Vitamin D deficiency in obese rats exacerbates nonalcoholic fatty liver disease and increases hepatic resistin and toll-like receptor activation
Vitamin D deficiency in obese rats exacerbates nonalcoholic fatty liver disease and increases hepatic resistin and toll-like receptor activation
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DOI：
10.1002/hep.24737
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发表时间：
2012-04-01
期刊：
影响因子：
13.5
通讯作者：
Kowdley, Kris V.
中科院分区：
文献类型：
--
作者：
Roth, Christian L.;Elfers, Clinton T.;Kowdley, Kris V.
儿童肥胖与2型糖尿病和非酒精性脂肪性肝病（NAFLD）有关。最近的研究发现，超重儿童中维生素D缺乏症（VDD）、胰岛素抵抗（IR）和NAFLD之间存在关联。为了进一步探索介导这些影响的机制，我们给年轻（25日龄）的Sprague-Dawley大鼠单独喂食低脂饮食（LFD）或缺乏维生素D （LFD+VDD）。第二组大鼠被暴露在西式饮食（WD：高脂肪/高果糖玉米糖浆）中，超重儿童通常食用这种饮食，并且要么是维生素D充足（WD），要么是维生素D缺乏（WD+VDD）。使用非酒精性脂肪性肝炎（NASH）临床研究网络（CRN）评分系统评估肝脏组织学，并在10周后测量肝脏和内脏脂肪组织中炎症通路相关基因的表达。在VDD组中，与对照组相比，25- oh维生素D水平降低至29%（95%可信区间[CI]: 23%-36%）。与LFD组相比，WD+VDD组表现出更大的肝脏脂肪变性。WD+VDD组小叶炎症及NAFLD活动评分（NAS）高于WD组（NAS: WD+VDD 3.2 +/- 0.47 vs WD 1.50 +/- 0.48, P < 0.05）。与WD组相比，WD+VDD组小鼠肝脏中toll样受体（TLR）2、TLR4、TLR9、抵抗素、白细胞介素(IL)-1 β、IL-4、IL-6和氧化应激标志物血红素加氧酶(HO)-1 mRNA水平升高（P < 0.05）。Logistic回归分析显示，NAS评分与肝脏TLRs 2、4和9、内毒素受体CD14以及过氧化物酶体增殖物激活受体（PPAR） mRNA水平之间存在显著相关性。和HO-1。结论：在WD大鼠模型中，VDD可能通过内毒素暴露的方式激活tlr，从而加重NAFLD。此外，它引起IR，肝抵抗素基因表达升高，肝脏炎症和氧化应激基因上调。(肝脏病学2012)
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)-1 beta, 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)?, and HO-1. Conclusion: 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. (HEPATOLOGY 2012)