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Karim M, Prey J, Willer F, Leiner H, Yasser M, Dombrowski F, Ribback S. Hepatic Deletion of Carbohydrate Response Element Binding Protein Impairs Hepatocarcinogenesis in a High-Fat Diet-Induced Mouse Model. Int J Mol Sci 2025; 26:2246. [PMID: 40076869 PMCID: PMC11900174 DOI: 10.3390/ijms26052246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 02/06/2025] [Accepted: 02/07/2025] [Indexed: 03/14/2025] Open
Abstract
The transcription factor carbohydrate response element binding protein (ChREBP) has emerged as a crucial regulator of hepatic glucose and lipid metabolism. The increased ChREBP activity involves the pro-oncogenic PI3K/AKT/mTOR signaling pathway that induces aberrant lipogenesis, thereby promoting hepatocellular carcinomas (HCC). However, the molecular pathogenesis of ChREBP-related hepatocarcinogenesis remains unexplored in the high-fat diet (HFD)-induced mouse model. Male C57BL/6J (WT) and liver-specific (L)-ChREBP-KO mice were maintained on either a HFD or a control diet for 12, 24, and 48 weeks, starting at the age of 4 weeks. At the end of the feeding period, mice were perfused, and liver tissues were formalin-fixed, paraffin-embedded, sectioned, and stained for histological and immunohistochemical analysis. Biochemical and gene expression analysis were conducted using serum and frozen liver tissue. Mice fed with HFD showed a significant increase (p < 0.05) in body weight from 8 weeks onwards compared to the control. WT and L-ChREBP-KO mice also demonstrated a significant increase (p < 0.05) in liver-to-body weight ratio in the 48-week HFD group. HFD mice exhibited a gradual rise in hepatic lipid accumulation over time, with 24-week mice showing a 20-30% increase in fat content, which further advanced to 80-100% fat accumulation at 48 weeks. Both dietary source and the increased expression of lipogenic pathways at transcriptional and protein levels induced steatosis and steatohepatitis in the HFD group. Moreover, WT mice on a HFD exhibited markedly higher inflammation compared to the L-ChREBP-KO mice. The enhanced lipogenesis, glycolysis, persistent inflammation, and activation of the AKT/mTOR pathway collectively resulted in significant metabolic disturbances, thereby promoting HCC development and progression in WT mice. In contrast, hepatic loss of ChREBP resulted in reduced hepatocyte proliferation in the HFD group, which significantly contributed to the impaired hepatocarcinogenesis and a reduced HCC occurrence in the L-ChREBP-KO mice. Our present study implicates that prolonged HFD feeding contributes to NAFLD/NASH, which in turn progresses to HCC development in WT mice. Collectively, hepatic ChREBP deletion ameliorates hepatic inflammation and metabolic alterations, thereby impairing NASH-driven hepatocarcinogenesis.
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Affiliation(s)
| | | | | | | | | | | | - Silvia Ribback
- Institute of Pathology, University Medicine Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (M.K.); (J.P.); (F.W.); (M.Y.); (F.D.)
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2
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Ribback S, Peters K, Yasser M, Prey J, Wilhelmi P, Su Q, Dombrowski F, Bannasch P. Hepatocellular Ballooning is Due to Highly Pronounced Glycogenosis Potentially Associated with Steatosis and Metabolic Reprogramming. J Clin Transl Hepatol 2024; 12:52-61. [PMID: 38250461 PMCID: PMC10794273 DOI: 10.14218/jcth.2023.00242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 08/22/2023] [Accepted: 09/05/2023] [Indexed: 01/23/2024] Open
Abstract
Background and Aims Hepatocellular ballooning is a common finding in chronic liver disease, mainly characterized by rarefied cytoplasm that often contains Mallory-Denk bodies (MDB). Ballooning has mostly been attributed to degeneration but its striking resemblance to glycogenotic/steatotic changes characterizing preneoplastic hepatocellular lesions in animal models and chronic human liver diseases prompts the question whether ballooned hepatocytes (BH) are damaged cells on the path to death or rather viable cells, possibly involved in neoplastic development. Methods Using specimens from 96 cirrhotic human livers, BH characteristics were assessed for their glycogen/lipid stores, enzyme activities, and proto-oncogenic signaling cascades by enzyme- and immunohistochemical approaches with serial paraffin and cryostat sections. Results BH were present in 43.8% of cirrhotic livers. Particularly pronounced excess glycogen storage of (glycogenosis) and/or lipids (steatosis) were characteristic, ground glass features and MDB were often observed. Decreased glucose-6-phosphatase, increased glucose-6-phosphate dehydrogenase activity and altered immunoreactivity of enzymes involved in glycolysis, lipid metabolism, and cholesterol biosynthesis were discovered. Furthermore, components of the insulin signaling cascade were upregulated along with insulin dependent glucose transporter glucose transporter 4 and the v-akt murine thymoma viral oncogene homolog/mammalian target of rapamycin signaling pathway associated with de novo lipogenesis. Conclusions BH are hallmarked by particularly pronounced glycogenosis with facultative steatosis, many of their features being reminiscent of metabolic aberrations documented in preneoplastic hepatocellular lesions in experimental animals and chronic human liver diseases. Hence, BH are not damaged entities facing death but rather viable cells featuring metabolic reprogramming, indicative of a preneoplastic nature.
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Affiliation(s)
- Silvia Ribback
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Kristin Peters
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Mohd Yasser
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Jessica Prey
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Paula Wilhelmi
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Qin Su
- Cell Marque, Millipore-Sigma, Rocklin, CA, USA
| | - Frank Dombrowski
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Peter Bannasch
- German Cancer Research Center (DKFZ), Heidelberg, Germany
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3
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Wang S, Zhou Y, Yu R, Ling J, Li B, Yang C, Cheng Z, Qian R, Lin Z, Yu C, Zheng J, Zheng X, Jia Q, Wu W, Wu Q, Chen M, Yuan S, Dong W, Shi Y, Jansen R, Yang C, Hao Y, Yao M, Qin W, Jin H. Loss of hepatic FTCD promotes lipid accumulation and hepatocarcinogenesis by upregulating PPARγ and SREBP2. JHEP Rep 2023; 5:100843. [PMID: 37675273 PMCID: PMC10477690 DOI: 10.1016/j.jhepr.2023.100843] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 06/02/2023] [Accepted: 06/26/2023] [Indexed: 09/08/2023] Open
Abstract
Background & Aims Exploiting key regulators responsible for hepatocarcinogenesis is of great importance for the prevention and treatment of hepatocellular carcinoma (HCC). However, the key players contributing to hepatocarcinogenesis remain poorly understood. We explored the molecular mechanisms underlying the carcinogenesis and progression of HCC for the development of potential new therapeutic targets. Methods The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) and Genotype-Tissue Expression (GTEx) databases were used to identify genes with enhanced expression in the liver associated with HCC progression. A murine liver-specific Ftcd knockout (Ftcd-LKO) model was generated to investigate the role of formimidoyltransferase cyclodeaminase (FTCD) in HCC. Multi-omics analysis of transcriptomics, metabolomics, and proteomics data were applied to further analyse the molecular effects of FTCD expression on hepatocarcinogenesis. Functional and biochemical studies were performed to determine the significance of loss of FTCD expression and the therapeutic potential of Akt inhibitors in FTCD-deficient cancer cells. Results FTCD is highly expressed in the liver but significantly downregulated in HCC. Patients with HCC and low levels of FTCD exhibited worse prognosis, and patients with liver cirrhosis and low FTCD levels exhibited a notable higher probability of developing HCC. Hepatocyte-specific knockout of FTCD promoted both chronic diethylnitrosamine-induced and spontaneous hepatocarcinogenesis in mice. Multi-omics analysis showed that loss of FTCD affected fatty acid and cholesterol metabolism in hepatocarcinogenesis. Mechanistically, loss of FTCD upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element-binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis. Conclusions Taken together, we identified a FTCD-regulated lipid metabolic mechanism involving PPARγ and SREBP2 signaling in hepatocarcinogenesis and provide a rationale for therapeutically targeting of HCC driven by downregulation of FTCD. Impact and implications Exploiting key molecules responsible for hepatocarcinogenesis is significant for the prevention and treatment of HCC. Herein, we identified formimidoyltransferase cyclodeaminase (FTCD) as the top enhanced gene, which could serve as a predictive and prognostic marker for patients with HCC. We generated and characterised the first Ftcd liver-specific knockout murine model. We found loss of FTCD expression upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element-binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis, and provided a rationale for therapeutic targeting of HCC driven by downregulation of FTCD.
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Affiliation(s)
- Siying Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yangyang Zhou
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ruobing Yu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Ling
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Botai Li
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen Yang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhuoan Cheng
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ruolan Qian
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhang Lin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chengtao Yu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiaojiao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xingling Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qi Jia
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Wu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiangxin Wu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mengnuo Chen
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shengxian Yuan
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Wei Dong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Yaoping Shi
- Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Robin Jansen
- Division of Molecular Carcinogenesis, Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Chen Yang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co. Ltd., Nanjing, China
| | - Yujun Hao
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming Yao
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haojie Jin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Fedulova MV, Bogomolov DV, Kupriyanov DD, Safronova AN. [Role of Kraevsky cells in forensic histological diagnostics]. Sud Med Ekspert 2023; 66:55-58. [PMID: 36719315 DOI: 10.17116/sudmed20236601155] [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: 02/01/2023]
Abstract
The study objective is to establish the role of light hepatocytes (Kraevsky cells) for forensic histological diagnosis of glycogen depletion in the liver due to various conditions, including shock. A standard histological examination of liver samples of persons who died from various causes was performed; routine staining with hematoxylin and eosin and additional staining by the PAS method was used. Histotopographic comparison of cross sections was performed to clarify the localization of light hepatocytes with different PAS staining results. It was shown that light hepatocytes have different morphological features, localization, and results of PAS staining, regardless of the cause of death, and are not related to glycogen depletion in them. Light hepatocytes (Kraevski cells) cannot be used as a sign of glycogen depletion and/or shock.
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Affiliation(s)
- M V Fedulova
- Russian Center of Forensic Medical Expertise, Moscow, Russia
| | - D V Bogomolov
- Russian Center of Forensic Medical Expertise, Moscow, Russia
| | - D D Kupriyanov
- Russian Center of Forensic Medical Expertise, Moscow, Russia
| | - A N Safronova
- Russian Center of Forensic Medical Expertise, Moscow, Russia
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Schelbert S, Schindeldecker M, Drebber U, Witzel HR, Weinmann A, Dries V, Schirmacher P, Roth W, Straub BK. Lipid Droplet-Associated Proteins Perilipin 1 and 2: Molecular Markers of Steatosis and Microvesicular Steatotic Foci in Chronic Hepatitis C. Int J Mol Sci 2022; 23:ijms232415456. [PMID: 36555099 PMCID: PMC9778710 DOI: 10.3390/ijms232415456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/29/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
Chronic infection with hepatitis C (HCV) is a major risk factor in the development of cirrhosis and hepatocellular carcinoma. Lipid metabolism plays a major role in the replication and deposition of HCV at lipid droplets (LDs). We have demonstrated the importance of LD-associated proteins of the perilipin family in steatotic liver diseases. Using a large collection of 231 human liver biopsies with HCV, perilipins 1 and 2 have been localized to LDs of hepatocytes that correlate with the degree of steatosis and specific HCV genotypes, but not significantly with the HCV viral load. Perilipin 1- and 2-positive microvesicular steatotic foci were observed in 36% of HCV liver biopsies, and also in chronic hepatitis B, autoimmune hepatitis and mildly steatotic or normal livers, but less or none were observed in normal livers of younger patients. Microvesicular steatotic foci did not frequently overlap with glycogenotic/clear cell foci as determined by PAS stain in serial sections. Steatotic foci were detected in all liver zones with slight architectural disarrays, as demonstrated by immunohistochemical glutamine synthetase staining of zone three, but without elevated Ki67-proliferation rates. In conclusion, microvesicular steatotic foci are frequently found in chronic viral hepatitis, but the clinical significance of these foci is so far not clear.
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Affiliation(s)
- Selina Schelbert
- Institute of Pathology, University Medical Center Mainz, 55131 Mainz, Germany
- Institute of Pathology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany
| | | | - Uta Drebber
- Institute of Pathology, University Clinic Cologne, 50931 Cologne, Germany
| | - Hagen Roland Witzel
- Institute of Pathology, University Medical Center Mainz, 55131 Mainz, Germany
| | - Arndt Weinmann
- Department of Internal Medicine, University Medical Center, 55131 Mainz, Germany
| | - Volker Dries
- Institute of Pathology, University Clinic Cologne, 50931 Cologne, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Medical Center Heidelberg, 69120 Heidelberg, Germany
| | - Wilfried Roth
- Institute of Pathology, University Medical Center Mainz, 55131 Mainz, Germany
| | - Beate Katharina Straub
- Institute of Pathology, University Medical Center Mainz, 55131 Mainz, Germany
- Correspondence: ; Tel.: +49-6131-17-7307
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6
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Research progress on the role of cholesterol in hepatocellular carcinoma. Eur J Pharmacol 2022; 938:175410. [DOI: 10.1016/j.ejphar.2022.175410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 11/07/2022] [Accepted: 11/21/2022] [Indexed: 11/27/2022]
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Ye Z, Song B, Lee PM, Ohliger MA, Laustsen C. Hyperpolarized carbon 13 MRI in liver diseases: Recent advances and future opportunities. Liver Int 2022; 42:973-983. [PMID: 35230742 PMCID: PMC9313895 DOI: 10.1111/liv.15222] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 01/20/2022] [Accepted: 02/04/2022] [Indexed: 02/05/2023]
Abstract
Hyperpolarized carbon-13 magnetic resonance imaging (HP 13 C MRI) is a recently translated metabolic imaging technique. With dissolution dynamic nuclear polarization (d-DNP), more than 10 000-fold signal enhancement can be readily reached, making it possible to visualize real-time metabolism and specific substrate-to-metabolite conversions in the liver after injecting carbon-13 labelled probes. Increasing evidence suggests that HP 13 C MRI is a potential tool in detecting liver abnormalities, predicting disease progression and monitoring response treatment. In this review, we will introduce the recent progresses of HP 13 C MRI in diffuse liver diseases and liver malignancies and discuss its future opportunities from a clinical perspective, hoping to provide a comprehensive overview of this novel technique in liver diseases and highlight its scientific and clinical potential in the field of hepatology.
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Affiliation(s)
- Zheng Ye
- Department of RadiologyWest China Hospital, Sichuan UniversityChengduSichuanChina
- The MR Research Center, Department of Clinical MedicineAarhus UniversityAarhusDenmark
| | - Bin Song
- Department of RadiologyWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Philip M. Lee
- Department of Radiology and Biomedical ImagingUniversity of CaliforniaSan FranciscoCaliforniaUSA
| | - Michael A. Ohliger
- Department of Radiology and Biomedical ImagingUniversity of CaliforniaSan FranciscoCaliforniaUSA
| | - Christoffer Laustsen
- The MR Research Center, Department of Clinical MedicineAarhus UniversityAarhusDenmark
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8
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Nuernberger V, Mortoga S, Metzendorf C, Burkert C, Ehricke K, Knuth E, Zimmer J, Singer S, Nath N, Karim M, Yasser M, Calvisi DF, Dombrowski F, Ribback S. Hormonally Induced Hepatocellular Carcinoma in Diabetic Wild Type and Carbohydrate Responsive Element Binding Protein Knockout Mice. Cells 2021; 10:2787. [PMID: 34685767 PMCID: PMC8534692 DOI: 10.3390/cells10102787] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 10/08/2021] [Accepted: 10/12/2021] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE In the rat, the pancreatic islet transplantation model is an established method to induce hepatocellular carcinomas (HCC), due to insulin-mediated metabolic and molecular alterations like increased glycolysis and de novo lipogenesis and the oncogenic AKT/mTOR pathway including upregulation of the transcription factor Carbohydrate-response element-binding protein (ChREBP). ChREBP could therefore represent an essential oncogenic co-factor during hormonally induced hepatocarcinogenesis. METHODS Pancreatic islet transplantation was implemented in diabetic C57Bl/6J (wild type, WT) and ChREBP-knockout (KO) mice for 6 and 12 months. Liver tissue was examined using histology, immunohistochemistry, electron microscopy and Western blot analysis. Finally, we performed NGS-based transcriptome analysis between WT and KO liver tumor tissues. RESULTS Three hepatocellular carcinomas were detectable after 6 and 12 months in diabetic transplanted WT mice, but only one in a KO mouse after 12 months. Pre-neoplastic clear cell foci (CCF) were also present in liver acini downstream of the islets in WT and KO mice. In KO tumors, glycolysis, de novo lipogenesis and AKT/mTOR signalling were strongly downregulated compared to WT lesions. Extrafocal liver tissue of diabetic, transplanted KO mice revealed less glycogen storage and proliferative activity than WT mice. From transcriptome analysis, we identified a set of transcripts pertaining to metabolic, oncogenic and immunogenic pathways that are differentially expressed between tumors of WT and KO mice. Of 315 metabolism-associated genes, we observed 199 genes that displayed upregulation in the tumor of WT mice, whereas 116 transcripts showed their downregulated expression in KO mice tumor. CONCLUSIONS The pancreatic islet transplantation model is a suitable method to study hormonally induced hepatocarcinogenesis also in mice, allowing combination with gene knockout models. Our data indicate that deletion of ChREBP delays insulin-induced hepatocarcinogenesis, suggesting a combined oncogenic and lipogenic function of ChREBP along AKT/mTOR-mediated proliferation of hepatocytes and induction of hepatocellular carcinoma.
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MESH Headings
- Animals
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism
- Carcinogenesis/metabolism
- Carcinogenesis/pathology
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/ultrastructure
- Cell Proliferation
- Diabetes Mellitus, Experimental/blood
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Experimental/metabolism
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Glycogen/metabolism
- Glycolysis
- Hormones/adverse effects
- Lipogenesis
- Liver/metabolism
- Liver/pathology
- Liver Neoplasms/blood
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Liver Neoplasms/ultrastructure
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Mice
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Affiliation(s)
- Vincent Nuernberger
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (V.N.); (S.M.); (C.M.); (C.B.); (K.E.); (E.K.); (J.Z.); (S.S.); (M.K.); (M.Y.); (F.D.)
| | - Sharif Mortoga
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (V.N.); (S.M.); (C.M.); (C.B.); (K.E.); (E.K.); (J.Z.); (S.S.); (M.K.); (M.Y.); (F.D.)
| | - Christoph Metzendorf
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (V.N.); (S.M.); (C.M.); (C.B.); (K.E.); (E.K.); (J.Z.); (S.S.); (M.K.); (M.Y.); (F.D.)
- Department of Immunology, Genetics and Pathology, Uppsala University, 75108 Uppsala, Sweden
| | - Christian Burkert
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (V.N.); (S.M.); (C.M.); (C.B.); (K.E.); (E.K.); (J.Z.); (S.S.); (M.K.); (M.Y.); (F.D.)
| | - Katrina Ehricke
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (V.N.); (S.M.); (C.M.); (C.B.); (K.E.); (E.K.); (J.Z.); (S.S.); (M.K.); (M.Y.); (F.D.)
| | - Elisa Knuth
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (V.N.); (S.M.); (C.M.); (C.B.); (K.E.); (E.K.); (J.Z.); (S.S.); (M.K.); (M.Y.); (F.D.)
| | - Jenny Zimmer
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (V.N.); (S.M.); (C.M.); (C.B.); (K.E.); (E.K.); (J.Z.); (S.S.); (M.K.); (M.Y.); (F.D.)
| | - Stephan Singer
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (V.N.); (S.M.); (C.M.); (C.B.); (K.E.); (E.K.); (J.Z.); (S.S.); (M.K.); (M.Y.); (F.D.)
- Institut fuer Pathologie, Universitaetsklinikum Tübingen, 72076 Tübingen, Germany
| | - Neetika Nath
- Institut fuer Bioinformatik, Universitaetsmedizin Greifswald, 17475 Greifswald, Germany;
| | - Majedul Karim
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (V.N.); (S.M.); (C.M.); (C.B.); (K.E.); (E.K.); (J.Z.); (S.S.); (M.K.); (M.Y.); (F.D.)
| | - Mohd Yasser
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (V.N.); (S.M.); (C.M.); (C.B.); (K.E.); (E.K.); (J.Z.); (S.S.); (M.K.); (M.Y.); (F.D.)
| | - Diego F. Calvisi
- Institut fuer Pathologie, Universitaetsklinikum Regensburg, 93053 Regensburg, Germany;
| | - Frank Dombrowski
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (V.N.); (S.M.); (C.M.); (C.B.); (K.E.); (E.K.); (J.Z.); (S.S.); (M.K.); (M.Y.); (F.D.)
| | - Silvia Ribback
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (V.N.); (S.M.); (C.M.); (C.B.); (K.E.); (E.K.); (J.Z.); (S.S.); (M.K.); (M.Y.); (F.D.)
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[Preneoplastic glycogenotic lesions of the liver and kidney : Metabolic and molecular alterations in preneoplastic clear cell lesions of the liver and the kidney in experimental and human carcinogenesis]. DER PATHOLOGE 2020; 41:83-90. [PMID: 33346873 DOI: 10.1007/s00292-020-00879-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/23/2020] [Indexed: 11/27/2022]
Abstract
AIM The focus of these five studies was on human clear cell, glycogen-storing lesions of the liver and kidney, which pertain to preneoplastic lesions of hepatocellular carcinoma and renal cell carcinoma in animal models of diabetes-associated carcinogenesis. MATERIAL AND METHODS Noncirrhotic hepatic and renal tissue of humans, rats, and mice were analyzed with histology, immunohistochemistry, electron microscopy, and molecular biologic methods. RESULTS In humans, clear cell lesions often occur in noncirrhotic liver and renal tissue. They resemble preneoplastic lesions of experimental hepato- and nephrocarcinogenesis regarding glycogen storage, increased proliferative activity, upregulation of glycolysis and de novo lipogenesis (lipogenic phenotype), and activated protooncogenic signaling pathway of AKT/mTOR. In two models of murine hepatocarcinogenesis, the important role of the transcription factor ChREBP as a "metabolic oncogene" was characterized. CONCLUSION In these studies, the significance of small glycogen storing parenchymal alterations for carcinogenesis in human noncirrhotic liver and kidney was demonstrated due to their already present metabolic and molecular alterations. Therefore, they have to represent indicator lesions for an increased risk of carcinogenesis. Activation of the protooncogenic pathway AKT/mTOR as well as the transcription factor ChREBP and the manifestation of the lipogenic phenotype are crucial during the processes of carcinogenesis.
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10
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Metzendorf C, Wineberger K, Rausch J, Cigliano A, Peters K, Sun B, Mennerich D, Kietzmann T, Calvisi DF, Dombrowski F, Ribback S. Transcriptomic and Proteomic Analysis of Clear Cell Foci (CCF) in the Human Non-Cirrhotic Liver Identifies Several Differentially Expressed Genes and Proteins with Functions in Cancer Cell Biology and Glycogen Metabolism. Molecules 2020; 25:molecules25184141. [PMID: 32927708 PMCID: PMC7570661 DOI: 10.3390/molecules25184141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/06/2020] [Accepted: 09/07/2020] [Indexed: 01/06/2023] Open
Abstract
Clear cell foci (CCF) of the liver are considered to be pre-neoplastic lesions of hepatocellular adenomas and carcinomas. They are hallmarked by glycogen overload and activation of AKT (v-akt murine thymoma viral oncogene homolog)/mTOR (mammalian target of rapamycin)-signaling. Here, we report the transcriptome and proteome of CCF extracted from human liver biopsies by laser capture microdissection. We found 14 genes and 22 proteins differentially expressed in CCF and the majority of these were expressed at lower levels in CCF. Using immunohistochemistry, the reduced expressions of STBD1 (starch-binding domain-containing protein 1), USP28 (ubiquitin-specific peptidase 28), monad/WDR92 (WD repeat domain 92), CYB5B (Cytochrome b5 type B), and HSPE1 (10 kDa heat shock protein, mitochondrial) were validated in CCF in independent specimens. Knockout of Stbd1, the gene coding for Starch-binding domain-containing protein 1, in mice did not have a significant effect on liver glycogen levels, indicating that additional factors are required for glycogen overload in CCF. Usp28 knockout mice did not show changes in glycogen storage in diethylnitrosamine-induced liver carcinoma, demonstrating that CCF are distinct from this type of cancer model, despite the decreased USP28 expression. Moreover, our data indicates that decreased USP28 expression is a novel factor contributing to the pre-neoplastic character of CCF. In summary, our work identifies several novel and unexpected candidates that are differentially expressed in CCF and that have functions in glycogen metabolism and tumorigenesis.
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Affiliation(s)
- Christoph Metzendorf
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (C.M.); (K.W.); (J.R.); (A.C.); (K.P.); (D.F.C.); (F.D.)
| | - Katharina Wineberger
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (C.M.); (K.W.); (J.R.); (A.C.); (K.P.); (D.F.C.); (F.D.)
| | - Jenny Rausch
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (C.M.); (K.W.); (J.R.); (A.C.); (K.P.); (D.F.C.); (F.D.)
| | - Antonio Cigliano
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (C.M.); (K.W.); (J.R.); (A.C.); (K.P.); (D.F.C.); (F.D.)
| | - Kristin Peters
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (C.M.); (K.W.); (J.R.); (A.C.); (K.P.); (D.F.C.); (F.D.)
| | - Baodong Sun
- Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA;
| | - Daniela Mennerich
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90570 Oulu, Finland; (D.M.); (T.K.)
- Biocenter Oulu, University of Oulu, 90570 Oulu, Finland
| | - Thomas Kietzmann
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90570 Oulu, Finland; (D.M.); (T.K.)
- Biocenter Oulu, University of Oulu, 90570 Oulu, Finland
| | - Diego F. Calvisi
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (C.M.); (K.W.); (J.R.); (A.C.); (K.P.); (D.F.C.); (F.D.)
| | - Frank Dombrowski
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (C.M.); (K.W.); (J.R.); (A.C.); (K.P.); (D.F.C.); (F.D.)
| | - Silvia Ribback
- Institut fuer Pathologie, Universitaetsmedizin Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (C.M.); (K.W.); (J.R.); (A.C.); (K.P.); (D.F.C.); (F.D.)
- Correspondence: ; Tel.: +49-383-486-5732; Fax: +49-383-486-5778
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11
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Pineau P, Ruiz E, Deharo E, Bertani S. On hepatocellular carcinoma in South America and early-age onset of the disease. Clin Res Hepatol Gastroenterol 2019; 43:522-526. [PMID: 30482474 DOI: 10.1016/j.clinre.2018.10.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Accepted: 10/26/2018] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most predominant tumor types worldwide, being particularly prevalent in sub-Saharan Africa and East Asia. However, HCC is inexplicably underreported in South America, despite unsettling clinical epidemiological trends of the disease on this continent. Here, we review the current knowledge on HCC presentation in Peru. We emphasize the well-documented occurrence of an early-age nosological form of the disease in Andean descent populations. We further discuss the reasons for such HCC clinical presentation, as well as the implications for liver cancer screening, management, and prevention.
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Affiliation(s)
- Pascal Pineau
- Institut Pasteur, Unité organisation nucléaire et oncogenèse, Inserm, U 993, 75015 Paris, France.
| | - Eloy Ruiz
- Instituto nacional de enfermedades neoplasicas, Departamento de cirugía en abdomen, 34 Lima, Peru
| | - Eric Deharo
- Université de Toulouse, IRD, UPS, UMR 152 Pharmadev, 31000 Toulouse, France
| | - Stéphane Bertani
- Université de Toulouse, IRD, UPS, UMR 152 Pharmadev, 31000 Toulouse, France.
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12
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Liver clear cell foci and viral infection are associated with non-cirrhotic, non-fibrolamellar hepatocellular carcinoma in young patients from South America. Sci Rep 2018; 8:9945. [PMID: 30061721 PMCID: PMC6065419 DOI: 10.1038/s41598-018-28286-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 06/19/2018] [Indexed: 02/07/2023] Open
Abstract
We previously described a divergent clinical and molecular presentation of hepatocellular carcinoma (HCC) in Peru. The present study aimed to further characterize the tissue features associated with this singular nosological form of HCC in order to gain insight into the natural history of the disease. We performed an exploratory analysis of the histology of both tumor and non-tumor liver (NTL) tissues from 50 Peruvian HCC patients, and compared with that of 75 individuals with non-HCC liver tumor or benign liver lesions as a baseline for NTL features. We complemented this approach with a transcriptome analysis in a subset of NTL tissue samples and also performed an ultra-sensitive hepatitis B virus (HBV) detection in liver tissues of the patients. Overall, results highlighted the low rate of liver parenchymal alterations in a young patient cohort (median age: 40 years old), despite a strong prevalence of underlying HBV infection (c. 67%). Withal, liver clear cell foci of cellular alteration were genuinely associated with HCC and appended to some changes in immune and G protein-coupled receptor gene expression ontologies. Our findings confirm the occurrence of a particular setting of HCC in South America, a region where the pathophysiology of liver cancer remains largely unexplored.
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13
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Moore MM, Schoeny RS, Becker RA, White K, Pottenger LH. Development of an adverse outcome pathway for chemically induced hepatocellular carcinoma: case study of AFB1, a human carcinogen with a mutagenic mode of action. Crit Rev Toxicol 2018; 48:312-337. [PMID: 29431554 DOI: 10.1080/10408444.2017.1423462] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Adverse outcome pathways (AOPs) are frameworks starting with a molecular initiating event (MIE), followed by key events (KEs) linked by KE relationships (KERs), ultimately resulting in a specific adverse outcome. Relevant data for the pathway and each KE/KER are evaluated to assess biological plausibility, weight-of-evidence, and confidence. We aimed to describe an AOP relevant to chemicals directly inducing mutation in cancer critical gene(s), via the formation of chemical-specific pro-mutagenic DNA adduct(s), as an early critical step in tumor etiology. Such chemicals have mutagenic modes-of-action (MOA) for tumor induction. To assist with developing this AOP, Aflatoxin B1 (AFB1) was selected as a case study because it has a rich database and is considered to have a mutagenic MOA. AFB1 information was used to define specific KEs, KERs, and to inform development of a generic AOP for mutagen-induced hepatocellular carcinoma (HCC). In assessing the AFB1 information, it became clear that existing data are, in fact, not optimal and for some KEs/KERs, the definitive data are not available. In particular, while there is substantial information that AFB1 can induce mutations (based on a number of mutation assays), the definitive evidence - the ability to induce mutation in the cancer critical gene(s) in the tumor target tissue - is not available. Thus, it is necessary to consider the patterns of results in the weight-of-evidence for KEs and KERs. It was important to determine whether there was sufficient evidence that AFB1 can induce the necessary critical mutations early in the carcinogenic process, which was the case.
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Affiliation(s)
- Martha M Moore
- a Ramboll Environ US Corporation , Little Rock , AR , USA
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14
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Bannasch P, Ribback S, Su Q, Mayer D. Clear cell hepatocellular carcinoma: origin, metabolic traits and fate of glycogenotic clear and ground glass cells. Hepatobiliary Pancreat Dis Int 2017; 16:570-594. [PMID: 29291777 DOI: 10.1016/s1499-3872(17)60071-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 08/14/2017] [Indexed: 02/05/2023]
Abstract
Clear cell hepatocellular carcinoma (CCHCC) has hitherto been considered an uncommon, highly differentiated variant of hepatocellular carcinoma (HCC) with a relatively favorable prognosis. CCHCC is composed of mixtures of clear and/or acidophilic ground glass hepatocytes with excessive glycogen and/or fat and shares histology, clinical features and etiology with common HCCs. Studies in animal models of chemical, hormonal and viral hepatocarcinogenesis and observations in patients with chronic liver diseases prone to develop HCC have shown that the majority of HCCs are preceded by, or associated with, focal or diffuse excessive storage of glycogen (glycogenosis) which later may be replaced by fat (lipidosis/steatosis). In ground glass cells, the glycogenosis is accompanied by proliferation of the smooth endoplasmic reticulum, which is closely related to glycogen particles and frequently harbors the hepatitis B surface antigen (HBsAg). From the findings in animal models a sequence of changes has been established, commencing with preneoplastic glycogenotic liver lesions, often containing ground glass cells, and progressing to glycogen-poor neoplasms via various intermediate stages, including glycogenotic/lipidotic clear cell foci, clear cell hepatocellular adenomas (CCHCA) rich in glycogen and/or fat, and CCHCC. A similar process seems to take place in humans, with clear cells frequently persisting in CCHCC and steatohepatitic HCC, which presumably represent intermediate stages in the development rather than particular variants of HCC. During the progression of the preneoplastic lesions, the clear and ground glass cells transform into cells characteristic of common HCC. The sequential cellular changes are associated with metabolic aberrations, which start with an activation of the insulin signaling cascade resulting in pre-neoplastic hepatic glycogenosis. The molecular and metabolic changes underlying the glycogenosis/lipidosis are apparently responsible for the dramatic metabolic shift from gluconeogenesis to the pentose phosphate pathway and Warburg-type glycolysis, which provide precursors and energy for an ever increasing cell proliferation during progression.
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Affiliation(s)
| | - Silvia Ribback
- Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Qin Su
- Cell Marque, Millipore-Sigma Rocklin, USA
| | - Doris Mayer
- German Cancer Research Center, Heidelberg, Germany
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15
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Ribback S, Sonke J, Lohr A, Frohme J, Peters K, Holm J, Peters M, Cigliano A, Calvisi DF, Dombrowski F. Hepatocellular glycogenotic foci after combined intraportal pancreatic islet transplantation and knockout of the carbohydrate responsive element binding protein in diabetic mice. Oncotarget 2017; 8:104315-104329. [PMID: 29262643 PMCID: PMC5732809 DOI: 10.18632/oncotarget.22234] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 10/05/2017] [Indexed: 01/01/2023] Open
Abstract
Aims The intraportal pancreatic islet transplantation (IPIT) model of diabetic rats is an insulin mediated model of hepatocarcinogenesis characterized by the induction of clear cell foci (CCF) of altered hepatocytes, which are pre-neoplastic lesions excessively storing glycogen (glycogenosis) and exhibiting activation of the AKT/mTOR protooncogenic pathway. In this study, we transferred the IPIT model to the mouse and combined it with the knockout of the transcription factor carbohydrate responsive element binding protein (chREBP). Methods C57BL/6J Wild-type (WT) and chREBP-knockout (chREBP-KO) mice (n = 297) were matched to 16 groups (WT/ chREBP-KO, experimental/control, streptozotocine-induced diabetic/not diabetic, one/four weeks). Experimental groups received the intraportal transplantation of 70 pancreatic islets. Liver and pancreatic tissue was examined using histology, morphometry, enzyme- and immunohistochemistry and electron microscopy. Results CCF emerged in the liver acini downstream of the transplanted islets. In comparison to WT lesions, CCF of chREBP-KO mice displayed more glycogen accumulation, reduced activity of the gluconeogenic enzyme glucose-6-phosphatase, decreased glycolysis, lipogenesis and reduced levels of the AKT/mTOR cascade members. Proliferative activity of CCF was ∼two folds higher in WT mice than in chREBP-KO mice. Conclusions The IPIT model is applicable to mice, as murine CCF resemble preneoplastic liver lesions from this hepatocarcinogenesis model in the rat in terms of morphological, metabolic and molecular alterations and proliferative activity, which is diminished after chREBP knockout. chREBP appears to be an essential component of AKT/mTOR mediated cell proliferation and the metabolic switch from a glycogenotic to lipogenic phenotype in precursor lesions of hepatocarcinogenesis.
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Affiliation(s)
- Silvia Ribback
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Jenny Sonke
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Andrea Lohr
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Josephine Frohme
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Kristin Peters
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Johannes Holm
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Michele Peters
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Antonio Cigliano
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Diego F Calvisi
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
| | - Frank Dombrowski
- Institut für Pathologie, Universitaetsmedizin Greifswald, Greifswald, Germany
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16
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Yu L, Chen X, Sun X, Wang L, Chen S. The Glycolytic Switch in Tumors: How Many Players Are Involved? J Cancer 2017; 8:3430-3440. [PMID: 29151926 PMCID: PMC5687156 DOI: 10.7150/jca.21125] [Citation(s) in RCA: 167] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 08/31/2017] [Indexed: 02/07/2023] Open
Abstract
Reprogramming of cellular metabolism is a hallmark of cancers. Cancer cells more readily use glycolysis, an inefficient metabolic pathway for energy metabolism, even when sufficient oxygen is available. This reliance on aerobic glycolysis is called the Warburg effect, and promotes tumorigenesis and malignancy progression. The mechanisms of the glycolytic shift in tumors are not fully understood. Growing evidence demonstrates that many signal molecules, including oncogenes and tumor suppressors, are involved in the process, but how oncogenic signals attenuate mitochondrial function and promote the switch to glycolysis remains unclear. Here, we summarize the current information on several main mediators and discuss their possible mechanisms for triggering the Warburg effect.
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Affiliation(s)
- Li Yu
- Department of Pathology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People's Republic of China
| | - Xun Chen
- Guanghua School and Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, People's Republic of China
| | - Xueqi Sun
- Department of Pathology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People's Republic of China
| | - Liantang Wang
- Department of Pathology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People's Republic of China
| | - Shangwu Chen
- State Key Laboratory for Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, Key Laboratory of Gene Engineering of the Ministry of Education, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, People's Republic of China
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17
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Ribback S, Sailer V, Böhning E, Günther J, Merz J, Steinmüller F, Utpatel K, Cigliano A, Peters K, Pilo MG, Evert M, Calvisi DF, Dombrowski F. The Epidermal Growth Factor Receptor (EGFR) Inhibitor Gefitinib Reduces but Does Not Prevent Tumorigenesis in Chemical and Hormonal Induced Hepatocarcinogenesis Rat Models. Int J Mol Sci 2016; 17:ijms17101618. [PMID: 27669229 PMCID: PMC5085651 DOI: 10.3390/ijms17101618] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Revised: 08/27/2016] [Accepted: 09/14/2016] [Indexed: 02/07/2023] Open
Abstract
Activation of the epidermal growth factor receptor (EGFR) signaling pathway promotes the development of hepatocellular adenoma (HCA) and carcinoma (HCC). The selective EGFR inhibitor Gefitinib was found to prevent hepatocarcinogenesis in rat cirrhotic livers. Thus, Gefitinib might reduce progression of pre-neoplastic liver lesions to HCC. In short- and long-term experiments, administration of N-Nitrosomorpholine (NNM) or intrahepatic transplantation of pancreatic islets in diabetic (PTx), thyroid follicles in thyroidectomized (TTx) and ovarian fragments in ovariectomized (OTx) rats was conducted for the induction of foci of altered hepatocytes (FAH). Gefitinib was administered for two weeks (20 mg/kg) or three and nine months (10 mg/kg). In NNM-treated rats, Gefitinib administration decreased the amount of FAH when compared to controls. The amount of HCA and HCC was decreased, but development was not prevented. Upon all transplantation models, proliferative activity of FAH was lower after administration of Gefitinib in short-term experiments. Nevertheless, the burden of HCA and HCC was not changed in later stages. Thus, EGFR inhibition by Gefitinib diminishes chemical and hormonal also induced hepatocarcinogenesis in the initiation stage in the non-cirrhotic liver. However, progression to malignant hepatocellular tumors was not prevented, indicating only a limited relevance of the EGFR signaling cascade in later stages of hepatocarcinogenesis.
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Affiliation(s)
- Silvia Ribback
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
| | - Verena Sailer
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
- Englander Institut for Precision Medicine, Weill Cornell University of Medicine, New York, NY 10065, USA.
| | - Enrico Böhning
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
| | - Julia Günther
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
| | - Jaqueline Merz
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
| | - Frauke Steinmüller
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
- Pathologisches Institut Diakonie-Krankenhaus, 27356 Rotenburg (Wümme), Germany.
| | - Kirsten Utpatel
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
- Institut für Pathologie, Universitätsklinikum Regensburg, 93053 Regensburg, Germany.
| | - Antonio Cigliano
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
| | - Kristin Peters
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
| | - Maria G Pilo
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
| | - Matthias Evert
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
- Institut für Pathologie, Universitätsklinikum Regensburg, 93053 Regensburg, Germany.
| | - Diego F Calvisi
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
| | - Frank Dombrowski
- Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany.
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18
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Ribback S, Cigliano A, Kroeger N, Pilo MG, Terracciano L, Burchardt M, Bannasch P, Calvisi DF, Dombrowski F. PI3K/AKT/mTOR pathway plays a major pathogenetic role in glycogen accumulation and tumor development in renal distal tubules of rats and men. Oncotarget 2016; 6:13036-48. [PMID: 25948777 PMCID: PMC4536997 DOI: 10.18632/oncotarget.3675] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 04/06/2015] [Indexed: 01/13/2023] Open
Abstract
Activation of the PI3K/AKT/mTOR pathway is a crucial molecular event in human clear cell renal cell carcinoma (ccRCC), and is also upregulated in diabetic nephropathy. In diabetic rats metabolic changes affect the renal distal tubular epithelium and lead to glycogen-storing Armanni-Ebstein lesions (AEL), precursor lesions of RCC in the diabetes induced nephrocarcinogenesis model. These lesions resemble human sporadic clear cell tubules (CCT) and tumor cells of human ccRCC. Human sporadic CCT were examined in a collection of 324 nephrectomy specimen, in terms of morphologic, metabolic and molecular alterations, and compared to preneoplastic CCT and RCC developed in the rat following streptozotocin-induced diabetes or N-Nitrosomorpholine administration. Diabetic and non-diabetic rats were subjected to the dual PI3K/mTOR inhibitor, NVP/BEZ235. Human sporadic CCT could be detected in 17.3% of kidney specimens. Human and rat renal CCT display a strong induction of the PI3K/AKT/mTOR pathway and related metabolic alterations. Proteins involved in glycolysis and de novo lipogenesis were upregulated. In in vivo experiments, dual inhibition of PI3K and mTOR resulted in a reduction of proliferation of rat diabetes related CCT and increased autophagic activity. The present data indicate that human sporadic CCT exhibit a pattern of morphologic and metabolic alterations similar to preneoplastic lesions in the rat model. Activation of the PI3K/AKT/mTOR pathway in glycogenotic tubuli is a remarkable molecular event and suggests a preneoplastic character of these lesions also in humans.
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Affiliation(s)
- Silvia Ribback
- Institut für Pathologie, Universitätsmedizin Greifswald, Germany
| | - Antonio Cigliano
- Institut für Pathologie, Universitätsmedizin Greifswald, Germany
| | - Nils Kroeger
- Klinik für Urologie, Universitätsmedizin Greifswald, Germany
| | - Maria G Pilo
- Institut für Pathologie, Universitätsmedizin Greifswald, Germany
| | - Luigi Terracciano
- Molekularpathologie, Institut für Pathologie, Universitätsspital Basel, Switzerland
| | | | | | - Diego F Calvisi
- Institut für Pathologie, Universitätsmedizin Greifswald, Germany
| | - Frank Dombrowski
- Institut für Pathologie, Universitätsmedizin Greifswald, Germany
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19
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Li L, Pilo GM, Li X, Cigliano A, Latte G, Che L, Joseph C, Mela M, Wang C, Jiang L, Ribback S, Simile MM, Pascale RM, Dombrowski F, Evert M, Semenkovich CF, Chen X, Calvisi DF. Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans. J Hepatol 2016; 64:333-341. [PMID: 26476289 PMCID: PMC4718802 DOI: 10.1016/j.jhep.2015.10.004] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 10/05/2015] [Accepted: 10/05/2015] [Indexed: 01/31/2023]
Abstract
BACKGROUND & AIMS Cumulating evidence underlines the crucial role of aberrant lipogenesis in human hepatocellular carcinoma (HCC). Here, we investigated the oncogenic potential of fatty acid synthase (FASN), the master regulator of de novo lipogenesis, in the mouse liver. METHODS FASN was overexpressed in the mouse liver, either alone or in combination with activated N-Ras, c-Met, or SCD1, via hydrodynamic injection. Activated AKT was overexpressed via hydrodynamic injection in livers of conditional FASN or Rictor knockout mice. FASN was suppressed in human hepatoma cell lines via specific small interfering RNA. RESULTS Overexpression of FASN, either alone or in combination with other genes associated with hepatocarcinogenesis, did not induce histological liver alterations. In contrast, genetic ablation of FASN resulted in the complete inhibition of hepatocarcinogenesis in AKT-overexpressing mice. In human HCC cell lines, FASN inactivation led to a decline in cell proliferation and a rise in apoptosis, which were paralleled by a decrease in the levels of phosphorylated/activated AKT, an event controlled by the mammalian target of rapamycin complex 2 (mTORC2). Downregulation of AKT phosphorylation/activation following FASN inactivation was associated with a strong inhibition of rapamycin-insensitive companion of mTOR (Rictor), the major component of mTORC2, at post-transcriptional level. Finally, genetic ablation of Rictor impaired AKT-driven hepatocarcinogenesis in mice. CONCLUSIONS FASN is not oncogenic per se in the mouse liver, but is necessary for AKT-driven hepatocarcinogenesis. Pharmacological blockade of FASN might be highly useful in the treatment of human HCC characterized by activation of the AKT pathway.
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Affiliation(s)
- Lei Li
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
| | - Giulia M Pilo
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - Xiaolei Li
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA; Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Antonio Cigliano
- Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Gavinella Latte
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - Li Che
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
| | - Christy Joseph
- Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Marta Mela
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - Chunmei Wang
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
| | - Lijie Jiang
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
| | - Silvia Ribback
- Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Maria M Simile
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - Rosa M Pascale
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - Frank Dombrowski
- Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Matthias Evert
- Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Clay F Semenkovich
- Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
| | - Diego F Calvisi
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
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[Molecular and metabolic changes in human clear cell liver foci]. DER PATHOLOGE 2015; 36 Suppl 2:210-5. [PMID: 26483250 DOI: 10.1007/s00292-015-0089-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Activation of the AKT/mTOR and Ras/MAPK pathways and the lipogenic phenotype are evident both in human hepatocellular carcinoma and in the rat model of insulin-induced hepatocarcinogenesis in the earliest preneoplastic lesions, i.e. clear cell foci (CCF) of altered hepatocytes. These CCFs have also been described in the human liver but characterization of molecular and metabolic changes are still pending. In this study, human sporadic CCFs were investigated in a collection of human non-cirrhotic liver specimens using histology, histochemistry, immunohistochemistry, electron microscopy and molecular pathological analysis. Human CCFs occurred in approximately 33 % of non-cirrhotic livers and stored masses of glycogen in the cytoplasm, largely due to reduced activity of glucose-6-phosphatase. Hepatocytes revealed an upregulation of the AKT/mTOR and the Ras/MAPK pathways, the insulin receptor, glucose transporters and enzymes of glycolysis and de novo lipogenesis. Proliferative activity was 2-fold higher than in extrafocal tissue. The CCFs of altered hepatocytes are metabolically and proliferatively active lesions even in humans. They resemble the well-known preneoplastic lesions from experimental models in terms of morphology, glycogen storage, overexpression of protooncogenic signaling pathways and activation of the lipogenic phenotype, which are also known in human hepatocellular carcinoma. This suggests that hepatic CCFs also represent very early lesions of hepatocarcinogenesis in humans.
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Giordano S, Martocchia A, Toussan L, Stefanelli M, Pastore F, Devito A, Risicato MG, Ruco L, Falaschi P. Diagnosis of hepatic glycogenosis in poorly controlled type 1 diabetes mellitus. World J Diabetes 2014; 5:882-888. [PMID: 25512791 PMCID: PMC4265875 DOI: 10.4239/wjd.v5.i6.882] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Revised: 10/02/2014] [Accepted: 10/27/2014] [Indexed: 02/05/2023] Open
Abstract
Hepatic glycogenosis (HG) in type 1 diabetes is a underrecognized complication. Mauriac firstly described the syndrome characterized by hepatomegaly with altered liver enzymes, growth impairment, delay puberty and Cushingoid features, during childhood. HG in adulthood is characterized by the liver disorder (with circulating aminotransferase increase) in the presence of poor glycemic control (elevation of glycated hemoglobin, HbA1c levels). The advances in the comprehension of the metabolic pathways driving to the hepatic glycogen deposition point out the role of glucose transporters and insulin mediated activations of glucokinase and glycogen synthase, with inhibition of glucose-6-phosphatase. The differential diagnosis of HG consists in the exclusion of causes of liver damage (infectious, metabolic, obstructive and autoimmune disease). The imaging study (ultrasonography and/or radiological examinations) gives information about the liver alterations (hepatomegaly), but the diagnosis needs to be confirmed by the liver biopsy. The main treatment of HG is the amelioration of glycemic control that is usually accompanied by the reversal of the liver disorder. In selected cases, more aggressive treatment options (transplantation) have been successfully reported.
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Regnault C, Worms IAM, Oger-Desfeux C, MelodeLima C, Veyrenc S, Bayle ML, Combourieu B, Bonin A, Renaud J, Raveton M, Reynaud S. Impaired liver function in Xenopus tropicalis exposed to benzo[a]pyrene: transcriptomic and metabolic evidence. BMC Genomics 2014; 15:666. [PMID: 25103525 PMCID: PMC4141109 DOI: 10.1186/1471-2164-15-666] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 07/30/2014] [Indexed: 12/20/2022] Open
Abstract
Background Despite numerous studies suggesting that amphibians are highly sensitive to cumulative anthropogenic stresses, the role pollutants play in the decline of amphibian populations remains unclear. Amongst the most common aquatic contaminants, polycyclic aromatic hydrocarbons (PAHs) have been shown to induce several adverse effects on amphibian species in the larval stages. Conversely, adults exposed to high concentrations of the ubiquitous PAH, benzo[a]pyrene (BaP), tolerate the compound thanks to their highly efficient hepatic detoxification mechanisms. Due to this apparent lack of toxic effect on adults, no studies have examined in depth the potential toxicological impact of PAH on the physiology of adult amphibian livers. This study sheds light on the hepatic responses of Xenopus tropicalis when exposed to high environmentally relevant concentrations of BaP, by combining a high throughput transcriptomic approach (mRNA deep sequencing) and a characterization of cellular and physiological modifications to the amphibian liver. Results Transcriptomic changes observed in BaP-exposed Xenopus were further characterized using a time-dependent enrichment analysis, which revealed the pollutant-dependent gene regulation of important biochemical pathways, such as cholesterol biosynthesis, insulin signaling, adipocytokines signaling, glycolysis/gluconeogenesis and MAPK signaling. These results were substantiated at the physiological level with the detection of a pronounced metabolic disorder resulting in a possible insulin resistance-like syndrome phenotype. Hepatotoxicity induced by lipid and cholesterol metabolism impairments was clearly identified in BaP-exposed individuals. Conclusions Our data suggested that BaP may disrupt overall liver physiology, and carbohydrate and cholesterol metabolism in particular, even after short-term exposure. These results are further discussed in terms of how this deregulation of liver physiology can lead to general metabolic impairment in amphibians chronically exposed to contaminants, thereby illustrating the role xenobiotics might play in the global decline in amphibian populations. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-666) contains supplementary material, which is available to authorized users.
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Li W, Wang J, Chen QD, Qian X, Li Q, Yin Y, Shi ZM, Wang L, Lin J, Liu LZ, Jiang BH. Insulin promotes glucose consumption via regulation of miR-99a/mTOR/PKM2 pathway. PLoS One 2013; 8:e64924. [PMID: 23762265 PMCID: PMC3677911 DOI: 10.1371/journal.pone.0064924] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Accepted: 04/20/2013] [Indexed: 01/17/2023] Open
Abstract
Insulin is known to regulate multiple cellular functions and is used for the treatment of diabetes. MicroRNAs have been demonstrated to be involved in many human diseases, including Type 2 diabetes. In this study, we showed that insulin decreased miR-99a expression levels, but induced glucose consumption and lactate production, and increased the expression of mTOR, HIF-1α and PKM2 in HepG2 and HL7702 cells. Forced expression of miR-99a or rapamycin treatment blocked insulin-induced PKM2 and HIF-1α expression, and glucose consumption and lactate production. Meanwhile, knockdown of HIF-1α inhibited PKM2 expression and insulin-induced glucose consumption. Taken together, these findings will reveal the role and mechanism of insulin in regulating glycolytic activities via miR-99a/mTOR.
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MESH Headings
- Antibiotics, Antineoplastic/pharmacology
- Blotting, Western
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carrier Proteins/genetics
- Carrier Proteins/metabolism
- Cells, Cultured
- Gene Expression Regulation, Neoplastic/drug effects
- Glucose/metabolism
- Humans
- Hypoglycemic Agents/pharmacology
- Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Insulin/pharmacology
- Lactates/metabolism
- Liver/metabolism
- Liver/pathology
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Luciferases/metabolism
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- MicroRNAs/genetics
- Phosphorylation
- RNA, Messenger/genetics
- RNA, Small Interfering/genetics
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction/drug effects
- Sirolimus/pharmacology
- TOR Serine-Threonine Kinases/genetics
- TOR Serine-Threonine Kinases/metabolism
- Thyroid Hormones/genetics
- Thyroid Hormones/metabolism
- Thyroid Hormone-Binding Proteins
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Affiliation(s)
- Wei Li
- Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing, China
| | - Jing Wang
- Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing, China
| | - Qiu-Dan Chen
- Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing, China
| | - Xu Qian
- Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing, China
| | - Qi Li
- Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing, China
| | - Yu Yin
- Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing, China
| | - Zhu-Mei Shi
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lin Wang
- Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing, China
| | - Jie Lin
- Faculty of Software, Fujian Normal University, Fuzhou, China
| | - Ling-Zhi Liu
- Department of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Bing-Hua Jiang
- Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing, China
- Department of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
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