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Imbalanced insulin substrate-1 and insulin substrate-2 signaling trigger hepatic steatosis in vitamin D deficient rats: 8-methoxypsoralen, a vitamin D receptor ligand with a promising anti-steatotic action.
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ( IF 3.9 ) Pub Date : 2020-02-08 , DOI: 10.1016/j.bbalip.2020.158657 Muhanad Elhafiz 1 , Guolin Zhao 2 , Mohammed Ismail 2 , Dengqiu Xu 2 , Debanjan Das 2 , Sisi Fan 2 , Nong Cheng 2 , Bashir A Yousef 3 , Zhenzhou Jiang 4 , Luyong Zhang 5
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ( IF 3.9 ) Pub Date : 2020-02-08 , DOI: 10.1016/j.bbalip.2020.158657 Muhanad Elhafiz 1 , Guolin Zhao 2 , Mohammed Ismail 2 , Dengqiu Xu 2 , Debanjan Das 2 , Sisi Fan 2 , Nong Cheng 2 , Bashir A Yousef 3 , Zhenzhou Jiang 4 , Luyong Zhang 5
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The exact role of VD deficiency in the development of non-alcoholic fatty liver disease (NAFLD) remains unknown. In this study, we induced VD deficiency by feeding Female Sprague-Dawley rats a VD deficient (VDD) Diet and studied the hepatic changes associated with VD deficiency. Simultaneously, we provided the VDD rats with VD or 8-methoxy psoralen (8-MOP), a suggested vitamin D receptor agonist, to test the reversibility of the hepatic changes. VDD Rats developed borderline non-alcoholic steatohepatitis (NASH) with considerable elevation in hepatic triglycerides, total cholesterol, and malondialdehyde. Furthermore, VD deficiency induced the expression of crucial enzymes and transcription factors involved in denovo lipogenesis, which justified the hepatic lipid accumulation. Insulin receptor signaling was affected by VD deficiency, demonstrated by the elevation in insulin substrate-1 (IRS1) and reduction in insulin substrate-2 (IRS2) signaling. Treatment with VD or 8-MOP attenuated IRS1 signaling and its downstream targets, leading to a decline in de novo lipogenesis, while the elevation in IRS2 expression resulted in the nuclear exclusion of forkhead box O1 (FoxO1) and diminished gluconeogenesis, a vital source of acetyl-CoA for de novo lipogenesis. Moreover, 8-MOP and Calcipotriol modulated insulin signaling in human hepatocyte cell line L02, which highlighted the crucial role of VD in the regulation of hepatic lipid contents in rats and humans. Silencing of the vitamin D receptor expression in L02 diminished the inhibitory effect of Calcipotriol and 8-MOP on fatty acid synthase and acetyl- CoA carboxylase 1 and provided the evidence that 8-MOP actions mediated via vitamin D receptor.
中文翻译：
维生素D缺乏大鼠的胰岛素底物1和胰岛素底物2信号失衡会触发肝脂肪变性：8-甲氧基补骨脂素，一种具有前途性抗脂肪变性作用的维生素D受体配体。
VD缺乏症在非酒精性脂肪肝疾病（NAFLD）发生中的确切作用仍然未知。在这项研究中，我们通过给雌性Sprague-Dawley大鼠喂食VD缺乏（VDD）饮食诱导了VD缺乏，并研究了与VD缺乏相关的肝变化。同时，我们为VDD大鼠提供VD或建议的维生素D受体激动剂8-甲氧基补骨脂素（8-MOP），以测试肝脏变化的可逆性。VDD大鼠发展为边缘性非酒精性脂肪性肝炎（NASH），其肝甘油三酸酯，总胆固醇和丙二醛含量明显升高。此外，VD缺乏诱导了与宫颈脂肪形成有关的关键酶和转录因子的表达，这证明了肝脂质的积累。胰岛素受体信号转导受VD缺乏症影响，通过胰岛素底物1（IRS1）的升高和胰岛素底物2（IRS2）信号的减少来证明。用VD或8-MOP处理可减弱IRS1信号及其下游靶点，从而导致新生脂肪形成的下降，而IRS2表达的升高则导致叉头箱O1（FoxO1）的核排斥和糖异生的减少，糖异生是糖原异生的重要来源乙酰辅酶A用于新生脂肪形成。此外，8-MOP和卡泊三醇调节人肝细胞L02中的胰岛素信号传导，突显了VD在调节大鼠和人肝脂质含量中的关键作用。
更新日期：2020-02-10
中文翻译：
维生素D缺乏大鼠的胰岛素底物1和胰岛素底物2信号失衡会触发肝脂肪变性：8-甲氧基补骨脂素，一种具有前途性抗脂肪变性作用的维生素D受体配体。
VD缺乏症在非酒精性脂肪肝疾病（NAFLD）发生中的确切作用仍然未知。在这项研究中，我们通过给雌性Sprague-Dawley大鼠喂食VD缺乏（VDD）饮食诱导了VD缺乏，并研究了与VD缺乏相关的肝变化。同时，我们为VDD大鼠提供VD或建议的维生素D受体激动剂8-甲氧基补骨脂素（8-MOP），以测试肝脏变化的可逆性。VDD大鼠发展为边缘性非酒精性脂肪性肝炎（NASH），其肝甘油三酸酯，总胆固醇和丙二醛含量明显升高。此外，VD缺乏诱导了与宫颈脂肪形成有关的关键酶和转录因子的表达，这证明了肝脂质的积累。胰岛素受体信号转导受VD缺乏症影响，通过胰岛素底物1（IRS1）的升高和胰岛素底物2（IRS2）信号的减少来证明。用VD或8-MOP处理可减弱IRS1信号及其下游靶点，从而导致新生脂肪形成的下降，而IRS2表达的升高则导致叉头箱O1（FoxO1）的核排斥和糖异生的减少，糖异生是糖原异生的重要来源乙酰辅酶A用于新生脂肪形成。此外，8-MOP和卡泊三醇调节人肝细胞L02中的胰岛素信号传导，突显了VD在调节大鼠和人肝脂质含量中的关键作用。
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