Division of Endocrinology, Seattle Children’s Hospital Research Institute, 1900 Ninth Avenue, Seattle, WA 98101, USA.
Hepatology. 2012 Apr;55(4):1103-11. doi: 10.1002/hep.24737. Epub 2012 Feb 15.
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.
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.
探讨维生素 D 缺乏 (VDD) 对超重儿童非酒精性脂肪性肝病 (NAFLD) 的影响及相关机制。
选择 25 日龄 Sprague-Dawley 大鼠，给予低脂饮食 (LFD) 或 LFD 联合 VDD 喂养，建立维生素 D 缺乏动物模型；另设 Western 饮食 (WD) 组，包括 WD 喂养组 (WD) 和 WD 联合 VDD 喂养组 (WD+VDD)。10 周后，采用非酒精性脂肪性肝炎临床研究网络 (NASH-CRN) 评分系统评估肝组织学变化，实时定量 PCR 检测肝脏和内脏脂肪组织中炎症通路相关基因的表达。
与对照组相比，VDD 组大鼠血清 25-羟维生素 D 水平下降至 29%(95%可信区间：23%-36%)。与 LFD 组相比，WD+VDD 组大鼠肝组织脂肪变性更明显，肝小叶炎症和 NAFLD 活动评分 (NAS) 更高 (NAS：WD+VDD 3.2±0.47 比 WD 1.50±0.48，P<0.05)。WD+VDD 组大鼠肝脏 Toll 样受体 (TLR)2、TLR4、TLR9、抵抗素、白细胞介素 (IL)-1β、IL-4、IL-6 和血红素加氧酶 (HO)-1 的 mRNA 水平较 WD 组升高(P<0.05)。Logistic 回归分析显示，NAS 评分与 TLR2、TLR4、TLR9、内毒素受体 CD14、过氧化物酶体增殖物激活受体 (PPAR)γ 和 HO-1 的肝脏 mRNA 水平显著相关。
维生素 D 缺乏加重 WD 大鼠的 NAFLD，可能与 TLR 激活有关，内毒素暴露是其潜在机制之一。此外，VDD 还可导致胰岛素抵抗、肝抵抗素基因表达增加以及肝脏炎症和氧化应激相关基因的上调。
