Dietary fat sources differentially modulate intestinal barrier and hepatic inflammation in alcohol-induced liver injury in rats

Abstract

toxemia is a causal factor in the development of alcoholic liver injury. The present study aimed at determining the interactions of ethanol with different fat sources at the gut-liver axis. Male Sprague-Dawley rats were pair fed control or ethanol liquid diet for 8 wk. The liquid diets were based on a modified Lieber-DeCarli formula, with 30% total calories derived from corn oil (rich in polyunsaturated fatty acids). To test the effects of saturated fats, corn oil in the ethanol diet was replaced by either cocoa butter (CB, rich in long-chain saturated fatty acids) or medium-chain triglycerides (MCT, exclusively medium-chain saturated fatty acids). Ethanol feeding increased hepatic lipid accumulation and inflammatory cell infiltration and perturbed hepatic and serum metabolite profiles. Ethanol feeding with CB or MCT alleviated ethanol-induced liver injury and attenuated ethanolinduced metabolic perturbation. Both CB and MCT also normalized ethanol-induced hepatic macrophage activation, cytokine expression, and neutrophil infiltration. Ethanol feeding elevated serum endotoxin level, which was normalized by MCT but not CB. In accordance, ethanol-induced downregulations of intestinal occludin and zonula occludens-1 were normalized by MCT but not CB. However, CB normalized ethanol-increased hepatic endotoxin level in association with upregulation of an endotoxin detoxifying enzyme, argininosuccinate synthase 1 (ASS1). Knockdown ASS1 in H4IIEC3 cells resulted in impaired endotoxin clearance and upregulated cytokine expression. These data demonstrate that the protection of saturated fats against alcohol-induced liver injury occur via different actions at the gut-liver axis and are chain length dependent. alcohol; saturated fat; endotoxemia; inflammation; liver injury ALCOHOLIC LIVER DISEASE (ALD) is a major health problem worldwide (19,41). Endotoxemia is closely associated with the pathogenesis of ALD through the stimulation of proinflammatory cytokine production (6, 37). Significantly increased levels of endotoxin were found in both alcoholic patients and experimental animal models of ALD, and the levels correlated well with the development of liver injury (7). Our previous study showed that neutralization of endotoxin by endotoxin neutralizing protein attenuates acute alcohol-induced cytokine production and liver injury, suggesting the importance of endotoxins in mediating alcoholic hepatotoxicity (51). Mechanistic studies have suggested that intestinal bacterial overgrowth and intestinal permeability increase contribute to the development of endotoxemia in alcoholics (35, 37). Our previous work showed that orally administrated lipopolysaccharide was detectable in the plasma of alcohol-intoxicated mice but not in control mice (52), providing direct evidence that alcohol increases gut permeability to endotoxins. Animal studies also showed that prevention of gut leakiness resulted in suppression of alcohol exposure-induced endotoxemia and liver damage (18, 44), suggesting that gut leakiness is a causal factor in the...

Gut microbiota‐derived lipopolysaccharide uptake and trafficking to adipose tissue: implications for inflammation and obesity

“…Additionally, acute and chronic alcohol intake lead to significant elevation of portal and systematic levels of LPS in rats (123) and humans (124,125), which could be related to alcohol-induced intestinal barrier dysfunction. This is further supported by observations that certain types of dietary fat ameliorated alcohol-mediated down-regulation of TJ proteins in the gastrointestinal tract mucosa (126).…”

Diet-driven microbiota dysbiosis is associated with vagal remodeling and obesity

“…Since Betaproteobacteria promotes fat deposition in the liver, HF/HSD driven increases in Actinobacteria and Tenericutes may explain the counterintuitive effect of HF consumption on liver fat in this study. Interestingly, a diet rich in medium and long chain saturated fatty acids has previously been shown to counterbalance the effect of ethanol on liver inflammation and fat accumulation [50]. …”

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