The mechanisms of alcohol-mediated advanced liver injury in HIV-infected individuals are poorly understood. Thus, this study was aimed to investigate the effect of binge alcohol on the inflammatory
liver disease in HIV transgenic rats as a model for simulating human conditions. Female wild-type (WT) or HIV transgenic rats were treated with three consecutive doses of binge
ethanol (EtOH) (3.5 g/kg/dose oral gavages at 12-h intervals) or
dextrose (Control). Blood and liver tissues were collected at 1 or 6-h following the last dose of
ethanol or
dextrose for the measurements of serum
endotoxin and liver pathology, respectively. Compared to the WT, the HIV rats showed increased sensitivity to alcohol-mediated gut leakiness, hepatic steatosis and
inflammation, as evidenced with the significantly elevated levels of serum
endotoxin, hepatic
triglycerides, histological fat accumulation and F4/80 staining. Real-time PCR analysis revealed that hepatic levels of toll-like receptor-4 (TLR4),
leptin and the downstream target
monocyte chemoattractant protein-1 (MCP-1) were significantly up-regulated in the HIV-EtOH rats, compared to all other groups. Subsequent experiments with primary cultured cells showed that both hepatocytes and hepatic Kupffer cells were the sources of the elevated MCP-1 in HIV-EtOH rats. Further, TLR4 and MCP-1 were found to be upregulated by
leptin. Collectively, these results show that HIV rats, similar to HIV-infected people being treated with the highly active anti-retroviral
therapy (
HAART), are more susceptible to binge alcohol-induced gut leakiness and inflammatory
liver disease than the corresponding WT, possibly due to additive or synergistic interaction between binge alcohol exposure and
HIV infection. Based on these results, HIV transgenic rats can be used as a surrogate model to study the molecular mechanisms of many disease states caused by heavy alcohol intake in HIV-infected people on
HAART.