Chronic calcitriol supplementation improves the inflammatory profiles of circulating monocytes and the associated intestinal/adipose tissue alteration in a diet-induced steatohepatitis rat model

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.

Modeling Diet-Induced NAFLD and NASH in Rats: A Comprehensive Review

“…In a recent study from Emamat et al [ 52 ], Sprague Dawley rats that were fed HFD (60% of total calories from butter-derived fat) for 7 weeks developed metabolic syndrome, encompassing the development of obesity, hypertriglyceridemia, hyperinsulinemia and hyperglycemia, which are associated with the development of NASH. Su et al published similar results with rats that were fed the HFD (mainly derived from lard, with a total of 5210 kcal/kg) for 14 weeks and observed a NAS score of over 5 [ 53 ]. In another study, the HFD (5600 kcal/kg; saturated lipids 30.4 g/100 g, unsaturated lipids 5.3 g/100 g, originating from corn starch and coconut oil) was extended to 24 weeks [ 54 ], but with no additional worsening phenotypes.…”

Calcitriol Attenuates Doxorubicin-Induced Cardiac Dysfunction and Inhibits Endothelial-to-Mesenchymal Transition in Mice

“…Previous reports claimed that calcitriol reduced the levels of systemic inflammatory parameters. Inflammatory cytokines such as interleukin (IL)-1β also triggered EndMT; [61,62]; therefore, we do not exclude the possibility that calcitriol attenuated EndMT by inhibiting the systemic inflammation process in vivo [63,64].…”

A Lipid-Based Nanocarrier Containing Active Vitamin D₃ Ameliorates NASH in Mice <i>via</i> Direct and Intestine-Mediated Effects on Liver Inflammation

“…Next, we used the NLC to treat a NASH model in mice induced by the MCD diet. Mice in this model reproduce NASHlike pathologic features 43) and intestinal permeability. 23) The NLC and free active vitamin D 3 suppressed intestinal permeability as evaluated by leakage of FITC-dextran of hydrodynamic size 2.8 nm (Fig.…”