Cholesterol, Its Metabolites, and Nonalcoholic Steatohepatitis

胆固醇、其代谢物和非酒精性脂肪性肝炎

基本信息

  • 批准号:
    9898208
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-10-01 至 2022-03-31
  • 项目状态:
    已结题

项目摘要

The metabolic pathways in nonalcoholic steatohepatitis (NASH) that contribute to fatty liver’s progression to inflammation are being intensely studied. One pathway which has been overlooked is the CYP27A1 initiated ‘alternative pathway.’ This pathway is responsible for the metabolism of cholesterol to intracellular regulatory oxysterols. The pathway’s subsequent 7α- hydroxylation of these oxysterols and their lipotoxic metabolites by CYP7B1 is what is believed to eliminate their regulatory effects. However, what controls cell levels of these oxysterols and their known metabolites remains incompletely defined. Furthermore, the potential for these alternative pathway cholesterol metabolites in eliciting cytotoxicity and inflammation in fatty liver has not been studied. A preliminary study in a ‘fatty liver’ mouse model showed that overexpression of the mitochondrial cholesterol delivery protein, StARD1, increased mitochondrial CYP27A1 cholesterol metabolism, and, led to a dramatic reduction in hepatic cholesterol, triglycerides, and free fatty acids levels. Unanticipated, we found significant down regulation of hepatic CYP7B1 expression coupled with high levels of the regulatory oxysterols, 25- hydroxycholesterol(25HC), 27-hydroxycholesterol(27HC), and 24(S)-hydroxycholesterol(24HC) and a marked increase in LFTs. Based upon these observations, we postulated that low CYP7B1 and increased oxysterol levels may represent a pathway to inflammation in fatty liver. More specifically, chronic down-regulation of CYP7B1 leading to chronically increased oxysterol levels may play a role in the transition from fatty liver to inflammation as seen in NASH. Supportive of this hypothesis we found significant suppression of CYP7B1 expression correlated to an increase in 27HC levels in human steatotic livers obtained from the NIH liver tissue cell distribution system. Furthermore, in Western diet fed mice, we have now shown that a low CYP7B1 is associated with an increase in 27HC levels and subsequent inflammasome activation as determined by increased IL-1B levels; outlining a pathway from fatty liver to inflammation as occurs in NASH. These observations also provided evidence for CYP7B1 being a key regulator of the levels and ratio of the three CYP27A1 generated oxysterols (24HC/25HC/27HC), and their hydroxylated metabolites In conclusion: we hypothesize that in nonalcoholic fatty liver (NAFL) there is chronic suppression of CYP7B1. The chronic effects of increased levels of cholesterol metabolites as controlled by down-regulated CYP7B1 have injurious effects, and represent the major driving force for transition from NAFL to steatohepatitis via inflammasome activation. The means by which CYP7B1 is suppressed in NAFL is unknown. We propose three specific aims to define the pathway: Aim1: To define the CYP27A1 initiated ‘alternative pathway’ of oxysterol/BAS. More specifically, more clearly define the pathway metabolites and quantitate their levels/ratios under different metabolic conditions to elucidate their role in mediating liver inflammation. Aim2: To investigate the regulation of CYP7B1 in NAFL, and its control over intracellular levels of regulatory and potentially toxic cholesterol metabolites Aim3: To demonstrate that chronically increased hepatic levels of oxysterols and their metabolites that occur in fatty liver represent a driving force to hepatic inflammation.
非酒精性脂肪性肝炎 (NASH) 中导致脂肪的代谢途径 肝脏炎症进展的一种途径正在被深入研究。 被忽视的是 CYP27A1 启动的“替代途径”。该途径负责 胆固醇代谢为细胞内调节性氧甾醇。 据信,CYP7B1 对这些氧甾醇及其脂毒性代谢物进行羟基化 然而,是什么控制着这些氧甾醇的细胞水平和 此外,它们的已知代谢物的潜力仍未完全确定。 替代途径胆固醇代谢物引起脂肪肝细胞毒性和炎症 还没有研究过。 对“脂肪肝”小鼠模型的初步研究表明,过度表达 线粒体胆固醇传递蛋白 StARD1,线粒体 CYP27A1 增加 胆固醇代谢,并导致肝脏胆固醇、甘油三酯、 出乎意料的是,我们发现肝脏的显着下调。 CYP7B1 表达与高水平的调节性氧甾醇相结合,25- 羟基胆固醇(25HC)、27-羟基胆固醇(27HC)、24(S)-羟基胆固醇(24HC) 根据这些观察,我们假设 LFT 显着增加。 CYP7B1 和氧甾醇水平升高可能代表脂肪肝炎症的途径。 更具体地说,CYP7B1 的长期下调导致氧甾醇长期增加 水平可能在从脂肪肝到炎症的转变中发挥作用,如 NASH 中所见。 我们发现 CYP7B1 表达显着受到抑制,支持了这一假设 与从 NIH 肝脏获得的人类脂肪肝中 27HC 水平的增加相关 此外,在西方饮食喂养的小鼠中,我们现在已经证明了这一点。 CYP7B1 水平较低与 27HC 水平升高和随后的炎症相关 通过增加 IL-1B 水平来确定激活,概述了从脂肪肝到 NASH 中发生的炎症也为 CYP7B1 的存在提供了证据。 三种 CYP27A1 生成的氧甾醇的水平和比例的关键调节因子 (24HC/25HC/27HC) 及其羟基化代谢物 结论:我们认为非酒精性脂肪肝 (NAFL) 存在慢性 CYP7B1 的抑制导致胆固醇代谢物水平升高的慢性影响。 由下调的 CYP7B1 控制具有有害作用,并且是主要的驱动因素 通过炎症小体激活从 NAFL 转变为脂肪性肝炎的力量。 NAFL 中哪些 CYP7B1 被抑制尚不清楚,我们提出了三个具体目标来定义。 途径: 目标 1:定义 CYP27A1 启动的氧甾醇/BAS 的“替代途径”。 具体来说,更清楚地定义途径代谢物并定量其水平/比率 不同的代谢条件来阐明它们在介导肝脏炎症中的作用。 目的2:研究CYP7B1在NAFL中的调控及其对NAFL的控制 调节性和潜在毒性胆固醇代谢物的细胞内水平 目标 3:证明肝脏中氧化甾醇水平长期升高及其影响 脂肪肝中发生的代谢物是肝脏炎症的驱动力。

项目成果

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WILLIAM M PANDAK其他文献

WILLIAM M PANDAK的其他文献

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{{ truncateString('WILLIAM M PANDAK', 18)}}的其他基金

Role of Cholesterol in Non Alcoholic Fatty Liver
胆固醇在非酒精性脂肪肝中的作用
  • 批准号:
    8811002
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Role of Cholesterol in Non Alcoholic Fatty Liver
胆固醇在非酒精性脂肪肝中的作用
  • 批准号:
    9280750
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Cholesterol, Its Metabolites, and Nonalcoholic Steatohepatitis
胆固醇、其代谢物和非酒精性脂肪性肝炎
  • 批准号:
    10265399
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Role of Cholesterol in Non Alcoholic Fatty Liver
胆固醇在非酒精性脂肪肝中的作用
  • 批准号:
    8974226
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Lipid Transport, Bile Acid Synthesis, and Cholesterol Homeostasis
脂质运输、胆汁酸合成和胆固醇稳态
  • 批准号:
    7792592
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Lipid Transport, Bile Acid Synthesis, and Cholesterol Homeostasis
脂质运输、胆汁酸合成和胆固醇稳态
  • 批准号:
    8391118
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Role of Cholesterol in Non Alcoholic Fatty Liver
胆固醇在非酒精性脂肪肝中的作用
  • 批准号:
    8628400
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Lipid Transport, Bile Acid Synthesis, and Cholesterol Homeostasis
脂质运输、胆汁酸合成和胆固醇稳态
  • 批准号:
    8195880
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Lipid Transport, Bile Acid Synthesis, and Cholesterol Homeostasis
脂质运输、胆汁酸合成和胆固醇稳态
  • 批准号:
    7907772
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
CHOLESTEROL/BILE ACID HOMEOSTASIS
胆固醇/胆汁酸稳态
  • 批准号:
    6346129
  • 财政年份:
    2000
  • 资助金额:
    --
  • 项目类别:

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