CHOLINE DEFICIENCY AUGMENTS AND ANTIBODY TO TUMOR-NECROSIS-FACTOR-ALPHA ATTENUATES ENDOTOXIN-INDUCED HEPATIC-INJURY

Alcoholic liver disease can be associated with hepatic choline deficie ncy and hepatic steatosis, abnormalities also observed in rats adminis tered choline-deficient (CD) diets. Bacterial lipopolysaccharides (LPS ) have been postulated to play a key role in this choline deficiency m odel of liver injury, and LPS hepatotoxicity is mediated to a major ex tent by the inflammatory cytokine tumor necrosis factor-alpha, (TNF-al pha). This study addressed the following questions: Does LPS administr ation exacerbate an in vivo liver injury induced by choline deficiency ? If so, do CD rats have increased serum TNF-alpha concentrations and does pretreatment anti-TNF-alpha IgG attenuate this injury? Rats admin istered choline-sufficient (CS) or CD diets for 16 days were intraveno usly administered either saline or LPS. One group of CD rats also rece ived a single dose of anti-TNF-alpha IgG before LPS administration. Ch anges in histology and serum transaminase levels were determined. Both liver histology and serum transaminases were unchanged in the CS grou p treated with LPS, compared with the CS group treated with saline (co ntrol group). However, compared with this control group, transaminases were 5- to 7-fold higher in saline-treated CD rats and 30- to 50-fold higher in LPS-treated CD rats. Livers of saline-treated CD rats had m assive fatty infiltration, and no necrosis but livers of LPS-treated C D rats showed both extensive fatty infiltration and large areas of nec rosis. Serum TNF-alpha concentrations in CD rats (saline or LPS treate d) were significantly elevated, compared with levels in corresponding CS rats. Pretreatment with the anti-TNF-alpha IgG prevented hepatonecr osis in LPS-treated CD rats and lowered their serum transaminases by o ne-third. Thus, LPS administration exacerbated liver injury induced by choline deficiency, and this injury was probably partially mediated b y TNF-alpha and attenuated by anti-TNF-alpha IgG.