10.1242/jcs.259996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 07/11/2022] [Indexed: 11/20/2022] Open
Abstract
Lipid droplets are cytoplasmic organelles that store lipids for energy and membrane synthesis. The oleaginous yeast Lipomyces starkeyi is one of the most promising lipid producers and has attracted attention as a biofuel source. It is known that the expansion of lipid droplets is enhanced under nutrient-poor conditions. Therefore, we prepared a novel nitrogen-depleted medium (N medium) in which to culture L. starkeyi cells. Lipid accumulation was rapidly induced, and this was reversed by the addition of ammonium. In this condition, cell proliferation stopped and cells with giant lipid droplets were arrested in G1 phase. We investigated whether cell cycle arrest at a specific phase is required for lipid accumulation. Lipid accumulation was repressed in hydroxyurea-synchronized S phase cells and was increased in nocodazole-arrested G2/M phase cells. Moreover, the enrichment of G1 phase cells by rapamycin induced massive lipid accumulation. From these results, we conclude that L. starkeyi cells store lipids from G2/M phase and then arrest cell proliferation in the subsequent G1 phase, where lipid accumulation is enhanced. Cell cycle control is an attractive approach for biofuel production.
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Affiliation(s)
| | - Shigeaki Saitoh
- Department of Cell Biology, Institute of Life Science, Kurume University, Fukuoka, Japan
| | - Yuko Takayama
- Department of Biosciences, Teikyo University, Tochigi, Japan.,Graduate School of Science and Engineering, Teikyo University, Tochigi, Japan
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23
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Liu F, Zhang W, Liu H. Letter to the editor: Hepatocyte proliferation peak and β-oxidation in liver regeneration after partial hepatectomy. Hepatology 2022; 75:1346-1347. [PMID: 35080251 DOI: 10.1002/hep.32357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 12/08/2022]
Affiliation(s)
- Fuchen Liu
- The Third Department of Hepatic SurgeryEastern Hepatobiliary Surgery HospitalNaval Medical UniversityShanghaiChina
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24
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Hadjittofi C, Feretis M, Martin J, Harper S, Huguet E. Liver regeneration biology: Implications for liver tumour therapies. World J Clin Oncol 2021; 12:1101-1156. [PMID: 35070734 PMCID: PMC8716989 DOI: 10.5306/wjco.v12.i12.1101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
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Affiliation(s)
- Christopher Hadjittofi
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Michael Feretis
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jack Martin
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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25
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Hello from the other side: Membrane contact of lipid droplets with other organelles and subsequent functional implications. Prog Lipid Res 2021; 85:101141. [PMID: 34793861 DOI: 10.1016/j.plipres.2021.101141] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/10/2021] [Accepted: 11/10/2021] [Indexed: 02/06/2023]
Abstract
Lipid droplets (LDs) are ubiquitous organelles that play crucial roles in response to physiological and environmental cues. The identification of several neutral lipid synthesizing and regulatory protein complexes have propelled significant advance on the mechanisms of LD biogenesis in the endoplasmic reticulum (ER). Increasing evidence suggests that distinct proteins and regulatory factors, which localize to membrane contact sites (MCS), are involved not only in interorganellar lipid exchange and transport, but also function in other important cellular processes, including autophagy, mitochondrial dynamics and inheritance, ion signaling and inter-regulation of these MCS. More and more tethers and molecular determinants are associated to MCS and to a diversity of cellular and pathophysiological processes, demonstrating the dynamics and importance of these junctions in health and disease. The conjugation of lipids with proteins in supramolecular complexes is known to be paramount for many biological processes, namely membrane biosynthesis, cell homeostasis, regulation of organelle division and biogenesis, and cell growth. Ultimately, this physical organization allows the contact sites to function as crucial metabolic hubs that control the occurrence of chemical reactions. This leads to biochemical and metabolite compartmentalization for the purposes of energetic efficiency and cellular homeostasis. In this review, we will focus on the structural and functional aspects of LD-organelle interactions and how they ensure signaling exchange and metabolites transfer between organelles.
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26
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Bosch M, Sweet MJ, Parton RG, Pol A. Lipid droplets and the host-pathogen dynamic: FATal attraction? J Cell Biol 2021; 220:e202104005. [PMID: 34165498 PMCID: PMC8240858 DOI: 10.1083/jcb.202104005] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/02/2021] [Accepted: 06/03/2021] [Indexed: 02/06/2023] Open
Abstract
In the ongoing conflict between eukaryotic cells and pathogens, lipid droplets (LDs) emerge as a choke point in the battle for nutrients. While many pathogens seek the lipids stored in LDs to fuel an expensive lifestyle, innate immunity rewires lipid metabolism and weaponizes LDs to defend cells and animals. Viruses, bacteria, and parasites directly and remotely manipulate LDs to obtain substrates for metabolic energy, replication compartments, assembly platforms, membrane blocks, and tools for host colonization and/or evasion such as anti-inflammatory mediators, lipoviroparticles, and even exosomes. Host LDs counterattack such advances by synthesizing bioactive lipids and toxic nucleotides, organizing immune signaling platforms, and recruiting a plethora of antimicrobial proteins to provide a front-line defense against the invader. Here, we review the current state of this conflict. We will discuss why, when, and how LDs efficiently coordinate and precisely execute a plethora of immune defenses. In the age of antimicrobial resistance and viral pandemics, understanding innate immune strategies developed by eukaryotic cells to fight and defeat dangerous microorganisms may inform future anti-infective strategies.
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Affiliation(s)
- Marta Bosch
- Lipid Trafficking and Disease Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Department of Biomedical Sciences, Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain
| | - Matthew J. Sweet
- Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
- Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
- Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Australia
| | - Robert G. Parton
- Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
- Centre for Microscopy and Microanalysis, University of Queensland, Brisbane, Australia
| | - Albert Pol
- Lipid Trafficking and Disease Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
- Department of Biomedical Sciences, Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
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27
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Micó-Carnero M, Casillas-Ramírez A, Caballeria-Casals A, Rojano-Alfonso C, Sánchez-González A, Peralta C. Role of Dietary Nutritional Treatment on Hepatic and Intestinal Damage in Transplantation with Steatotic and Non-Steatotic Liver Grafts from Brain Dead Donors. Nutrients 2021; 13:2554. [PMID: 34444713 PMCID: PMC8400262 DOI: 10.3390/nu13082554] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/09/2021] [Accepted: 07/22/2021] [Indexed: 12/13/2022] Open
Abstract
Herein, we investigate whether: (1) the administration of glucose or a lipid emulsion is useful in liver transplantation (LT) using steatotic (induced genetically or nutritionally) or non-steatotic livers from donors after brain death (DBDs); and (2) any such benefits are due to reductions in intestinal damage and consequently to gut microbiota preservation. In recipients from DBDs, we show increased hepatic damage and failure in the maintenance of ATP, glycogen, phospholipid and growth factor (HGF, IGF1 and VEGFA) levels, compared to recipients from non-DBDs. In recipients of non-steatotic grafts from DBDs, the administration of glucose or lipids did not protect against hepatic damage. This was associated with unchanged ATP, glycogen, phospholipid and growth factor levels. However, the administration of lipids in steatotic grafts from DBDs protected against damage and ATP and glycogen drop and increased phospholipid levels. This was associated with increases in growth factors. In all recipients from DBDs, intestinal inflammation and damage (evaluated by LPS, vascular permeability, mucosal damage, TLR4, TNF, IL1, IL-10, MPO, MDA and edema formation) was not shown. In such cases, potential changes in gut microbiota would not be relevant since neither inflammation nor damage was evidenced in the intestine following LT in any of the groups evaluated. In conclusion, lipid treatment is the preferable nutritional support to protect against hepatic damage in steatotic LT from DBDs; the benefits were independent of alterations in the recipient intestine.
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Affiliation(s)
- Marc Micó-Carnero
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-C.); (A.C.-C.); (C.R.-A.)
| | - Araní Casillas-Ramírez
- Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, 87087 Ciudad Victoria, Mexico; (A.C.-R.); (A.S.-G.)
- Facultad de Medicina e Ingeniería en Sistemas Computacionales de Matamoros, Universidad Autónoma de Tamaulipas, 87300 Matamoros, Mexico
| | - Albert Caballeria-Casals
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-C.); (A.C.-C.); (C.R.-A.)
| | - Carlos Rojano-Alfonso
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-C.); (A.C.-C.); (C.R.-A.)
| | - Alfredo Sánchez-González
- Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, 87087 Ciudad Victoria, Mexico; (A.C.-R.); (A.S.-G.)
| | - Carmen Peralta
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-C.); (A.C.-C.); (C.R.-A.)
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28
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Luo Z, Huang J, Li Z, Liu Z, Fu L, Hu Y, Shen X. Cajanolactone A, a Stilbenoid From Cajanus canjan (L.) Millsp, Prevents High-Fat Diet-Induced Obesity via Suppressing Energy Intake. Front Pharmacol 2021; 12:695561. [PMID: 34135763 PMCID: PMC8201603 DOI: 10.3389/fphar.2021.695561] [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: 04/15/2021] [Accepted: 05/20/2021] [Indexed: 12/13/2022] Open
Abstract
Cajanolactone A (CLA) is a stilbenoid isolated from Cajanus canjan (L.) Millsp with the potential to prevent postmenopausal obesity. In this study, the effect of CLA on high-fat diet (HFD)-induced obesity in female C57BL/6 mice was investigated. It was found that, treatment with CLA reduced the energy intake and effectively protected the mice from HFD-induced body weight gain, fat accumulation within the adipose tissues and liver, and impairment in energy metabolism. Further investigation revealed that CLA significantly down-regulated the expression of ORX, ORXR2, pMCH, and Gal in the hypothalamus and antagonized HFD-induced changes in the expression of UCP1, Pgc-1α, Tfam, and Mfn1 in the inguinal white adipose tissue (iWAT); Caveolin-1, MT and UCP3 in the perigonadal white adipose tissue (pWAT); and Pdhb, IRS2, Mttp, Hadhb, and Cpt1b in the liver. CLA also protected the pWAT and liver from HFD-induced mitochondrial damage. However, neither HFD nor CLA showed an effect on the mass of brown adipose tissue (BAT) or the expression of UCP1 in the BAT. In summary, our findings suggest that CLA is a potential drug candidate for preventing diet-induced obesity, at least in females. CLA works most likely by suppressing the hypothalamic expression of orexigenic genes, which leads to reduced energy intake, and subsequently, reduced fat accumulation, thereby protecting the adipose tissues and the liver from lipid-induced mitochondrial dysfunction.
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Affiliation(s)
- Zhuohui Luo
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiawen Huang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhiping Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhiwen Liu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Linchun Fu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yingjie Hu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaoling Shen
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
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29
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Boucher DM, Vijithakumar V, Ouimet M. Lipid Droplets as Regulators of Metabolism and Immunity. IMMUNOMETABOLISM 2021; 3. [DOI: 10.20900/immunometab20210021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 05/28/2021] [Indexed: 01/03/2025]
Abstract
Abstract
A hallmark of sterile and nonsterile inflammation is the increased accumulation of cytoplasmic lipid droplets (LDs) in non-adipose cells. LDs are ubiquitous organelles specialized in neutral lipid storage and hydrolysis. Originating in the ER, LDs are comprised of a core of neutral lipids (cholesterol esters, triglycerides) surrounded by a phospholipid monolayer and several LD-associated proteins. The perilipin (PLIN1-5) family are the most abundant structural proteins present on the surface of LDs. While PLIN1 is primarily expressed in adipocytes, PLIN2 and PLIN3 are ubiquitously expressed. LDs also acquire a host of enzymes and proteins that regulate LD metabolism. Amongst these are neutral lipases and selective lipophagy factors that promote hydrolysis of LD-associated neutral lipid. In addition, LDs physically associate with other organelles such as mitochondria through inter-organelle membrane contact sites that facilitate lipid transport. Beyond serving as a source of energy storage, LDs participate in inflammatory and infectious diseases, regulating both innate and adaptive host immune responses. Here, we review recent studies on the role of LDs in the regulation of immunometabolism.
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Affiliation(s)
- Dominique M. Boucher
- University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, ON, K1Y 4W7, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Viyashini Vijithakumar
- University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, ON, K1Y 4W7, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Mireille Ouimet
- University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, ON, K1Y 4W7, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
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30
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Grewal T, Rentero C, Enrich C, Wahba M, Raabe CA, Rescher U. Annexin Animal Models-From Fundamental Principles to Translational Research. Int J Mol Sci 2021; 22:ijms22073439. [PMID: 33810523 PMCID: PMC8037771 DOI: 10.3390/ijms22073439] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/18/2021] [Accepted: 03/24/2021] [Indexed: 02/07/2023] Open
Abstract
Routine manipulation of the mouse genome has become a landmark in biomedical research. Traits that are only associated with advanced developmental stages can now be investigated within a living organism, and the in vivo analysis of corresponding phenotypes and functions advances the translation into the clinical setting. The annexins, a family of closely related calcium (Ca2+)- and lipid-binding proteins, are found at various intra- and extracellular locations, and interact with a broad range of membrane lipids and proteins. Their impacts on cellular functions has been extensively assessed in vitro, yet annexin-deficient mouse models generally develop normally and do not display obvious phenotypes. Only in recent years, studies examining genetically modified annexin mouse models which were exposed to stress conditions mimicking human disease often revealed striking phenotypes. This review is the first comprehensive overview of annexin-related research using animal models and their exciting future use for relevant issues in biology and experimental medicine.
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Affiliation(s)
- Thomas Grewal
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia;
- Correspondence: (T.G.); (U.R.); Tel.: +61-(0)2-9351-8496 (T.G.); +49-(0)251-83-52121 (U.R.)
| | - Carles Rentero
- Departament de Biomedicina, Unitat de Biologia Cel·lular, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, 08036 Barcelona, Spain; (C.R.); (C.E.)
- Centre de Recerca Biomèdica CELLEX, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Carlos Enrich
- Departament de Biomedicina, Unitat de Biologia Cel·lular, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, 08036 Barcelona, Spain; (C.R.); (C.E.)
- Centre de Recerca Biomèdica CELLEX, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Mohamed Wahba
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia;
| | - Carsten A. Raabe
- Research Group Regulatory Mechanisms of Inflammation, Center for Molecular Biology of Inflammation (ZMBE) and Cells in Motion Interfaculty Center (CiM), Institute of Medical Biochemistry, University of Muenster, 48149 Muenster, Germany;
| | - Ursula Rescher
- Research Group Regulatory Mechanisms of Inflammation, Center for Molecular Biology of Inflammation (ZMBE) and Cells in Motion Interfaculty Center (CiM), Institute of Medical Biochemistry, University of Muenster, 48149 Muenster, Germany;
- Correspondence: (T.G.); (U.R.); Tel.: +61-(0)2-9351-8496 (T.G.); +49-(0)251-83-52121 (U.R.)
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31
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Parton RG, Tillu V, McMahon KA, Collins BM. Key phases in the formation of caveolae. Curr Opin Cell Biol 2021; 71:7-14. [PMID: 33677149 DOI: 10.1016/j.ceb.2021.01.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/28/2021] [Accepted: 01/30/2021] [Indexed: 12/20/2022]
Abstract
Caveolae are abundant plasma membrane pits formed by the coordinated action of peripheral and integral membrane proteins and membrane lipids. Here, we discuss recent studies that are starting to provide a glimpse of how filamentous cavin proteins, membrane-embedded caveolin proteins, and specific plasma membrane lipids are brought together to make the unique caveola surface domain. Protein assembly involves multiple low-affinity interactions that are dependent on 'fuzzy' charge-dependent interactions mediated in part by disordered cavin and caveolin domains. We propose that cavins help generate a lipid domain conducive to full insertion of caveolin into the bilayer to promote caveola formation. The synergistic assembly of these dynamic protein complexes supports the formation of a metastable membrane domain that can be readily disassembled both in response to cellular stress and during endocytic trafficking. We present a mechanistic model for generation of caveolae based on these new insights.
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Affiliation(s)
- Robert G Parton
- The University of Queensland, Institute for Molecular Bioscience, Brisbane, Queensland, 4072, Australia; The University of Queensland, Centre for Microscopy and Microanalysis, Brisbane, Queensland, 4072, Australia.
| | - Vikas Tillu
- The University of Queensland, Institute for Molecular Bioscience, Brisbane, Queensland, 4072, Australia
| | - Kerrie-Ann McMahon
- The University of Queensland, Institute for Molecular Bioscience, Brisbane, Queensland, 4072, Australia
| | - Brett M Collins
- The University of Queensland, Institute for Molecular Bioscience, Brisbane, Queensland, 4072, Australia.
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32
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Zeng CW, Kamei Y, Shigenobu S, Sheu JC, Tsai HJ. Injury-induced Cavl-expressing cells at lesion rostral side play major roles in spinal cord regeneration. Open Biol 2021; 11:200304. [PMID: 33622104 PMCID: PMC8061693 DOI: 10.1098/rsob.200304] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The extent of cellular heterogeneity involved in neuronal regeneration after spinal cord injury (SCI) remains unclear. Therefore, we established stress-responsive transgenic zebrafish embryos with SCI. As a result, we found an SCI-induced cell population, termed SCI stress-responsive regenerating cells (SrRCs), essential for neuronal regeneration post-SCI. SrRCs were mostly composed of subtypes of radial glia (RGs-SrRCs) and neuron stem/progenitor cells (NSPCs-SrRCs) that are able to differentiate into neurons, and they formed a bridge across the lesion and connected with neighbouring undamaged motor neurons post-SCI. Compared to SrRCs at the caudal side of the SCI site (caudal-SrRCs), rostral-SrRCs participated more actively in neuronal regeneration. After RNA-seq analysis, we discovered that caveolin 1 (cav1) was significantly upregulated in rostral-SrRCs and that cav1 was responsible for the axonal regrowth and regenerative capability of rostral-SrRCs. Collectively, we define a specific SCI-induced cell population, SrRCs, involved in neuronal regeneration, demonstrate that rostral-SrRCs exhibit higher neuronal differentiation capability and prove that cav1 is predominantly expressed in rostral-SrRCs, playing a major role in neuronal regeneration after SCI.
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Affiliation(s)
- Chih-Wei Zeng
- Institute of Molecular and Cellular Biology, College of Life Science, National Taiwan University, Taipei 10617, Taiwan.,Liver Disease Prevention and Treatment Research Foundation, Taipei 10008, Taiwan
| | - Yasuhiro Kamei
- Spectrography and Bioimaging Facility, National Institute for Basic Biology (NIBB), National Institutes of Natural Sciences (NINS), Okazaki 444-8585, Japan.,Department of Basic Biology, The Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8585, Japan
| | - Shuji Shigenobu
- Department of Basic Biology, The Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8585, Japan.,Functional Genomics Facility, NIBB, NINS, Okazaki 444-8585, Japan
| | - Jin-Chuan Sheu
- Liver Disease Prevention and Treatment Research Foundation, Taipei 10008, Taiwan
| | - Huai-Jen Tsai
- Institute of Biomedical Sciences, Mackay Medical College, New Taipei City 25245, Taiwan.,Department of Life Science, Fu Jen Catholic University, New Taipei City 242062, Taiwan
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33
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Ishikawa M, Brooks AJ, Fernández-Rojo MA, Medina J, Chhabra Y, Minami S, Tunny KA, Parton RG, Vivian JP, Rossjohn J, Chikani V, Ramm GA, Ho KKY, Waters MJ. Growth Hormone Stops Excessive Inflammation After Partial Hepatectomy, Allowing Liver Regeneration and Survival Through Induction of H2-Bl/HLA-G. Hepatology 2021; 73:759-775. [PMID: 32342533 PMCID: PMC7894545 DOI: 10.1002/hep.31297] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND AIMS Growth hormone (GH) is important for liver regeneration after partial hepatectomy (PHx). We investigated this process in C57BL/6 mice that express different forms of the GH receptor (GHR) with deletions in key signaling domains. APPROACH AND RESULTS PHx was performed on C57BL/6 mice lacking GHR (Ghr-/- ), disabled for all GH-dependent Janus kinase 2 signaling (Box1-/- ), or lacking only GH-dependent signal transducer and activator of transcription 5 (STAT5) signaling (Ghr391-/- ), and wild-type littermates. C57BL/6 Ghr-/- mice showed striking mortality within 48 hours after PHx, whereas Box1-/- or Ghr391-/- mice survived with normal liver regeneration. Ghr-/- mortality was associated with increased apoptosis and elevated natural killer/natural killer T cell and macrophage cell markers. We identified H2-Bl, a key immunotolerance protein, which is up-regulated by PHx through a GH-mediated, Janus kinase 2-independent, SRC family kinase-dependent pathway. GH treatment was confirmed to up-regulate expression of the human homolog of H2-Bl (human leukocyte antigen G [HLA-G]) in primary human hepatocytes and in the serum of GH-deficient patients. We find that injury-associated innate immune attack by natural killer/natural killer T cell and macrophage cells are instrumental in the failure of liver regeneration, and this can be overcome in Ghr-/- mice by adenoviral delivery of H2-Bl or by infusion of HLA-G protein. Further, H2-Bl knockdown in wild-type C57BL/6 mice showed elevated markers of inflammation after PHx, whereas Ghr-/- backcrossed on a strain with high endogenous H2-Bl expression showed a high rate of survival following PHx. CONCLUSIONS GH induction of H2-Bl expression is crucial for reducing innate immune-mediated apoptosis and promoting survival after PHx in C57BL/6 mice. Treatment with HLA-G may lead to improved clinical outcomes following liver surgery or transplantation.
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Affiliation(s)
- Mayumi Ishikawa
- Institute for Molecular BioscienceThe University of QueenslandSt. LuciaQLDAustralia.,Center for Endocrinology, Diabetes and ArteriosclerosisNippon Medical School Musashikosugi HospitalKawasakiJapan
| | - Andrew J Brooks
- Institute for Molecular BioscienceThe University of QueenslandSt. LuciaQLDAustralia.,The University of Queensland Diamantina InstituteThe University of QueenslandWoolloongabbaQLDAustralia
| | - Manuel A Fernández-Rojo
- Institute for Molecular BioscienceThe University of QueenslandSt. LuciaQLDAustralia.,The University of Queensland Diamantina InstituteThe University of QueenslandWoolloongabbaQLDAustralia.,Hepatic Fibrosis GroupQIMR Berghofer Medical Research InstituteBrisbaneQLDAustralia.,School of MedicineThe University of QueenslandBrisbaneQLDAustralia.,Hepatic Regenerative Medicine LaboratoryMadrid Institute for Advanced Studies in FoodCEI UAM+CSICMadridSpain
| | - Johan Medina
- The University of Queensland Diamantina InstituteThe University of QueenslandWoolloongabbaQLDAustralia
| | - Yash Chhabra
- Institute for Molecular BioscienceThe University of QueenslandSt. LuciaQLDAustralia.,The University of Queensland Diamantina InstituteThe University of QueenslandWoolloongabbaQLDAustralia
| | - Shiro Minami
- Center for Endocrinology, Diabetes and ArteriosclerosisNippon Medical School Musashikosugi HospitalKawasakiJapan
| | - Kathryn A Tunny
- The University of Queensland Diamantina InstituteThe University of QueenslandWoolloongabbaQLDAustralia
| | - Robert G Parton
- Institute for Molecular BioscienceThe University of QueenslandSt. LuciaQLDAustralia.,Centre for Microscopy and MicroanalysisThe University of QueenslandBrisbaneQLDAustralia
| | - Julian P Vivian
- Department of Biochemistry and Molecular Biology School of Biomedical SciencesMonash UniversityClaytonVICAustralia.,Australian Research Council Centre of Excellence in Advanced Molecular ImagingMonash UniversityClaytonVICAustralia
| | - Jamie Rossjohn
- Department of Biochemistry and Molecular Biology School of Biomedical SciencesMonash UniversityClaytonVICAustralia.,Australian Research Council Centre of Excellence in Advanced Molecular ImagingMonash UniversityClaytonVICAustralia.,Institute of Infection and ImmunityCardiff University School of MedicineHeath ParkCardiffUnited Kingdom
| | - Viral Chikani
- Princess Alexandra Hospital and Faculty of MedicineThe University of QueenslandBrisbaneQLDAustralia
| | - Grant A Ramm
- Hepatic Fibrosis GroupQIMR Berghofer Medical Research InstituteBrisbaneQLDAustralia.,School of MedicineThe University of QueenslandBrisbaneQLDAustralia
| | - Ken K Y Ho
- Princess Alexandra Hospital and Faculty of MedicineThe University of QueenslandBrisbaneQLDAustralia
| | - Michael J Waters
- Institute for Molecular BioscienceThe University of QueenslandSt. LuciaQLDAustralia
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34
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Lolo FN, Jiménez-Jiménez V, Sánchez-Álvarez M, Del Pozo MÁ. Tumor-stroma biomechanical crosstalk: a perspective on the role of caveolin-1 in tumor progression. Cancer Metastasis Rev 2021; 39:485-503. [PMID: 32514892 DOI: 10.1007/s10555-020-09900-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Tumor stiffening is a hallmark of malignancy that actively drives tumor progression and aggressiveness. Recent research has shed light onto several molecular underpinnings of this biomechanical process, which has a reciprocal crosstalk between tumor cells, stromal fibroblasts, and extracellular matrix remodeling at its core. This dynamic communication shapes the tumor microenvironment; significantly determines disease features including therapeutic resistance, relapse, or metastasis; and potentially holds the key for novel antitumor strategies. Caveolae and their components emerge as integrators of different aspects of cell function, mechanotransduction, and ECM-cell interaction. Here, we review our current knowledge on the several pivotal roles of the essential caveolar component caveolin-1 in this multidirectional biomechanical crosstalk and highlight standing questions in the field.
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Affiliation(s)
- Fidel Nicolás Lolo
- Mechanoadaptation and Caveolae Biology Lab, Cell and Developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Víctor Jiménez-Jiménez
- Mechanoadaptation and Caveolae Biology Lab, Cell and Developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Miguel Sánchez-Álvarez
- Mechanoadaptation and Caveolae Biology Lab, Cell and Developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Miguel Ángel Del Pozo
- Mechanoadaptation and Caveolae Biology Lab, Cell and Developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
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35
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Alvarez-Guaita A, Blanco-Muñoz P, Meneses-Salas E, Wahba M, Pollock AH, Jose J, Casado M, Bosch M, Artuch R, Gaus K, Lu A, Pol A, Tebar F, Moss SE, Grewal T, Enrich C, Rentero C. Annexin A6 Is Critical to Maintain Glucose Homeostasis and Survival During Liver Regeneration in Mice. Hepatology 2020; 72:2149-2164. [PMID: 32170749 DOI: 10.1002/hep.31232] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 02/20/2020] [Accepted: 02/28/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS Liver regeneration requires the organized and sequential activation of events that lead to restoration of hepatic mass. During this process, other vital liver functions need to be preserved, such as maintenance of blood glucose homeostasis, balancing the degradation of hepatic glycogen stores, and gluconeogenesis (GNG). Under metabolic stress, alanine is the main hepatic gluconeogenic substrate, and its availability is the rate-limiting step in this pathway. Na+ -coupled neutral amino acid transporters (SNATs) 2 and 4 are believed to facilitate hepatic alanine uptake. In previous studies, we demonstrated that a member of the Ca2+ -dependent phospholipid binding annexins, Annexin A6 (AnxA6), regulates membrane trafficking along endo- and exocytic pathways. Yet, although AnxA6 is abundantly expressed in the liver, its function in hepatic physiology remains unknown. In this study, we investigated the potential contribution of AnxA6 in liver regeneration. APPROACH AND RESULTS Utilizing AnxA6 knockout mice (AnxA6-/- ), we challenged liver function after partial hepatectomy (PHx), inducing acute proliferative and metabolic stress. Biochemical and immunofluorescent approaches were used to dissect AnxA6-/- mice liver proliferation and energetic metabolism. Most strikingly, AnxA6-/- mice exhibited low survival after PHx. This was associated with an irreversible and progressive drop of blood glucose levels. Whereas exogenous glucose administration or restoration of hepatic AnxA6 expression rescued AnxA6-/- mice survival after PHx, the sustained hypoglycemia in partially hepatectomized AnxA6-/- mice was the consequence of an impaired alanine-dependent GNG in AnxA6-/- hepatocytes. Mechanistically, cytoplasmic SNAT4 failed to recycle to the sinusoidal plasma membrane of AnxA6-/- hepatocytes 48 hours after PHx, impairing alanine uptake and, consequently, glucose production. CONCLUSIONS We conclude that the lack of AnxA6 compromises alanine-dependent GNG and liver regeneration in mice.
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Affiliation(s)
- Anna Alvarez-Guaita
- Unit of Cell Biology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.,Currently at Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Patricia Blanco-Muñoz
- Unit of Cell Biology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.,Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Elsa Meneses-Salas
- Unit of Cell Biology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.,Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Mohamed Wahba
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Abigail H Pollock
- Center for Vascular Research, The University of New South Wales, Sydney, NSW, Australia
| | - Jaimy Jose
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Mercedes Casado
- Clinical Biochemistry Department, Institut de Recerca Sant Joan de Déu and CIBERER, Barcelona, Spain
| | - Marta Bosch
- Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Rafael Artuch
- Clinical Biochemistry Department, Institut de Recerca Sant Joan de Déu and CIBERER, Barcelona, Spain
| | - Katharina Gaus
- Center for Vascular Research, The University of New South Wales, Sydney, NSW, Australia
| | - Albert Lu
- Department of Biochemistry, Stanford University School of Medicine, Stanford, CA
| | - Albert Pol
- Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Francesc Tebar
- Unit of Cell Biology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.,Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Stephen E Moss
- Institute of Ophthalmology, University College of London, London, United Kingdom
| | - Thomas Grewal
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Carlos Enrich
- Unit of Cell Biology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.,Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Carles Rentero
- Unit of Cell Biology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.,Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
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Fatty-acid-induced FABP5/HIF-1 reprograms lipid metabolism and enhances the proliferation of liver cancer cells. Commun Biol 2020; 3:638. [PMID: 33128030 PMCID: PMC7599230 DOI: 10.1038/s42003-020-01367-5] [Citation(s) in RCA: 134] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 10/08/2020] [Indexed: 12/14/2022] Open
Abstract
Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor essential for cancer cell survival. The reprogramming of lipid metabolism has emerged as a hallmark of cancer, yet the relevance of HIF-1α to this process remains elusive. In this study, we profile HIF-1α-interacting proteins using proteomics analysis and identify fatty acid-binding protein 5 (FABP5) as a critical HIF-1α-binding partner. In hepatocellular carcinoma (HCC) tissues, both FABP5 and HIF-1α are upregulated, and their expression levels are associated with poor prognosis. FABP5 enhances HIF-1α activity by promoting HIF-1α synthesis while disrupting FIH/HIF-1α interaction at the same time. Oleic-acid treatment activates the FABP5/HIF-1α axis, thereby promoting lipid accumulation and cell proliferation in HCC cells. Our results indicate that fatty-acid-induced FABP5 upregulation drives HCC progression through HIF-1-driven lipid metabolism reprogramming. Seo et al. identify fatty acid-binding protein 5 (FABP5) as a booster of HIF-1α activity. They find that oleic-acid treatment activates the FABP5/HIF-1α axis, promoting lipid accumulation and cell proliferation in liver cancer cells. This study provides insights into how fatty acids drive the progression of cancer.
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Oliva-Vilarnau N, Vorrink SU, Ingelman-Sundberg M, Lauschke VM. A 3D Cell Culture Model Identifies Wnt/ β-Catenin Mediated Inhibition of p53 as a Critical Step during Human Hepatocyte Regeneration. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2020; 7:2000248. [PMID: 32775153 PMCID: PMC7404138 DOI: 10.1002/advs.202000248] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 06/01/2020] [Indexed: 05/14/2023]
Abstract
The liver is a highly regenerative organ. While mature hepatocytes under homeostatic conditions are largely quiescent, upon injury, they rapidly enter the cell cycle to recover the damaged tissue. In rodents, a variety of injury models have provided important insights into the molecular underpinnings that govern the proliferative activation of quiescent hepatocytes. However, little is known about the molecular mechanisms of human hepatocyte regeneration and experimental methods to expand primary human hepatocytes (PHH). Here, a 3D spheroid model of PHH is established to study hepatocyte regeneration and integrative time-lapse multi-omics analyses show that upon isolation from the native liver PHH acquire a regenerative phenotype, as seen in vivo upon partial hepatectomy. However, proliferation is limited. By analyzing global promoter motif activities, it is predicted that activation of Wnt/β-catenin and inhibition of p53 signaling are critical factors required for human hepatocyte proliferation. Functional validations reveal that activation of Wnt signaling through external cues alone is sufficient to inhibit p53 and its proliferative senescence-inducing target PAI1 (SERPINE1) and drive proliferation of >50% of all PHH. A scalable 3D culture model is established to study the molecular and cellular biology of human hepatocyte regeneration. By using this model, an essential role of Wnt/β-catenin signaling during human hepatocyte regeneration is identified.
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Affiliation(s)
- Nuria Oliva-Vilarnau
- Department of Physiology and Pharmacology Karolinska Institutet Stockholm 171 77 Sweden
| | - Sabine U Vorrink
- Department of Physiology and Pharmacology Karolinska Institutet Stockholm 171 77 Sweden
| | | | - Volker M Lauschke
- Department of Physiology and Pharmacology Karolinska Institutet Stockholm 171 77 Sweden
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38
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Caldez MJ, Bjorklund M, Kaldis P. Cell cycle regulation in NAFLD: when imbalanced metabolism limits cell division. Hepatol Int 2020; 14:463-474. [PMID: 32578019 PMCID: PMC7366567 DOI: 10.1007/s12072-020-10066-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 06/06/2020] [Indexed: 12/12/2022]
Abstract
Cell division is essential for organismal growth and tissue homeostasis. It is exceptionally significant in tissues chronically exposed to intrinsic and external damage, like the liver. After decades of studying the regulation of cell cycle by extracellular signals, there are still gaps in our knowledge on how these two interact with metabolic pathways in vivo. Studying the cross-talk of these pathways has direct clinical implications as defects in cell division, signaling pathways, and metabolic homeostasis are frequently observed in liver diseases. In this review, we will focus on recent reports which describe various functions of cell cycle regulators in hepatic homeostasis. We will describe the interplay between the cell cycle and metabolism during liver regeneration after acute and chronic damage. We will focus our attention on non-alcoholic fatty liver disease, especially non-alcoholic steatohepatitis. The global incidence of non-alcoholic fatty liver disease is increasing exponentially. Therefore, understanding the interplay between cell cycle regulators and metabolism may lead to the discovery of novel therapeutic targets amenable to intervention.
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Affiliation(s)
- Matias J Caldez
- WPI Immunology Frontiers Research Centre, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Mikael Bjorklund
- Zhejiang University-University of Edinburgh (ZJU-UoE) Institute and 2nd Affiliated Hospital, Zhejiang University School of Medicine, 718 East Haizhou Rd., Haining, 314400, Zhejiang, People's Republic of China
| | - Philipp Kaldis
- Department of Clinical Sciences, Clinical Research Centre (CRC), Lund University, Box 50332, 202 13, Malmö, Sweden.
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Pol A, Morales-Paytuví F, Bosch M, Parton RG. Non-caveolar caveolins – duties outside the caves. J Cell Sci 2020; 133:133/9/jcs241562. [DOI: 10.1242/jcs.241562] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
ABSTRACT
Caveolae are invaginations of the plasma membrane that are remarkably abundant in adipocytes, endothelial cells and muscle. Caveolae provide cells with resources for mechanoprotection, can undergo fission from the plasma membrane and can regulate a variety of signaling pathways. Caveolins are fundamental components of caveolae, but many cells, such as hepatocytes and many neurons, express caveolins without forming distinguishable caveolae. Thus, the function of caveolins goes beyond their roles as caveolar components. The membrane-organizing and -sculpting capacities of caveolins, in combination with their complex intracellular trafficking, might contribute to these additional roles. Furthermore, non-caveolar caveolins can potentially interact with proteins normally excluded from caveolae. Here, we revisit the non-canonical roles of caveolins in a variety of cellular contexts including liver, brain, lymphocytes, cilia and cancer cells, as well as consider insights from invertebrate systems. Non-caveolar caveolins can determine the intracellular fluxes of active lipids, including cholesterol and sphingolipids. Accordingly, caveolins directly or remotely control a plethora of lipid-dependent processes such as the endocytosis of specific cargoes, sorting and transport in endocytic compartments, or different signaling pathways. Indeed, loss-of-function of non-caveolar caveolins might contribute to the common phenotypes and pathologies of caveolin-deficient cells and animals.
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Affiliation(s)
- Albert Pol
- Cell Compartments and Signaling Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036, Barcelona, Spain
- Department of Biomedical Sciences, Faculty of Medicine, Universitat de Barcelona, 08036, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Spain
| | - Frederic Morales-Paytuví
- Cell Compartments and Signaling Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036, Barcelona, Spain
| | - Marta Bosch
- Cell Compartments and Signaling Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036, Barcelona, Spain
- Department of Biomedical Sciences, Faculty of Medicine, Universitat de Barcelona, 08036, Barcelona, Spain
| | - Robert G. Parton
- Institute for Molecular Bioscience (IMB), The University of Queensland (UQ), Brisbane, Queensland 4072, Australia
- Centre for Microscopy and Microanalysis (CMM) IMB, The University of Queensland (UQ), Brisbane, Queensland 4072, Australia
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40
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Nutrient mTORC1 signaling contributes to hepatic lipid metabolism in the pathogenesis of non-alcoholic fatty liver disease. LIVER RESEARCH 2020. [DOI: 10.1016/j.livres.2020.02.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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41
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Hepatocyte caveolin-1 modulates metabolic gene profiles and functions in non-alcoholic fatty liver disease. Cell Death Dis 2020; 11:104. [PMID: 32029710 PMCID: PMC7005160 DOI: 10.1038/s41419-020-2295-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 01/18/2020] [Accepted: 01/20/2020] [Indexed: 11/08/2022]
Abstract
Caveolin-1 (CAV1) is a crucial regulator of lipid accumulation and metabolism. Previous studies have shown that global Cav1 deficiency affects lipid metabolism and hepatic steatosis. We aimed to analyze the consequences of hepatocyte-specific Cav1 knockout under healthy conditions and upon non-alcoholic fatty liver disease (NAFLD) development. Male and female hepatocyte-specific Cav1 knockout (HepCAV1ko) mice were fed a methionine/choline (MCD) deficient diet for 4 weeks. MCD feeding caused severe hepatic steatosis and slight fibrosis. In addition, liver function parameters, i.e., ALT, AST, and GLDH, were elevated, while cholesterol and glucose level were reduced upon MCD feeding. These differences were not affected by hepatocyte-specific Cav1 knockout. Microarray analysis showed strong differences in gene expression profiles of livers from HepCAV1ko mice compared those of global Cav1 knockout animals. Pathway enrichment analysis identified that metabolic alterations were sex-dimorphically regulated by hepatocyte-specific CAV1. In male HepCAV1ko mice, metabolic pathways were suppressed in NAFLD, whereas in female knockout mice induced. Moreover, gender-specific transcription profiles were modulated in healthy animals. In conclusion, our results demonstrate that hepatocyte-specific Cav1 knockout significantly altered gene profiles, did not affect liver steatosis and fibrosis in NAFLD and that gender had severe impact on gene expression patterns in healthy and diseased hepatocyte-specific Cav1 knockout mice.
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Haddad D, Al Madhoun A, Nizam R, Al-Mulla F. Role of Caveolin-1 in Diabetes and Its Complications. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:9761539. [PMID: 32082483 PMCID: PMC7007939 DOI: 10.1155/2020/9761539] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 12/10/2019] [Accepted: 12/26/2019] [Indexed: 12/25/2022]
Abstract
It is estimated that in 2017 there were 451 million people with diabetes worldwide. These figures are expected to increase to 693 million by 2045; thus, innovative preventative programs and treatments are a necessity to fight this escalating pandemic disorder. Caveolin-1 (CAV1), an integral membrane protein, is the principal component of caveolae in membranes and is involved in multiple cellular functions such as endocytosis, cholesterol homeostasis, signal transduction, and mechanoprotection. Previous studies demonstrated that CAV1 is critical for insulin receptor-mediated signaling, insulin secretion, and potentially the development of insulin resistance. Here, we summarize the recent progress on the role of CAV1 in diabetes and diabetic complications.
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Affiliation(s)
- Dania Haddad
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Ashraf Al Madhoun
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Rasheeba Nizam
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Fahd Al-Mulla
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
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Bao Q, Yu L, Chen D, Li L. Variation in the gut microbial community is associated with the progression of liver regeneration. Hepatol Res 2020; 50:121-136. [PMID: 31465626 DOI: 10.1111/hepr.13424] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 08/07/2019] [Accepted: 08/08/2019] [Indexed: 12/23/2022]
Abstract
AIM To highlight a potential dynamic interaction between intestinal bacteria (IB) and metabolites that might contribute to liver regeneration (LR). METHODS Male Sprague-Dawley rats were subjected to surgical removal of two-thirds of the liver and samples were collected over a 14-day period. Intestinal community and metabolic profiles were characterized to establish their potential interactions during liver regeneration. RESULTS Partial hepatectomy caused fluctuating changes in the gut microbiome, which paralleled the biological processes of LR. Briefly, the enhanced cell proliferation occurring within 30-48 h was associated with a decreased ratio of Firmicutes to Bacteroidetes reflected by a reduction in Ruminococcaceae and Lachnospiraceae, and an increase in Bacteroidaceae, Rikenellaceae, and Porphyromonadaceae, which was indicative of a lean phenotype. The microbiota derived from rats at 12-24 h and 3-14 days were characterized by elevated F/B ratios, suggesting the differing energy extract behaviors of microbiota during the course of LR. Functional changes of the shifted microbiota revealed by PICRUSt software confirmed the pyrosequencing results. The microbiome derived from hour 12 rats showed overpresentation of metabolism-related modules. In contrast, the microbiome derived from day 2 rats was functionally unique in "replication and repair", "amino acid metabolism," and "nucleoid metabolism." Upon examining the dynamic pattern of metabolic response, the specific pathways, including glycerophospholipid metabolism, taurine, and hypotaurine metabolism, were identified to be attributable to the systemic alterations in LR-related metabolism. Moreover, our data indicated that several key functional bacteria were strongly related to perturbations of the above pathways. CONCLUSION Gut flora could play a central role in manipulating metabolic responses in LR.
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Affiliation(s)
- Qiongling Bao
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Liang Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Deying Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
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Caveolin-1 Modulates Mechanotransduction Responses to Substrate Stiffness through Actin-Dependent Control of YAP. Cell Rep 2019; 25:1622-1635.e6. [PMID: 30404014 PMCID: PMC6231326 DOI: 10.1016/j.celrep.2018.10.024] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 08/16/2018] [Accepted: 10/03/2018] [Indexed: 02/04/2023] Open
Abstract
The transcriptional regulator YAP orchestrates many cellular functions, including tissue homeostasis, organ growth control, and tumorigenesis. Mechanical stimuli are a key input to YAP activity, but the mechanisms controlling this regulation remain largely uncharacterized. We show that CAV1 positively modulates the YAP mechanoresponse to substrate stiffness through actin-cytoskeleton-dependent and Hippo-kinase-independent mechanisms. RHO activity is necessary, but not sufficient, for CAV1-dependent mechanoregulation of YAP activity. Systematic quantitative interactomic studies and image-based small interfering RNA (siRNA) screens provide evidence that this actin-dependent regulation is determined by YAP interaction with the 14-3-3 protein YWHAH. Constitutive YAP activation rescued phenotypes associated with CAV1 loss, including defective extracellular matrix (ECM) remodeling. CAV1-mediated control of YAP activity was validated in vivo in a model of pancreatitis-driven acinar-to-ductal metaplasia. We propose that this CAV1-YAP mechanotransduction system controls a significant share of cell programs linked to these two pivotal regulators, with potentially broad physiological and pathological implications.
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45
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Role of farnesoid X receptor in hepatic steatosis in nonalcoholic fatty liver disease. Biomed Pharmacother 2019; 121:109609. [PMID: 31731192 DOI: 10.1016/j.biopha.2019.109609] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 10/23/2019] [Accepted: 10/25/2019] [Indexed: 12/12/2022] Open
Abstract
With the increased incidence of obesity, nonalcoholic fatty liver disease (NAFLD) has become a major global health concern. The pathogenesis of NAFLD has not yet been fully elucidated, and as few efficient pharmaceutical treatments are available for the condition, economic and medical burdens are heavy. Hepatic steatosis, as a precursor of NAFLD, plays a vital role in the pathological process of NAFLD. Hepatic steatosis is a consequence of lipid acquisition (i.e. free fatty acid uptake and de novo lipogenesis) exceeding lipid disposal (i.e. fatty acid oxidation and export as very-low-density lipoproteins). Therefore, restoring lipid homeostasis in the liver is an important therapeutic strategy of NAFLD. Farnesoid X receptor (FXR) is a major member of the ligand-activated nuclear receptor superfamily. Previous reviews have shown that FXR is a multipurpose receptor that plays an important role in regulating bile acid homeostasis, glucose and lipid metabolism, intestinal bacterial growth, and hepatic regeneration. This review focuses on the role of FXR in individual pathways that contribute to hepatic steatosis; it further demonstrates the molecular function of FXR in the pathogenesis of NAFLD.
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46
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Dohi T, Padmanabhan J, Akaishi S, Than PA, Terashima M, Matsumoto NN, Ogawa R, Gurtner GC. The Interplay of Mechanical Stress, Strain, and Stiffness at the Keloid Periphery Correlates with Increased Caveolin-1/ROCK Signaling and Scar Progression. Plast Reconstr Surg 2019; 144:58e-67e. [PMID: 31246819 DOI: 10.1097/prs.0000000000005717] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Fibroproliferative disorders result in excessive scar formation, are associated with high morbidity, and cost billions of dollars every year. Of these, keloid disease presents a particularly challenging clinical problem because the cutaneous scars progress beyond the original site of injury. Altered mechanotransduction has been implicated in keloid development, but the mechanisms governing scar progression into the surrounding tissue remain unknown. The role of mechanotransduction in keloids is further complicated by the differential mechanical properties of keloids and the surrounding skin. METHODS The authors used human mechanical testing, finite element modeling, and immunohistologic analyses of human specimens to clarify the complex interplay of mechanical stress, strain, and stiffness in keloid scar progression. RESULTS Changes in human position (i.e., standing, sitting, and supine) are correlated to dynamic changes in local stress/strain distribution, particularly in regions with a predilection for keloids. Keloids are composed of stiff tissue, which displays a fibrotic phenotype with relatively low proliferation. In contrast, the soft skin surrounding keloids is exposed to high mechanical strain that correlates with increased expression of the caveolin-1/rho signaling via rho kinase mechanotransduction pathway and elevated inflammation and proliferation, which may lead to keloid progression. CONCLUSIONS The authors conclude that changes in human position are strongly correlated with mechanical loading of the predilection sites, which leads to increased mechanical strain in the peripheral tissue surrounding keloids. Furthermore, increased mechanical strain in the peripheral tissue, which is the site of keloid progression, was correlated with aberrant expression of caveolin-1/ROCK signaling pathway. These findings suggest a novel mechanism for keloid progression.
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Affiliation(s)
- Teruyuki Dohi
- From the Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine; the Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School; and the Department of Civil and Environmental Engineering, Stanford University School of Engineering
| | - Jagannath Padmanabhan
- From the Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine; the Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School; and the Department of Civil and Environmental Engineering, Stanford University School of Engineering
| | - Satoshi Akaishi
- From the Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine; the Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School; and the Department of Civil and Environmental Engineering, Stanford University School of Engineering
| | - Peter A Than
- From the Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine; the Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School; and the Department of Civil and Environmental Engineering, Stanford University School of Engineering
| | - Masao Terashima
- From the Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine; the Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School; and the Department of Civil and Environmental Engineering, Stanford University School of Engineering
| | - Noriko N Matsumoto
- From the Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine; the Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School; and the Department of Civil and Environmental Engineering, Stanford University School of Engineering
| | - Rei Ogawa
- From the Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine; the Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School; and the Department of Civil and Environmental Engineering, Stanford University School of Engineering
| | - Geoffrey C Gurtner
- From the Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine; the Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School; and the Department of Civil and Environmental Engineering, Stanford University School of Engineering
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Cell Cycle Progression Regulates Biogenesis and Cellular Localization of Lipid Droplets. Mol Cell Biol 2019; 39:MCB.00374-18. [PMID: 30782775 PMCID: PMC6469922 DOI: 10.1128/mcb.00374-18] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 01/25/2019] [Indexed: 12/19/2022] Open
Abstract
Intracellular lipid accumulation has been associated with a poor prognosis in cancer. We have previously reported the involvement of lipid droplets in cell proliferation in colon cancer cells, suggesting a role for these organelles in cancer development. Intracellular lipid accumulation has been associated with a poor prognosis in cancer. We have previously reported the involvement of lipid droplets in cell proliferation in colon cancer cells, suggesting a role for these organelles in cancer development. In this study, we evaluate the role of lipid droplets in cell cycle regulation and cellular transformation. Cell cycle synchronization of NIH 3T3 cells revealed increased numbers and dispersed distribution of lipid droplets specifically during S phase. Also, the transformed cell lineage NIH 3T3-H-rasV12 showed an accumulation of both lipid droplets and PLIN2 protein above the levels in NIH 3T3 cells. PLIN2 gene overexpression, however, was not able to induce NIH 3T3 cell transformation, disproving the hypothesis that PLIN2 is an oncogene. Furthermore, positive PLIN2 staining was strongly associated with highly proliferative Ki-67-positive areas in human colon adenocarcinoma tissue samples. Taken together, these results indicate that cell cycle progression is associated with tight regulation of lipid droplets, a process that is altered in transformed cells, suggesting the existence of a mechanism that connects cell cycle progression and cell proliferation with lipid accumulation.
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Ju C, Liu C, Yan S, Wang Y, Mao X, Liang M, Huang K. Poly(ADP-ribose) Polymerase-1 is required for hepatocyte proliferation and liver regeneration in mice. Biochem Biophys Res Commun 2019; 511:531-535. [DOI: 10.1016/j.bbrc.2019.02.091] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 02/10/2019] [Accepted: 02/17/2019] [Indexed: 12/22/2022]
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49
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Jiang Y, Feng D, Ma X, Fan S, Gao Y, Fu K, Wang Y, Sun J, Yao X, Liu C, Zhang H, Xu L, Liu A, Gonzalez FJ, Yang Y, Gao B, Huang M, Bi H. Pregnane X Receptor Regulates Liver Size and Liver Cell Fate by Yes-Associated Protein Activation in Mice. Hepatology 2019; 69:343-358. [PMID: 30048004 PMCID: PMC6324985 DOI: 10.1002/hep.30131] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Accepted: 05/30/2018] [Indexed: 12/13/2022]
Abstract
Activation of pregnane X receptor (PXR), a nuclear receptor that controls xenobiotic and endobiotic metabolism, is known to induce liver enlargement, but the molecular signals and cell types responding to PXR-induced hepatomegaly remain unknown. In this study, the effect of PXR activation on liver enlargement and cell change was evaluated in several strains of genetically modified mice and animal models. Lineage labeling using AAV-Tbg-Cre-treated Rosa26EYFP mice or Sox9-CreERT , Rosa26EYFP mice was performed and Pxr-null mice or AAV Yap short hairpin RNA (shRNA)-treated mice were used to confirm the role of PXR or yes-associated protein (YAP). Treatment with selective PXR activators induced liver enlargement and accelerated regeneration in wild-type (WT) and PXR-humanized mice, but not in Pxr-null mice, by increase of cell size, induction of a regenerative hybrid hepatocyte (HybHP) reprogramming, and promotion of hepatocyte and HybHP proliferation. Mechanistically, PXR interacted with YAP and PXR activation induced nuclear translocation of YAP. Blockade of YAP abolished PXR-induced liver enlargement in mice. Conclusion: These findings revealed a function of PXR in enlarging liver size and changing liver cell fate by activation of the YAP signaling pathway. These results have implications for understanding the physiological functions of PXR and suggest the potential for manipulation of liver size and liver cell fate.
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Affiliation(s)
- Yiming Jiang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Xiaochao Ma
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Shicheng Fan
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Yue Gao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Kaili Fu
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Ying Wang
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiahong Sun
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Xinpeng Yao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Conghui Liu
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Huizhen Zhang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Leqian Xu
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Aiming Liu
- Medical School of Ningbo University, Ningbo, China
| | - Frank J. Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Yingzi Yang
- Harvard School of Dental Medicine, Boston, MA, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Min Huang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Huichang Bi
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.,Correspondence to: Hui-chang Bi, Ph.D., School of Pharmaceutical Sciences, Sun Yat-sen University, 132# Waihuandong Road, Guangzhou University City, Guangzhou 510006, P. R. China, Phone: +86-20-39943470, Fax: +86-20-39943000,
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Rausch V, Bostrom JR, Park J, Bravo IR, Feng Y, Hay DC, Link BA, Hansen CG. The Hippo Pathway Regulates Caveolae Expression and Mediates Flow Response via Caveolae. Curr Biol 2018; 29:242-255.e6. [PMID: 30595521 PMCID: PMC6345631 DOI: 10.1016/j.cub.2018.11.066] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 09/27/2018] [Accepted: 11/28/2018] [Indexed: 12/11/2022]
Abstract
The Hippo pathway plays major roles in development, regeneration, and cancer. Its activity is tightly regulated by both diffusible chemical ligands and mechanical stimuli. The pathway consists of a series of kinases that can control the sub-cellular localization and stability of YAP or TAZ, homologous transcriptional co-factors. Caveolae, small (60–100 nm) bulb-like invaginations of the plasma membrane, are comprised predominantly of caveolin and cavin proteins and can respond to mechanical stimuli. Here, we show that YAP/TAZ, the major transcriptional mediators of the Hippo pathway, are critical for expression of caveolae components and therefore caveolae formation in both mammalian cells and zebrafish. In essence, without YAP/TAZ, the cell loses an entire organelle. CAVEOLIN1 and CAVIN1, the two essential caveolar genes, are direct target genes of YAP/TAZ, regulated via TEA domain (TEAD) transcription factors. Notably, YAP/TAZ become nuclear enriched and facilitate target gene transcription in cells with diminished levels of caveolae. Furthermore, caveolar-mediated shear stress response activates YAP/TAZ. These data link caveolae to Hippo signaling in the context of cellular responses to mechanical stimuli and suggest activity-based feedback regulation between components of caveolae and the outputs of the Hippo pathway.
YAP/TAZ are critical for CAVIN1 and CAVEOLIN1 expression and caveolae formation The essential caveolar genes CAVIN1 and CAVEOLIN1 are direct YAP/TAZ-TEAD target genes YAP/TAZ are hyperactivated in caveolae-deficient cells Caveolae facilitate YAP/TAZ-mediated shear stress response
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Affiliation(s)
- Valentina Rausch
- University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh bioQuarter, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Jonathan R Bostrom
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Jiwon Park
- University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh bioQuarter, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Isabel R Bravo
- University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh bioQuarter, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Yi Feng
- University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh bioQuarter, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - David C Hay
- MRC Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh bioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Brian A Link
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Carsten G Hansen
- University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh bioQuarter, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
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