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Exp Mol Pathol. 2015 Feb;98(1):85-92. doi: 10.1016/j.yexmp.2014.12.006. Epub 2014 Dec 20.

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

Author information

1
Fondazione Italiana Fegato, Centro Studi Fegato, Area Science Park Basovizza Bldg. Q SS14 Km 163.5, 34149 Trieste, Italy.
2
Fondazione Italiana Fegato, Centro Studi Fegato, Area Science Park Basovizza Bldg. Q SS14 Km 163.5, 34149 Trieste, Italy; Liver Research Unit, Médica Sur Clinic & Foundation, Puente de Piedra 150, Col. Toriello Guerra, Tlalpan, C.P. 14050 Mexico City, Mexico.
3
Fondazione Italiana Fegato, Centro Studi Fegato, Area Science Park Basovizza Bldg. Q SS14 Km 163.5, 34149 Trieste, Italy; Department of Medical Sciences, University of Trieste, 34100 Trieste, Italy.
4
Fondazione Italiana Fegato, Centro Studi Fegato, Area Science Park Basovizza Bldg. Q SS14 Km 163.5, 34149 Trieste, Italy. Electronic address: natalia.rosso@csf.units.it.

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.

KEYWORDS:

Extracellular matrix turnover; Fibrogenesis; Hepatic stellate cells; Hepatocytes; Steatosis

PMID:
25533546
DOI:
10.1016/j.yexmp.2014.12.006
[Indexed for MEDLINE]

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