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Nonalcoholic Steatohepatitis (NASH): Mechanism of hepatotoxic sensitivity
Author(s) -
donthamsetty shashikiran,
bhave vishakha S,
mitra mayur,
mehendale harihara,
latendresse john
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1136-c
Subject(s) - steatosis , downregulation and upregulation , liver injury , fatty liver , ccl4 , steatohepatitis , endocrinology , medicine , biology , chemistry , carbon tetrachloride , biochemistry , organic chemistry , gene , disease
The objectives were to test whether NASH sensitizes liver to drug/toxicant‐initiated liver injury and to investigate the mechanisms of such hepatotoxic sensitivity. Male SD rats were fed methionine and choline deficient diet for 28 days to induce steatosis. On day 29, administration of a nonlethal dose of CCl4 (2 ml/kg) yielded 90% mortality in steatotic rats between 12 to 48 h after CCl4 treatment, while all non steatotic rats survived. CCl4‐initiated liver injury in steatotic rats did not differ from that of non steatotic rats until 12 h suggesting that neither uptake nor altered bioactivation is likely to explain amplified CCl4 hepatotoxicity. Moreover, CYP2E1 levels and covalent binding of 14CCl4–derived radiolabel and did not differ between the groups. Injury escalated progressively only in the steatotic liver after 24 h as assessed by plasma ALT, AST and histopathology. S‐phase DNA synthesis (3H‐thymidine incorporation and PCNA) were inhibited in the steatotic livers after CCl4 exposure. The hypothesis that fatty hepatocytes undergo cell cycle arrest due to either a) inability to replenish ATP due to overexpressed mitochondrial uncoupling protein‐2 (UCP‐2), or b) inhibition of Fox m1b transcription factor was tested. Western blotting revealed downregulation of Fox m1b that led to upregulation of p21 and lower p‐pRb in steatotic livers. Hepatic ATP content was 10 fold lower in steatotic rats leading to suppressed cell division response. These results suggest that failure to replenish ATP stores due to overexpression of UCP‐2 and downregulated Fox m1b transcription factor impede the advance of fatty hepatocytes through cell division cycle.