Recombinant Humanized IgG1 Antibody Promotes Reverse Cholesterol Transport through FcRn-ERK1/2-PPARα Pathway in Hepatocytes.
Recombinant Humanized IgG1 Antibody Promotes Reverse Cholesterol Transport through FcRn-ERK1/2-PPARα Pathway in Hepatocytes.
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DOI：
10.3390/ijms232314607
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发表时间：
2022-11-23
影响因子：
5.6
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中科院分区：
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高脂血症相关的脂质紊乱被认为是动脉粥样硬化性心血管疾病的原因。胆固醇反向转运（RCT）是一种将多余的外周胆固醇转运至肝脏并进一步转化为胆汁酸，通过粪便从体内排出的机制，有助于减少高脂血症和心血管疾病。我们之前发现重组人源化IgG1抗体可促进巨噬细胞吞噬脂质，并通过ATP结合盒亚家族A1（ABCA1）（与RCT相关的关键蛋白之一）增加胆固醇流出至高密度脂蛋白（HDL）。在本研究中，我们探讨了肝细胞上其他RCT相关蛋白的表达，包括B型清道夫受体I（SR-BI）、载脂蛋白A-I（ApoA-I）和载脂蛋白A-II（ApoA-II）及其调节机制。我们证实重组人源化 IgG1 抗体选择性激活 ERK1/2，上调小鼠肝脏和人肝癌细胞系 HepG2 细胞中 SR-BI、ApoA-I 和 ApoA-II 的表达。胆汁酸合成的限速酶，包括胆固醇7α-羟化酶（CYP7A1）和甾醇27-羟化酶（CYP27A1），在用重组人源化IgG1抗体处理后表现出显着增加，并且粪便中胆汁酸的排泄增加。此外，即使在重组人源化IgG1抗体存在的情况下，SR-BI启动子上的过氧化物酶体增殖物激活受体α（PPARα）/RXR结合位点的废除或突变也消除了SR-BI报告基因荧光素酶活性。敲低肝细胞上的新生儿 Fc 受体 (FcRn) 会损害重组人源化 IgG1 抗体对 ERK1/2 激活以及 SR-BI、ApoA-I 和 ApoA-II 表达上调的作用。总之，重组人源化 IgG1 抗体减轻高脂饮食 ApoE−/− 小鼠模型高脂血症的机制之一可能是通过 FcRn-ERK1/2-PPARα 依赖性方式增强肝脏 RCT 功能。
Hyperlipidemia-associated lipid disorders are considered the cause of atherosclerotic cardiovascular disease. Reverse cholesterol transport (RCT) is a mechanism by which excess peripheral cholesterol is transported to the liver and further converted into bile acid for excretion from the body in feces, which contributes to reducing hyperlipidemia as well as cardiovascular disease. We previously found that the recombinant humanized IgG1 antibody promotes macrophages to engulf lipids and increases cholesterol efflux to high-density lipoprotein (HDL) through ATP-binding cassette sub-family A1 (ABCA1), one of the key proteins related to RCT. In the present study, we explored other RCT related proteins expression on hepatocytes, including scavenger receptor class B type I (SR-BI), apolipoprotein A-I (ApoA-I), and apolipoprotein A-II (ApoA-II), and its modulation mechanism involved. We confirmed that the recombinant humanized IgG1 antibody selectively activated ERK1/2 to upregulate SR-BI, ApoA-I, and ApoA-II expression in mice liver and human hepatocellular carcinoma cell lines HepG2 cells. The rate-limiting enzymes of bile acid synthesis, including cholesterol 7α-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1), exhibited a significant increase when treated with the recombinant humanized IgG1 antibody, as well as increased excretion of bile acids in feces. Besides, abolishment or mutation of peroxisome proliferator-activated receptor α (PPARα)/RXR binding site on SR-BI promoter eliminated SR-BI reporter gene luciferase activity even in the presence of the recombinant humanized IgG1 antibody. Knock down the neonatal Fc receptor (FcRn) on hepatocytes impaired the effect of recombinant humanized IgG1 antibody on activation of ERK1/2, as well as upregulation of SR-BI, ApoA-I, and ApoA-II expression. In conclusion, one of the mechanisms on the recombinant humanized IgG1 antibody attenuates hyperlipidemia in ApoE−/− mice model fed with high-fat-diet might be through reinforcement of liver RCT function in an FcRn-ERK1/2-PPARα dependent manner.
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