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Volume 125, Issue 2, Pages 437-443 (August 2003)
Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis Ariel E Feldstein, Ali Canbay, Paul Angulo, Makiko Taniai, Lawrence J Burgart, Keith D Lindor, Gregory J Gores Gastroenterology Volume 125, Issue 2, Pages (August 2003) DOI: /S (03)
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Figure 1 (A) TUNEL-positive cells are numerous in NASH. Liver sections of patients with NASH (n = 34) and of normal liver (n = 28) were stained using the TUNEL assay. (B) Quantitation of TUNEL-positive cells showed a significant increase in apoptosis in patients with NASH compared with controls (4 ± 2.3 vs. 0.8 ± 0.2 apoptotic cells/×400 field, respectively, P < 0.01). Gastroenterology , DOI: ( /S (03) )
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Figure 2 TUNEL-positive cells are significantly increased in liver sections from NASH patients (n = 34) compared with those from alcoholic hepatitis patients (n = 26) and simple steatosis (n = 10) (4 ± 2.3 vs. 2.0 ± 0.3 vs. 1.1 ± 0.4 apoptotic cells/×400 field, respectively, P ≤ 0.05). Gastroenterology , DOI: ( /S (03) )
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Figure 3 Activated caspases 3 and 7 are readily detected in hepatocytes in patients with NASH. Immunohistochemistry for activated caspases 3 and 7 was performed in liver tissue using an antibody that selectively recognizes the neoepitope of cleaved activated caspases 3/7 (original magnification 200×). Gastroenterology , DOI: ( /S (03) )
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Figure 4 Hepatocyte apoptosis was correlated with biochemical and histopathologic markers of liver injury. (A) Patients were divided into a group with an AST/ALT ratio higher than 1 (n = 12) and a group with a ratio lower than 1 (n = 22). Hepatocyte apoptosis was significantly higher in those patients with a ratio higher than 1 compared with those with a ratio lower than 1 (5.4 ± 2 vs. 2.9 ± 1.3, respectively, P < 0.05). (B) Apoptosis was significantly higher in patients with advance fibrosis compared with those with early fibrosis (5.9 ± 2 vs. 3.2 ± 1 apoptotic cells/×400 field, respectively, P = 0.02) and those with no fibrosis (5.9 ± 2 vs.1.9 ± 1.2 apoptotic cells/×400 field, respectively, P = 0.01). (C) Finally, apoptosis was significantly higher in patients with moderate to severe steatohepatitis (SH) compared with those patients with only mild inflammatory activity (5.8 ± 2.5 vs. 2.2 ± 0.9 apoptotic cells/×400 field, respectively, P = 0.02). Gastroenterology , DOI: ( /S (03) )
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Figure 5 Fas expression is increased in NASH. Fas receptor is strongly expressed in hepatocytes of patients with NASH as detected by immunostaining of liver tissue sections (original magnification 200×). Gastroenterology , DOI: ( /S (03) )
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Figure 6 Activation of Fas receptor promotes mitochondrial dysfunction via caspase 8 cleavage of Bid, a proapoptotic molecule that translocates to mitochondria following truncation by caspase 8 (Li et al.27, 1998, No. 73). The resultant mitochondrial dysfunction generates reactive oxygen species and is also associated with release of cytochrome c, activation of caspases 3 and 7, and apoptosis, which further exacerbates tissue injury and inflammation. In this model, the apoptosis and reactive oxygen species are caspase dependent. Gastroenterology , DOI: ( /S (03) )
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