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...

Celý popis

Uloženo v:
Podrobná bibliografie
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
On-line přístup:Získat plný text
Tagy: Přidat tag
Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!
Popis
Shrnutí: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.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.90954