Stress-induced soluble major histocompatibility complex class I-related chains A/B (MIC A/B) are increased in chronic liver diseases and hepatocellular malignancy. We investigated the impact of these molecules on liver injury, apoptosis, and fibrosis in nonalcoholic steatohepatitis (NASH). Blood and liver tissue were obtained from 40 patients with NASH undergoing bariatric surgery for obesity. The control group consisted of 10 healthy individuals. We also investigated 10 patients with nonalcoholic fatty liver (NAFL). Polymerase chain reaction was used to measure messenger RNA (

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Cell death is known to play a crucial role in liver diseases. We compared the clinical courses of two cases of liver failure of different origins correlated with the extent of cell death (apoptosis and/or necrosis), measured in the patient's blood. Patient 1 was admitted with acute liver failure following acetaminophen intoxication. Intravenous therapy with acetylcysteine was performed. The percentage of apoptotic cell death measured by M30 was three times higher than normal and the overall cell death measured by M65 was more than 30 x higher than normal. High levels of aminotransferases were detected, indicating high rates of necrosis. M30 and M65 values rapidly returned to normal levels, while the liver function test (LFT) levels decreased with latency. Patient 2 was admitted with acute-on-chronic liver failure with known liver fibrosis. M30 values were 16 x higher than normal. In contrast, M65 values were lower than in the first case. This time, no movement in M30 levels was seen until the M30 levels rapidly increased indicating the inevitable death of the patient, while LFTs did not change. These results indicate the role of M30 and M65 immunoexpression as markers for functioning liver cell mass, capacity for recovery and therefore as predictive markers in acute liver failure.

Aim-To ascertain whether resveratrol affects the expression of free fatty acids (FFA)-induced profibrogenic genes, death receptors, and/or apoptosis-related molecules in human hepatic stellate cells, using the LX-2 cell line.Methods-Cells were cultured in the presence of FFAs (2:1 oleate : palmitate) and subsequently treated with resveratrol. Gene expression rates were determined by quantitative realtime PCR. The 50% lethal dose (LD 50 ) of resveratrol in the presence of FFAs was assessed with the MTT viability test.Results-Compared to vehicle controls, incubation of LX-2 cells with 0.5 mM FFAs induced profibrogenic genes (α-SMA × 2.9; TGF-β1 × 1.6; TIMP-1 × 1.4), death receptors (CD95/Fas × 3.8; TNFR-1 × 1.4), and anti-apoptotic molecules (Bcl-2 × 2.3; Mcl-1 × 1.3). Subsequent addition of 15 μM resveratrol (LD 50 = 23.2 μM) significantly (P < 0.05) upregulated further these genes (α-SMA × 6.5; TGF-β1 × 1.9; TIMP-1 × 2.2; CD95/Fas × 13.1, TNFR-1 × 2.1; Bcl-2 × 3.6; Mcl-1 × 1.9). Importantly, this effect was only observed in the presence of FFAs.Conclusion-Resveratrol amplifies the profibrogenic activation of human hepatic LX-2 stellate cells. This finding raises the possibility that in obese patients with elevated FFAs reserveratrol could provoke hepatic fibrogenesis. In-vivo studies are necessary to further validate this conclusion.

Chronic hepatitis C infection leads to increased hepatocyte apoptosis. Because engulfment of apoptotic bodies (ABs) by hepatic stellate cells (HSC) is profibrogenic, we compared the effects of ABs derived from HCV-negative vs. HCV-infected (Con1+) Huh7 hepatoblastoma cells on fibrogenic and activation-related mRNA expression by a human hepatic stellate cell line (LX2). Uptake of Huh7 Con1+ ABs by LX2 cells dose-dependently upregulated profibrotic genes (COL1A1, TGFB1; TIMP1; TIMP2). When normalized to the apoptotic cytokeratin-18 M30 neoepitope, HCV + ABs exhibited a more pronounced effect than HCV − ABs. In contrast, neither non-ingested ABs nor nucleic acids obtained from Huh7, Huh7 Con1+ , or HepG2 cells triggered those ABdependent effects. Both the engulfment of Huh7 Con1+ ABs and their effects were partially blocked by masking of phosphatidylserine with annexin V, and completely inhibited by the class-A scavenger receptor ligand, polyinosinic acid. Our findings demonstrate that AB uptake stimulates HSCs, and indicate that HCV infection leads to amplified fibrogenic mRNA expression and enhanced HSC activation.