Mechanism and Effect of HNF4α Decrease in a Rat Model of Cirrhosis and Liver FailureSummary
Background & Aims: HNF4α, a master regulator of liver development and the mature hepatocyte phenotype, is down-regulated in chronic and inflammatory liver disease. We used contemporary transcriptomics and epigenomics to study the cause and effects of this down-regulation and characterized a...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X23002047 |
| _version_ | 1827348482216689664 |
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| author | Marta Melis Rebecca Marino Jianmin Tian Carla Johnson Rahil Sethi Michael Oertel Ira J. Fox Joseph Locker |
| author_facet | Marta Melis Rebecca Marino Jianmin Tian Carla Johnson Rahil Sethi Michael Oertel Ira J. Fox Joseph Locker |
| author_sort | Marta Melis |
| collection | DOAJ |
| description | Background & Aims: HNF4α, a master regulator of liver development and the mature hepatocyte phenotype, is down-regulated in chronic and inflammatory liver disease. We used contemporary transcriptomics and epigenomics to study the cause and effects of this down-regulation and characterized a multicellular etiology. Methods: Progressive changes in the rat carbon tetrachloride model were studied by deep RNA sequencing and genome-wide chromatin immunoprecipitation sequencing analysis of transcription factor (TF) binding and chromatin modification. Studies compared decompensated cirrhosis with liver failure after 26 weeks of treatment with earlier compensated cirrhosis and with additional rat models of chronic fibrosis. Finally, to resolve cell-specific responses and intercellular signaling, we compared transcriptomes of liver, nonparenchymal, and inflammatory cells. Results: HNF4α was significantly lower in 26-week cirrhosis, part of a general reduction of TFs that regulate metabolism. Nevertheless, increased binding of HNF4α contributed to strong activation of major phenotypic genes, whereas reduced binding to other genes had a moderate phenotypic effect. Decreased Hnf4a expression was the combined effect of STAT3 and nuclear factor kappa B (NFκB) activation, which similarly reduced expression of other metabolic TFs. STAT/NFκB also induced de novo expression of Osmr by hepatocytes to complement induced expression of Osm by nonparenchymal cells. Conclusions: Liver decompensation by inflammatory STAT3 and NFκB signaling was not a direct consequence of progressive cirrhosis. Despite significant reduction of Hnf4a expression, residual levels of this abundant TF still stimulated strong new gene expression. Reduction of HNF4α was part of a broad hepatocyte transcriptional response to inflammation. |
| first_indexed | 2024-03-08T00:12:50Z |
| format | Article |
| id | doaj.art-270e6dc5cdb04a1fb26e7c7fe9fb3567 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-03-08T00:12:50Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-270e6dc5cdb04a1fb26e7c7fe9fb35672024-02-17T06:37:45ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2024-01-01173453479Mechanism and Effect of HNF4α Decrease in a Rat Model of Cirrhosis and Liver FailureSummaryMarta Melis0Rebecca Marino1Jianmin Tian2Carla Johnson3Rahil Sethi4Michael Oertel5Ira J. Fox6Joseph Locker7Department of Surgery, University of Pittsburgh, Pittsburgh, PennsylvaniaDepartment of Pathology, University of Pittsburgh, Pittsburgh, PennsylvaniaDepartment of Pathology, University of Pittsburgh, Pittsburgh, PennsylvaniaDepartment of Pathology, University of Pittsburgh, Pittsburgh, PennsylvaniaDepartment of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PennsylvaniaDepartment of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania; The McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PennsylvaniaDepartment of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania; The McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PennsylvaniaDepartment of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; The McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Correspondence Address correspondence to: Joseph Locker, MD, PhD, Department of Pathology, School of Medicine, University of Pittsburgh, BST South, Room 421, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213.Background & Aims: HNF4α, a master regulator of liver development and the mature hepatocyte phenotype, is down-regulated in chronic and inflammatory liver disease. We used contemporary transcriptomics and epigenomics to study the cause and effects of this down-regulation and characterized a multicellular etiology. Methods: Progressive changes in the rat carbon tetrachloride model were studied by deep RNA sequencing and genome-wide chromatin immunoprecipitation sequencing analysis of transcription factor (TF) binding and chromatin modification. Studies compared decompensated cirrhosis with liver failure after 26 weeks of treatment with earlier compensated cirrhosis and with additional rat models of chronic fibrosis. Finally, to resolve cell-specific responses and intercellular signaling, we compared transcriptomes of liver, nonparenchymal, and inflammatory cells. Results: HNF4α was significantly lower in 26-week cirrhosis, part of a general reduction of TFs that regulate metabolism. Nevertheless, increased binding of HNF4α contributed to strong activation of major phenotypic genes, whereas reduced binding to other genes had a moderate phenotypic effect. Decreased Hnf4a expression was the combined effect of STAT3 and nuclear factor kappa B (NFκB) activation, which similarly reduced expression of other metabolic TFs. STAT/NFκB also induced de novo expression of Osmr by hepatocytes to complement induced expression of Osm by nonparenchymal cells. Conclusions: Liver decompensation by inflammatory STAT3 and NFκB signaling was not a direct consequence of progressive cirrhosis. Despite significant reduction of Hnf4a expression, residual levels of this abundant TF still stimulated strong new gene expression. Reduction of HNF4α was part of a broad hepatocyte transcriptional response to inflammation.http://www.sciencedirect.com/science/article/pii/S2352345X23002047STAT3NFκBOncostatin M Receptor (Osmr)Liver EpigenomicsHnf4a Isoforms |
| spellingShingle | Marta Melis Rebecca Marino Jianmin Tian Carla Johnson Rahil Sethi Michael Oertel Ira J. Fox Joseph Locker Mechanism and Effect of HNF4α Decrease in a Rat Model of Cirrhosis and Liver FailureSummary Cellular and Molecular Gastroenterology and Hepatology STAT3 NFκB Oncostatin M Receptor (Osmr) Liver Epigenomics Hnf4a Isoforms |
| title | Mechanism and Effect of HNF4α Decrease in a Rat Model of Cirrhosis and Liver FailureSummary |
| title_full | Mechanism and Effect of HNF4α Decrease in a Rat Model of Cirrhosis and Liver FailureSummary |
| title_fullStr | Mechanism and Effect of HNF4α Decrease in a Rat Model of Cirrhosis and Liver FailureSummary |
| title_full_unstemmed | Mechanism and Effect of HNF4α Decrease in a Rat Model of Cirrhosis and Liver FailureSummary |
| title_short | Mechanism and Effect of HNF4α Decrease in a Rat Model of Cirrhosis and Liver FailureSummary |
| title_sort | mechanism and effect of hnf4α decrease in a rat model of cirrhosis and liver failuresummary |
| topic | STAT3 NFκB Oncostatin M Receptor (Osmr) Liver Epigenomics Hnf4a Isoforms |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X23002047 |
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