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H epatic fibrosis is a major histological finding associated with the progression of chronic liver disease to cirrhosis; it is characterized by increased deposition of components of the extracellular matrix (ECM), in particular fibrillar collagens type I and type III. 1 Hepatic stellate cells (HSC) are currently considered to be one of the major sources of ECM proteins in the liver; expansion of their pool is a key step in the fibrogenic process. 2 Following hepatic injury, HSC develop a myofibroblast-like phenotype, characterized by a reduced content of vitamin A, increased proliferation and migration, enhanced expression of matrix protein, and production of matrix metalloproteinases (MMPs). 3 Evidence from experimental and clinical studies indicates that production of reactive oxygen species (ROS) and lipid peroxidation of cell membranes are often associated with the development of hepatic fibrogenesis and

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Oxidative stress is associated with liver fibrosis and with hepatic stellate cell (HSC) activation in vivo. However, it remains controversial whether oxidative stress contributes to HSC activation either directly or through a paracrine stimulation by damaged hepatocytes. A medium containing products released from cells undergoing oxidative stress was obtained after incubation of hepatocytes with (HCM/Fe) or without (HCM) 0.1 mmol/L ferric nitrilotriacetate complex (FeNTA). Exposure of HSC to HCM/Fe for 24 hours significantly increased the number of proliferating HSC compared with HCM and to controls at all dilutions tested. The simultaneous coincubation of HSC with HCM/Fe and desferrioxamine (50 micromol/L) did not reduce the observed increase in cell proliferation, thus excluding a role for eventually contaminating iron in HCM/Fe. HCM/Fe induced also a significant increase in collagen type I accumulation in HSC culture media. To study the cellular mechanism underlying HCM/Fe effects, we evaluated the activity of the Na+/H+ exchanger, which plays a role in regulating HSC proliferation. The incubation of HSC for 24 hours with HCM/Fe significantly increased baseline intracellular pH (pHi) and Na+/H+ exchanger activity, indicating a plausible role of this antiport in mediating cell response. In conclusion, hepatocytes undergoing oxidative stress release factors which are fibrogenic for HSC, thereby, confirming what has been only hypothesized in vivo. In addition, HSC proliferation is associated with changes in the Na+/H+ exchanger activity, thus providing a useful target for the evaluation of inhibitors of this pathway for the treatment of hepatic fibrosis.

Ethanol induces liver fibrosis by several means that include, among others, the direct fibrogenic action of acetaldehyde on hepatic stellate cells (HSC). However the mechanisms responsible for this effect are not well understood. In this communication we investigated signal transduction pathways triggered by acetaldehyde leading to upregulation of ␣2(I) collagen and fibronectin gene expression in human HSC. Run-on assays showed that acetaldehyde-enhanced transcription of these 2 genes as early as 2 hours, via de novo protein synthesis-independent and -dependent mechanisms. It also stimulated a time-dependent induction in phosphorylation of pp70 S6K and extracellular-regulated kinase 1/2 (ERK1/2). These effects were completely prevented by calphostin C, a protein kinase C inhibitor. As expected, acetaldehyde-elicited ERK1/2 phosphorylation was inhibited by PD98059, a MEK inhibitor, but not by wortmannin, a PI3K inhibitor. On the other hand, both of these inhibitors partially inhibited phosphorylation of pp70 S6K induced by acetaldehyde suggesting that its activation is ERK1/2-and PI3K-dependent. Acetaldehyde-elicited fibronectin and ␣2(I) collagen upregulation was inhibited by calphostin C. However, while PD98059, wortmannin and rapamycin (a pp70 S6K inhibitor) completely abrogated ␣2(I) collagen upregulation, they had no effect on fibronectin expression. Overall, these data suggest that protein kinase C is an upstream component from which acetaldehyde signals are transduced to other pathways such as PI3K and ERK1/2. In addition, differential activation of these pathways is needed for the increase in fibronectin and ␣2(I) collagen gene expression induced by acetaldehyde in human HSC.

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Post-load insulin resistance (OGIS <9.8 mg/kg/min) is associated with severe hepatic fibrosis in both NAFLD and CHC patients, and may help identify subjects at risk of progressive disease.