Laboratory of Investigative Toxicology and Pathology, Department of Environmental and Occupational Health, Indiana University, Bloomington, IN 47405, United States.
Laboratory of Investigative Toxicology and Pathology, Department of Environmental and Occupational Health, Indiana University, Bloomington, IN 47405, United States.
Toxicology. 2018 Dec 1;410:199-213. doi: 10.1016/j.tox.2018.08.007. Epub 2018 Aug 16.
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the western countries. The histological spectrum of NAFLD includes simple steatosis, steatohepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma. Nuclear receptors are a large group of ligand-dependent transcription factors that sense the environmental and endogenous changes and regulate numerous physiological and pathological processes. Accumulating evidence has suggested that a dysregulation of nuclear receptors in NAFLD may effect on the metabolism of endogenous and exogenous chemicals in the liver. The current study was designed to systematically characterize the time-dependent modulation of nuclear receptors including the peroxisome proliferator-activated receptors (PPARs), the constitutive androstane receptor (CAR), the pregnane X receptor (PXR), the liver X receptor (LXR), and the farnesoid X receptor (FXR) in the progression of NAFLD. Male C57BL/6 mice fed by a high fat diet were used to induce NAFLD. Hepatic steatosis, lobular inflammation, progressive fibrosis, increased hepatocyte DNA synthesis, and liver tumor formation were observed at various time points in our mouse model. During the development of hepatic steatosis (8-16 weeks), PPARα was activated as indicated by its target genes as well as the elevated peroxisomal acyl-CoA oxidase activity. The mRNA level of Pparγ was also upregulated while Pparδ gene expression was significantly reduced during the development of hepatic steatosis. PXR target gene Cyp3a11 was consistently increased 3-4-fold in addition to the increased microsomal Cyp3a enzymatic activity at all stages of NAFLD. In contrast, CAR mediated Cyp2b10 gene expression was found increased only by week 12. LXRα target genes Abcg5 and Abcg8 were significantly elevated during the whole course of NAFLD. The mRNA of Fxr was downregulated at 24 and 32 weeks in high fat diet fed mice, which might correlate with the development of progressive fibrosis at the stage of steatohepatitis. The results of our study provided a systematic evaluation of the changes of nuclear receptors and their downstream chemicalmetabolism and transport enzymes in the progression of NAFLD.
非酒精性脂肪性肝病 (NAFLD) 是西方国家最常见的慢性肝病。NAFLD 的组织学谱包括单纯性脂肪变性、脂肪性肝炎、纤维化、肝硬化甚至肝细胞癌。核受体是一大类配体依赖性转录因子，可感知环境和内源性变化，并调节许多生理和病理过程。越来越多的证据表明，NAFLD 中核受体的失调可能会影响肝脏内外源化学物质的代谢。本研究旨在系统描述核受体（包括过氧化物酶体增殖物激活受体 (PPARs)、组成型雄烷受体 (CAR)、孕烷 X 受体 (PXR)、肝 X 受体 (LXR) 和法尼醇 X 受体 (FXR)）在 NAFLD 进展过程中的时间依赖性调节。用高脂肪饮食喂养雄性 C57BL/6 小鼠诱导 NAFLD。在我们的小鼠模型中，在不同时间点观察到肝脂肪变性、小叶炎症、进行性纤维化、肝细胞 DNA 合成增加和肝肿瘤形成。在肝脂肪变性发展过程中（8-16 周），PPARα 被激活，其靶基因以及过氧化物酶体酰基辅酶 A 氧化酶活性升高。Pparγ 的 mRNA 水平也上调，而 Pparδ 基因表达在肝脂肪变性发展过程中显著降低。PXR 靶基因 Cyp3a11 在 NAFLD 的所有阶段持续增加 3-4 倍，此外，微体 Cyp3a 酶活性增加。相反，CAR 介导的 Cyp2b10 基因表达仅在第 12 周增加。LXRα 靶基因 Abcg5 和 Abcg8 在整个 NAFLD 过程中显著升高。高脂饮食喂养小鼠在 24 和 32 周时 Fxr 的 mRNA 下调，这可能与脂肪性肝炎阶段进行性纤维化的发展有关。本研究结果系统评价了核受体及其下游化学代谢和转运酶在 NAFLD 进展过程中的变化。
