Abstract
Vitamin D deficiency and up-regulated TNFα-related signals are reported to be involved in abnormalities including intestinal hyper-permeability, bacterial translocation, systemic/portal endotoxemia, intestinal/adipose tissue/hepatic inflammation, and hepatic steatosis in nonalcoholic steatohepatitis (NASH). This study aims to explore the molecular mechanisms and effects of chronic calcitriol [1,25-(OH)2D3, hormonal form of vitamin D] on gut-adipose tissue-liver axis abnormalities using a high-fat diet (HFD)-fed rat model of NASH. In HFD-fed obese rats on a 10-week calcitriol (0.3 μg/kg/TIW) or vehicle treatment (NASH-vit. D and NASH-V rats) reigme, various in vivo and in vitro experiments were undertaken. Through anti-TNFα-TNFR1-NFκB signaling effects, chronic calcitriol treatment significantly restored plasma calcitriol levels and significantly improved vitamin D receptor (VDR) expression in monocytes and the small intestine of NASH-vit. D rats. Significantly, plasma and portal endotoxin/TNFα levels, bacterial translocation to mesenteric lymph nodes, plasma DX-4000-FITC, fecal albumin-assessed intestinal hyper-permeability, over-expression of TNFα-related immune profiles in monocytes, inflammation of intestinal/mesenteric adipose tissue (MAT)/liver and hepatic steatosis were improved by chronic calcitriol treatment of NASH rats. Additionally, in vitro experiments with acute calcitriol co-incubation reversed NASH-V rat monocyte supernatant/TNFα-induced monolayer barrier dysfunction in caco-2 cells, cytokine release from MAT-derived adipocytes, and triglyceride synthesis by lean-V rat hepatocytes. Using in vivo and in vitro experiments, our study reported calcitriol signaling in the gut as well as in adipose tissue. Meanwhile, our study suggests that restoration of systemic and intestinal vitamin D deficiency using by chronic vitamin D treatment effectively reduces TNFα-mediated immunological abnormalities associated with the gut-adipose tissue-liver axis and hepatic steatosis in NASH rats.
Highlights
Higher levels of plasma and intestinal lipopolysaccharide (LPS, called endotoxin) are noted in nonalcoholic steatohepatitis (NASH) patients than in healthy subjects [1,2]
Compared to the NASH-V group, restoration of plasma calcitriol levels in NASHvit.D rats by 10 weeks of calcitriol treatment was accompanied by the suppression of plasma and portal endotoxin levels as well as the reduction of LPS-binding protein (LBP) and tumor necrosis factor-α (TNFα) levels (Table 2)
Data were expressed as mean ±SD; †P
Summary
Higher levels of plasma and intestinal lipopolysaccharide (LPS, called endotoxin) are noted in nonalcoholic steatohepatitis (NASH) patients than in healthy subjects [1,2]. Significantly high LPS-stimulated TNFα production is observed in cultured whole blood cells from NASH patients [2]. In NASH, increased TNFα can exacerbate intestinal inflammation and mucosal barrier disruption [3,4,5]. In the inflamed intestinal epithelium, TNFα produced from infiltrated immune cells further results in systemic/portal inflammation and endotoxemia [3,4,5,6]. NASH is characterized by remarkable intestinal hyper-permeability, epithelial tight junctions disruption and endotoxemia [5,7]
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