Hepatic inflammation induced by high-fructose diet is associated with altered 11 beta HSD1 expression in the liver of Wistar rats

Abstract

High fructose consumption provokes metabolic perturbations that result in chronic low-grade inflammation and insulin resistance. Glucocorticoids, potent anti-inflammatory hormones, have important role in pathogenesis of diet-induced metabolic disturbances. The aim of this study was to examine the link between glucocorticoid metabolism and inflammation in the liver of fructose-fed rats. Fructose-fed male Wistar rats consumed 60 \% fructose solution for 9 weeks. Glucocorticoid prereceptor metabolism and signaling were analyzed by measuring the level of 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1) and hexose-6-phosphate dehydrogenase expression, as well as via determination of intracellular corticosterone concentration, glucocorticoid receptor subcellular distribution and expression of its target gene, phosphoenolpyruvate carboxykinase. Nuclear factor kappa B (NF kappa B), tumor necrosis factor alpha (TNF alpha) and the level of inhibitory phosphorylation of insulin receptor substrate-1 (IRS-1) on Ser(307) were analyzed as markers of hepatic inflammation. The protein and/or mRNA levels of all examined molecules were assessed by Western blot and/or qPCR. Fructose-rich diet led to an enhancement of 11 beta HSD1 protein level in the liver, without affecting intracellular level of corticosterone and downstream glucocorticoid signaling. On the other hand, proinflammatory state was achieved through NF kappa B activation and increased TNF alpha expression, while elevated level of inhibitory phosphorylation of IRS-1 was observed as an early hallmark of insulin resistance. High-fructose diet does not influence hepatic glucocorticoid signaling downstream of the receptor, permitting development of NF kappa B-driven inflammation. The alteration in 11 beta HSD1 expression is most likely the consequence of enhanced inflammation, finally leading to disruption of insulin signaling in the rat liver.