Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitis

A barrier to drug development for nonalcoholic steatohepatitis (NASH) is the absence of translational preclinical human-relevant systems. An in vitro liver model was engineered to incorporate hepatic sinusoidal flow, transport, and lipotoxic stress risk factors (glucose, insulin, free fatty acids) w...

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Vydáno v:	JCI insight Ročník 1; číslo 20; s. e90954
Hlavní autoři:	Feaver, Ryan E., Cole, Banumathi K., Lawson, Mark J., Hoang, Stephen A., Marukian, Svetlana, Blackman, Brett R., Figler, Robert A., Sanyal, Arun J., Wamhoff, Brian R., Dash, Ajit
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States American Society for Clinical Investigation 08.12.2016
Témata:	Animals Coculture Techniques Glucose - metabolism Hepatic Stellate Cells - cytology Hepatocytes - cytology Humans Inflammation Insulin Resistance Lipids - analysis Liver Macrophages - cytology Metabolome Mice, Inbred C57BL Models, Biological Non-alcoholic Fatty Liver Disease - physiopathology Technical Advance Transcriptome
ISSN:	2379-3708, 2379-3708
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Abstract	A barrier to drug development for nonalcoholic steatohepatitis (NASH) is the absence of translational preclinical human-relevant systems. An in vitro liver model was engineered to incorporate hepatic sinusoidal flow, transport, and lipotoxic stress risk factors (glucose, insulin, free fatty acids) with cocultured primary human hepatocytes, hepatic stellate cells (HSCs), and macrophages. Transcriptomic, lipidomic, and functional endpoints were evaluated and compared with clinical data from NASH patient biopsies. The lipotoxic milieu promoted hepatocyte lipid accumulation (4-fold increase, < 0.01) and a lipidomics signature similar to NASH biopsies. Hepatocyte glucose output increased with decreased insulin sensitivity. These changes were accompanied by increased inflammatory analyte secretion (e.g., IL-6, IL-8, alanine aminotransferase). Fibrogenic activation markers increased with lipotoxic conditions, including secreted TGF-β (>5-fold increase, < 0.05), extracellular matrix gene expression, and HSC activation. Significant pathway correlation existed between this in vitro model and human biopsies. Consistent with clinical trial data, 0.5 μM obeticholic acid in this model promoted a healthy lipidomic signature, reduced inflammatory and fibrotic secreted factors, but also increased ApoB secretion, suggesting a potential adverse effect on lipoprotein metabolism. Lipotoxic stress activates similar biological signatures observed in NASH patients in this system, which may be relevant for interrogating novel therapeutic approaches to treat NASH.
AbstractList	A barrier to drug development for nonalcoholic steatohepatitis (NASH) is the absence of translational preclinical human-relevant systems. An in vitro liver model was engineered to incorporate hepatic sinusoidal flow, transport, and lipotoxic stress risk factors (glucose, insulin, free fatty acids) with cocultured primary human hepatocytes, hepatic stellate cells (HSCs), and macrophages. Transcriptomic, lipidomic, and functional endpoints were evaluated and compared with clinical data from NASH patient biopsies. The lipotoxic milieu promoted hepatocyte lipid accumulation (4-fold increase, P < 0.01) and a lipidomics signature similar to NASH biopsies. Hepatocyte glucose output increased with decreased insulin sensitivity. These changes were accompanied by increased inflammatory analyte secretion (e.g., IL-6, IL-8, alanine aminotransferase). Fibrogenic activation markers increased with lipotoxic conditions, including secreted TGF-β (>5-fold increase, P < 0.05), extracellular matrix gene expression, and HSC activation. Significant pathway correlation existed between this in vitro model and human biopsies. Consistent with clinical trial data, 0.5 μM obeticholic acid in this model promoted a healthy lipidomic signature, reduced inflammatory and fibrotic secreted factors, but also increased ApoB secretion, suggesting a potential adverse effect on lipoprotein metabolism. Lipotoxic stress activates similar biological signatures observed in NASH patients in this system, which may be relevant for interrogating novel therapeutic approaches to treat NASH. An in vitro lipotoxic liver system that exhibits a clinical disease phenotype and therapeutic drug response similar to NASH patients. A barrier to drug development for nonalcoholic steatohepatitis (NASH) is the absence of translational preclinical human-relevant systems. An in vitro liver model was engineered to incorporate hepatic sinusoidal flow, transport, and lipotoxic stress risk factors (glucose, insulin, free fatty acids) with cocultured primary human hepatocytes, hepatic stellate cells (HSCs), and macrophages. Transcriptomic, lipidomic, and functional endpoints were evaluated and compared with clinical data from NASH patient biopsies. The lipotoxic milieu promoted hepatocyte lipid accumulation (4-fold increase, P < 0.01) and a lipidomics signature similar to NASH biopsies. Hepatocyte glucose output increased with decreased insulin sensitivity. These changes were accompanied by increased inflammatory analyte secretion (e.g., IL-6, IL-8, alanine aminotransferase). Fibrogenic activation markers increased with lipotoxic conditions, including secreted TGF-β (>5-fold increase, P < 0.05), extracellular matrix gene expression, and HSC activation. Significant pathway correlation existed between this in vitro model and human biopsies. Consistent with clinical trial data, 0.5 μM obeticholic acid in this model promoted a healthy lipidomic signature, reduced inflammatory and fibrotic secreted factors, but also increased ApoB secretion, suggesting a potential adverse effect on lipoprotein metabolism. Lipotoxic stress activates similar biological signatures observed in NASH patients in this system, which may be relevant for interrogating novel therapeutic approaches to treat NASH. A barrier to drug development for nonalcoholic steatohepatitis (NASH) is the absence of translational preclinical human-relevant systems. An in vitro liver model was engineered to incorporate hepatic sinusoidal flow, transport, and lipotoxic stress risk factors (glucose, insulin, free fatty acids) with cocultured primary human hepatocytes, hepatic stellate cells (HSCs), and macrophages. Transcriptomic, lipidomic, and functional endpoints were evaluated and compared with clinical data from NASH patient biopsies. The lipotoxic milieu promoted hepatocyte lipid accumulation (4-fold increase, < 0.01) and a lipidomics signature similar to NASH biopsies. Hepatocyte glucose output increased with decreased insulin sensitivity. These changes were accompanied by increased inflammatory analyte secretion (e.g., IL-6, IL-8, alanine aminotransferase). Fibrogenic activation markers increased with lipotoxic conditions, including secreted TGF-β (>5-fold increase, < 0.05), extracellular matrix gene expression, and HSC activation. Significant pathway correlation existed between this in vitro model and human biopsies. Consistent with clinical trial data, 0.5 μM obeticholic acid in this model promoted a healthy lipidomic signature, reduced inflammatory and fibrotic secreted factors, but also increased ApoB secretion, suggesting a potential adverse effect on lipoprotein metabolism. Lipotoxic stress activates similar biological signatures observed in NASH patients in this system, which may be relevant for interrogating novel therapeutic approaches to treat NASH.
Author	Cole, Banumathi K. Wamhoff, Brian R. Feaver, Ryan E. Lawson, Mark J. Hoang, Stephen A. Marukian, Svetlana Dash, Ajit Figler, Robert A. Blackman, Brett R. Sanyal, Arun J.
AuthorAffiliation	1 HemoShear Therapeutics LLC, Charlottesville, Virginia, USA 2 VL37, Inc., Cambridge, Massachusetts, USA 3 Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virgina, USA
AuthorAffiliation_xml	– name: 3 Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virgina, USA – name: 1 HemoShear Therapeutics LLC, Charlottesville, Virginia, USA – name: 2 VL37, Inc., Cambridge, Massachusetts, USA
Author_xml	– sequence: 1 givenname: Ryan E. surname: Feaver fullname: Feaver, Ryan E. – sequence: 2 givenname: Banumathi K. surname: Cole fullname: Cole, Banumathi K. – sequence: 3 givenname: Mark J. surname: Lawson fullname: Lawson, Mark J. – sequence: 4 givenname: Stephen A. surname: Hoang fullname: Hoang, Stephen A. – sequence: 5 givenname: Svetlana surname: Marukian fullname: Marukian, Svetlana – sequence: 6 givenname: Brett R. surname: Blackman fullname: Blackman, Brett R. – sequence: 7 givenname: Robert A. surname: Figler fullname: Figler, Robert A. – sequence: 8 givenname: Arun J. surname: Sanyal fullname: Sanyal, Arun J. – sequence: 9 givenname: Brian R. surname: Wamhoff fullname: Wamhoff, Brian R. – sequence: 10 givenname: Ajit surname: Dash fullname: Dash, Ajit
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/27942596$$D View this record in MEDLINE/PubMed
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Snippet	A barrier to drug development for nonalcoholic steatohepatitis (NASH) is the absence of translational preclinical human-relevant systems. An in vitro liver...
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SubjectTerms	Animals Coculture Techniques Glucose - metabolism Hepatic Stellate Cells - cytology Hepatocytes - cytology Humans Inflammation Insulin Resistance Lipids - analysis Liver Macrophages - cytology Metabolome Mice, Inbred C57BL Models, Biological Non-alcoholic Fatty Liver Disease - physiopathology Technical Advance Transcriptome
Title	Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitis
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