The importance of the interaction between hepatocyte and hepatic stellate cells in fibrogenesis induced by fatty accumulation.

Abstract

BACKGROUND & AIMS:

Non-alcoholic fatty liver disease is characterized by an initial accumulation of triglycerides that can progress to non-alcoholic steatohepatitis, which can ultimately evolve to cirrhosis and hepatocellular carcinoma. Hepatic stellate cells play a key role in liver fibrogenesis by an increased activation and an altered profile of genes involved in the turnover of extracellular matrix components. To reproduce in-vitro the functional cell connections observed in vivo it is essential to consider cell-to-cell proximity and interaction. The aim of this study was to determine the response to free fatty acids in a simultaneous co-culture model of hepatocytes and hepatic stellate cells.

METHODS:

Simultaneous co-culture model and monoculture of each cell type (control) were exposed to FFA for 24 up to 144 h. Quantification of steatosis; stellate cell activation; assessment of fibrogenic response; expression and activity of metalloproteinases as well as collagen biosynthesis were evaluated.

RESULTS:

Free fatty acids induced comparable steatosis in simultaneous co-culture and monoculture. However, the activation of the stellate cells assessed by alpha-smooth muscle actin expression is greater when cells were in close contact. Furthermore, a time-dependent increment of tissue inhibitor metalloproteinase-2 protein was observed, which was inversely correlated with protein expression and activity of matrix-metalloproteinases, suggesting enhanced collagen biosynthesis. This behavior was absent in cell monoculture.

CONCLUSIONS:

These data indicate that cell-to-cell proximity between hepatocytes and stellate cells is necessary for the initiation of the fibrotic process.

• Authors: Pablo J Giraudi, Varenka J Barbero Becerra, Veronica Marin, Norberto C Chavez-Tapia, Claudio Tiribelli, Natalia Rosso
• Journal: Experimental and molecular pathology (Exp Mol Pathol) Vol. 98 Issue 1 Pg. 85-92 (Feb 2015) ISSN: 1096-0945 [Electronic] Netherlands
• PMID: 25533546 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Fatty Acids, Nonesterified
• RNA, Messenger
• TIMP2 protein, human
• Tissue Inhibitor of Metalloproteinase-2
• Collagen
• MMP2 protein, human
• Matrix Metalloproteinase 2

Topics

• Blotting, Western
• Cells, Cultured
• Coculture Techniques
• Collagen (metabolism)
• Extracellular Matrix (drug effects, metabolism)
• Fatty Acids, Nonesterified (pharmacology)
• Hepatic Stellate Cells (drug effects, metabolism, pathology)
• Hepatocytes (drug effects, metabolism, pathology)
• Humans
• Immunoenzyme Techniques
• Liver (drug effects, metabolism, pathology)
• Liver Cirrhosis (chemically induced, metabolism, pathology)
• Matrix Metalloproteinase 2 (genetics, metabolism)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Tissue Inhibitor of Metalloproteinase-2 (genetics, metabolism)