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

PLoS One. 2018 Apr 23;13(4):e0194867. doi: 10.1371/journal.pone.0194867. eCollection 2018.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Adipose Tissue / pathology*
  • Animals
  • Caco-2 Cells
  • Calcitriol / administration & dosage*
  • Calcitriol / pharmacology
  • Cells, Cultured
  • Diet, High-Fat
  • Dietary Supplements
  • Disease Models, Animal
  • Drug Administration Schedule
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Inflammation Mediators / blood*
  • Inflammation Mediators / metabolism
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Intestines / pathology*
  • Lipogenesis / drug effects
  • Male
  • Monocytes / drug effects
  • Monocytes / metabolism*
  • Non-alcoholic Fatty Liver Disease / drug therapy*
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Inflammation Mediators
  • Calcitriol

Grant support

We especially thank Yun-Ru Wang, Fan-Yi Jhan, Che-Jui Chang and Yen-Ling Lin for their excellent technical supports. This work was entirely supported by research grants NSC-102-2314-B-010-036-MY3 and from the National Science Council, and V106EA-007, VGHUST105-GI-2-2 and by the Taipei Veterans General Hospital.