title: Vitamin D deficiency in obese rats exacerbates nonalcoholic fatty liver disease and increases hepatic resistin and Toll-like receptor activation.
abstract: Childhood obesity is associated with type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD). Recent studies have found associations between vitamin D deficiency (VDD), insulin resistance (IR), and NAFLD among overweight children. To further explore mechanisms mediating these effects, we fed young (age 25 days) Sprague-Dawley rats with a low-fat diet (LFD) alone or with vitamin D depletion (LFD+VDD). A second group of rats was exposed to a Westernized diet (WD: high-fat/high-fructose corn syrup) that is more typically consumed by overweight children, and was either replete (WD) or deficient in vitamin D (WD+VDD). Liver histology was assessed using the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) scoring system and expression of genes involved in inflammatory pathways were measured in liver and visceral adipose tissue after 10 weeks. In VDD groups, 25-OH-vitamin D levels were reduced to 29% (95% confidence interval [CI]: 23%-36%) compared to controls. WD+VDD animals exhibited significantly greater hepatic steatosis compared to LFD groups. Lobular inflammation as well as NAFLD Activity Score (NAS) were higher in WD+VDD versus the WD group (NAS: WD+VDD 3.2 ± 0.47 versus WD 1.50 ± 0.48, P < 0.05). Hepatic messenger RNA (mRNA) levels of Toll-like receptors (TLR)2, TLR4, and TLR9, as well as resistin, interleukins (IL)-1β, IL-4, and IL-6 and oxidative stress marker heme oxygenase (HO)-1, were higher in WD+VDD versus WD animals (P < 0.05). Logistic regression analyses showed significant associations between NAS score and liver mRNA levels of TLRs 2, 4, and 9, endotoxin receptor CD14, as well as peroxisome proliferator activated receptor (PPAR)γ, and HO-1.
  
  
  CONCLUSIONS
  VDD exacerbates NAFLD through TLR-activation, possibly by way of endotoxin exposure in a WD rat model. In addition it causes IR, higher hepatic resistin gene expression, and up-regulation of hepatic inflammatory and oxidative stress genes.
authors: Division of Endocrinology, Seattle Children’s Hospital Research Institute, 1900 Ninth Avenue, Seattle, WA 98101, USA. christian.roth@seattlechildrens.org
authors: Christian L
authors: CL
authors: Roth
authors: Clinton T
authors: CT
authors: Elfers
authors: Dianne P
authors: DP
authors: Figlewicz
authors: Susan J
authors: SJ
authors: Melhorn
authors: Gregory J
authors: GJ
authors: Morton
authors: Andrew
authors: A
authors: Hoofnagle
authors: Matthew M
authors: MM
authors: Yeh
authors: James E
authors: JE
authors: Nelson
authors: Kris V
authors: KV
authors: Kowdley
mesh_terms: D000818:Animals; D015897:Comorbidity; D004040:Dietary Carbohydrates / Q000009:adverse effects; D004041:Dietary Fats / Q000009:adverse effects; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000453:epidemiology* / Q000378:metabolism / Q000503:physiopathology*; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000453:epidemiology* / Q000209:etiology / Q000503:physiopathology; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D052243:Resistin / Q000378:metabolism*; D012720:Severity of Illness Index; D051193:Toll-Like Receptors / Q000378:metabolism*; D014808:Vitamin D Deficiency / Q000453:epidemiology* / Q000503:physiopathology
chemical_list: D004040:Dietary Carbohydrates; D004041:Dietary Fats; D052243:Resistin; D051193:Toll-Like Receptors