Abstract
BACKGROUND: Interactions between the gut, immune system, and the liver, as well as the type of fat in the diet, are critical components of alcoholic liver disease (ALD). The goal of the present study was to determine the effects of saturated fat (SF) and unsaturated fat (USF) on ethanol (EtOH)-induced gut-liver interactions in a mouse model of ALD. METHODS: C57BL/6N mice were fed Lieber-DeCarli liquid diets containing EtOH and enriched in USF (corn oil) or SF (medium chain triglycerides:beef tallow). Control mice were pair-fed on an isocaloric basis. Liver injury and steatosis, blood endotoxin levels, intestinal permeability, and tight junction (TJ) integrity, as well as hepatic Toll-like receptor (TLR) gene expression, were evaluated. RESULTS: After 8 weeks of EtOH feeding, liver injury and steatosis were observed in USF + EtOH group compared with control and SF + EtOH. Significantly increased intestinal permeability in conjunction with elevated blood endotoxin levels were observed in the ileal segments of the mice fed USF + EtOH. USF diet alone resulted in down-regulation of intestinal TJ protein mRNA expression compared with SF. Importantly, alcohol further suppressed TJ proteins in USF + EtOH, but did not affect intestinal TJ in SF + EtOH group. The type of fat in the diet alone did not affect hepatic TLR expression. Compared with control animals, hepatic TLR (TLR 1, 2, 3, 4, 7, 8, 9) mRNA expression was significantly (p < 0.05) increased in USF + EtOH, but not in SF + EtOH group. Notably, TLR5 was the only up-regulated TLR in both SF + EtOH and USF + EtOH groups. CONCLUSIONS: Dietary fat is an important cofactor in alcohol-associated liver injury. We demonstrate that USF (corn oil/linoleic acid) by itself results in dysregulation of intestinal TJ integrity leading to increased gut permeability, and alcohol further exacerbates these alterations. We postulate that elevated blood endotoxin levels in response to USF and alcohol in conjunction with up-regulation of hepatic TLRs combine to cause hepatic injury in ALD.