Interleukin-32 upregulates the expression of ABCA1 and ABCG1 resulting in reduced intracellular lipid concentrations in primary human hepatocytes
Interleukin-32 upregulates the expression of ABCA1 and ABCG1 resulting in reduced intracellular lipid concentrations in primary human hepatocytes
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DOI：
10.1016/j.atherosclerosis.2018.02.027
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发表时间：
2018-04-01
期刊：
影响因子：
5.3
通讯作者：
Heinhuis, Bas
中科院分区：
文献类型：
--
作者：
Damen, Michelle S. M. A.;dos Santos, Jessica Cristina;Heinhuis, Bas
背景和目的：白介素32在炎症条件下的作用已被公认，然而，其在动脉粥样硬化中作用的机制仍不清楚。我们小组报告了IL-32基因启动子单核苷酸多态性与高密度脂蛋白(HDL)浓度升高相关。我们假设人单核细胞系肝细胞和颈动脉斑块组织中的内源性IL-32可以通过胆固醇转运体/介质的表达来调节高密度脂蛋白的稳态，从而影响动脉粥样硬化。方法：用重组人(Rh)肿瘤坏死因子α和PolyI：C刺激人原代肝细胞，研究IL-32和介质在胆固醇途径中的表达。此外，IL-32在HepG2细胞中过表达，在THP-1细胞中过表达和沉默，以研究IL-32对胆固醇转运体表达和功能的直接影响。结果：刺激人原代肝细胞可诱导IL-32α、IL-32β和IL-32γmRNA的表达(p<；0.01)。IL-32γ的表达与ABCA1、Abcg1、LXRα和apoA1显著相关(p<；0.01)，内源性IL-32可降低细胞内脂质浓度(p<；0.05)。结论：IL-32在人原代肝细胞、HepG2和THP-1细胞中的调节强烈影响ABCA1、Abcg1、LXRα和apoA1的mRNA表达，并影响细胞内脂质浓度。这些数据第一次显示了IL32在胆固醇动态平衡中的重要作用。(C)2018年作者。爱思唯尔出版公司(Elsevier B.V.)
Background and aims: The role of interleukin (IL-) 32 in inflammatory conditions is well-established, however, the mechanism behind its role in atherosclerosis remains unexplained. Our group reported a promoter single nucleotide polymorphism in IL-32 associated with higher high-density lipoprotein (HDL) concentrations. We hypothesize that endogenous IL-32 in liver cells, a human monocytic cell line and carotid plaque tissue, can affect atherosclerosis by regulating (HDL) cholesterol homeostasis via expression of cholesterol transporters/mediators.Methods: Human primary liver cells were stimulated with recombinant human (rh) TNF alpha and poly I:C to study the expression of IL-32 and mediators in cholesterol pathways. Additionally, IL-32 was overexpressed in HepG2 cells and overexpressed and silenced in THP-1 cells to study the direct effect of IL-32 on cholesterol transporters expression and function.Results: Stimulation of human primary liver cells resulted in induction of IL-32 alpha, IL-32 beta and IL-32 gamma mRNA expression (p < 0.01). A strong correlation between the expression of IL-32 gamma and ABCA1, ABCG1, LXR alpha and apoA1 was observed (p < 0.01), and intracellular lipid concentrations were reduced in the presence of endogenous IL-32 (p < 0.05). Finally, IL32 gamma and ABCA1 mRNA expression was upregulated in carotid plaque tissue and when IL-32 was silenced in THP-1 cells, mRNA expression of ABCA1 was strongly reduced.Conclusions: Regulation of IL-32 in human primary liver cells, HepG2 and THP-1 cells strongly influences the mRNA expression of ABCA1, ABCG1, LXR alpha and apoA1 and affects intracellular lipid concentrations in the presence of endogenous IL-32. These data, for the first time, show an important role for IL32 in cholesterol homeostasis. (C) 2018 The Authors. Published by Elsevier B.V.