Hepatic Niemann-Pick C1-Like 1 exacerbates non-alcoholic fatty liver disease by re-absorbing specific biliary oxysterols.
Hepatic Niemann-Pick C1-Like 1 exacerbates non-alcoholic fatty liver disease by re-absorbing specific biliary oxysterols.
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DOI：
10.1016/j.biopha.2022.113877
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发表时间：
2022-10
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影响因子：
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通讯作者：
Yoshihide Yamanashi;T. Takada;Yusuke Tanaka;Yutaka Ogata;Y. Toyoda;Sayo M Ito;Maiko Kitani;N. Oshida;Kosuke Okada;J. Shoda;H. Suzuki
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文献类型：
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作者：
Yoshihide Yamanashi;T. Takada;Yusuke Tanaka;Yutaka Ogata;Y. Toyoda;Sayo M Ito;Maiko Kitani;N. Oshida;Kosuke Okada;J. Shoda;H. Suzuki
背景膳食氧甾醇被认为与非酒精性脂肪肝病（NAFLD）的进展有关。然而，人们对膳食氧甾醇与 NAFLD 之间关联的分子基础知之甚少。我们假设肝脏 Niemann-Pick C1-Like 1 (NPC1L1)，一种从胆汁到肝脏的胆固醇重吸收剂，会调节肝脏氧甾醇水平并影响 NAFLD 进展。方法和结果考虑到肝脏 NPC1L1 表达的物种差异，我们使用肝脏特异性 NPC1L1 转基因 (NPC1L1Tg) 小鼠作为人类模型，并证明富含氧甾醇的加热胆固醇以肝脏 NPC1L1 依赖性方式加剧高脂饮食诱导的脂肪变性（NAFLD 的早期阶段）。对 NPC1L1Tg 小鼠肝脏和胆汁氧甾醇水平的分析以及对 NPC1L1 过表达细胞的体外氧甾醇摄取测定表明，NPC1L1 可以摄取部分（但不是全部）氧甾醇并抑制其胆汁排泄。此外，体外和体内分析表明，NPC1L1 底物 22(R)-羟基胆固醇 (22R-OHC) 和 25-羟基胆固醇 (25-OHC) 主要通过分别激活肝脏 X 受体 α 和类维生素A 相关孤儿受体 γ 参与脂肪变性进展。与这些结果一致，对临床样本的检查显示，在分析的 14 种主要氧甾醇中，22R-OHC 和 25-OHC 的血浆浓度与人类肝脏脂肪积累显着正相关。结论在主要膳食氧甾醇中，22R-OHC 和 25-OHC 以肝脏 NPC1L1 依赖性方式促进肝脂肪变性的进展特别有效。
BackgroundDietary oxysterols are believed to be associated with the progression of non-alcoholic fatty liver disease (NAFLD). However, the molecular basis of the association between dietary oxysterols and NAFLD is poorly understood. We hypothesized that hepatic Niemann-Pick C1-Like 1 (NPC1L1), a cholesterol re-absorber from bile to the liver, would regulate hepatic oxysterol levels and affects NAFLD progression.Methods and resultsConsidering the species differences in hepatic NPC1L1 expression, we used liver-specific NPC1L1 transgenic (NPC1L1Tg) mice as a human model and demonstrated that oxysterol-rich heated cholesterol exacerbated high-fat diet-induced steatosis, an early stage of NAFLD, in a hepatic NPC1L1-dependent manner. Analyses of hepatic and biliary oxysterol levels in NPC1L1Tgmice andin vitrooxysterol uptake assays with NPC1L1-overexpressing cells revealed that NPC1L1 can uptake some, but not all, oxysterols and suppress their biliary excretion. Furthermore,in vitroandin vivoanalyses revealed that 22(R)-hydroxycholesterol (22R-OHC) and 25-hydroxycholesterol (25-OHC), which are NPC1L1 substrates, were primarily involved in steatosis progression,viathe activation of liver X receptor α and retinoid-related orphan receptor γ, respectively. Consistent with these results, examination of clinical specimens revealed that among the 14 major oxysterols analyzed, plasma concentrations of 22R-OHC and 25-OHC were significantly positively correlated with hepatic fat accumulation in humans.ConclusionsAmong the major dietary oxysterols, 22R-OHC and 25-OHC are particularly potent in promoting the progression of hepatic steatosis in a hepatic NPC1L1-dependent manner.