Cluster of Differentiation 36 Deficiency Aggravates Macrophage Infiltration and Hepatic Inflammation by Upregulating Monocyte Chemotactic Protein-1 Expression of Hepatocytes Through Histone Deacetylase 2-Dependent Pathway
Cluster of Differentiation 36 Deficiency Aggravates Macrophage Infiltration and Hepatic Inflammation by Upregulating Monocyte Chemotactic Protein-1 Expression of Hepatocytes Through Histone Deacetylase 2-Dependent Pathway
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分化簇 36 缺陷通过组蛋白脱乙酰酶 2 依赖性途径上调肝细胞单核细胞趋化蛋白 1 表达，从而加剧巨噬细胞浸润和肝脏炎症
DOI：
10.1089/ars.2016.6808
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发表时间：
2017-08-01
影响因子：
6.6
通讯作者：
Ruan, Xiong Z.
中科院分区：
文献类型：
--
作者：
Zhong, Shan;Zhao, Lei;Ruan, Xiong Z.
目的：分化簇36（CD 36）参与非酒精性脂肪性肝炎（NASH）的发生。过量的CD 36促进肝细胞摄取脂肪酸，激活炎症信号，促进肝脏脂肪变性和炎症。然而，CD 36缺乏反而通过未知的机制促进非酒精性脂肪肝。结果：CD 36缺失小鼠（CD 36（-/-）mice）肝细胞单核细胞趋化蛋白-1（MCP-1）表达明显增加，巨噬细胞向肝脏迁移，肝脏炎症反应和纤维化加重。组蛋白去乙酰化酶2（HDAC 2）在野生型肝细胞中高度表达，并对乙酰组蛋白3（H3）具有抑制作用，其核表达在CD 36缺陷型肝细胞中减少。因此，在CD 36缺陷肝细胞中，与MCP-1启动子结合的乙酰基H3水平增加，导致肝特异性MCP-1转录激活。CD 36（-/-）小鼠肝脏和培养的肝细胞中细胞核HDAC 2的减少是由于细胞内活性氧（ROS）水平的降低，而低浓度过氧化氢（H2 O2）的补充克服了CD 36缺陷引起的HDAC 2抑制，降低了MCP-1基因转录和微噬细胞迁移。我们的研究结果提供了第一个证据，表明通过CD 36缺失减少ROS产生对肝脏也是有害的。结论：CD 36缺陷可通过减少肝细胞内ROS和核HDAC 2的表达，促进肝细胞MCP-1的转录，从而促进NASH的发生。
Aims: Cluster of differentiation 36 (CD36) is involved in the development of nonalcoholic steatohepatitis (NASH). Excess CD36 facilitates liver cells taking fatty acid and activates inflammatory signals to promote hepatic steatosis and inflammation. However, CD36 deficiency paradoxically promotes nonalcoholic fatty liver disease by unknown mechanisms. We explored the probable molecular mechanism of hepatic inflammation induced by CD36 deficiency.Results: CD36 deletion in mice (CD36(-/-) mice) specifically increased monocyte chemotactic protein-1 (MCP-1) in hepatocytes, promoted macrophage migration to the liver, and aggravated hepatic inflammatory response and fibrosis. The nuclear expression of histone deacetylase 2 (HDAC2), which highly expresses in wild-type hepatocytes and has an inhibitory effect on acetyl histone 3 (H3), was reduced in CD36-deficient hepatocytes. Consequently, the level of acetyl H3 binding to MCP-1 promoters was increased in CD36-deficient hepatocytes, causing hepatic-specific MCP-1 transcriptional activation. Reduction of nuclear HDAC2 in both CD36(-/-) mice liver and cultured hepatocytes was due to reduction of intracellular reactive oxygen species (ROS) level, while supplement of low-concentration hydrogen peroxide (H2O2) overcame the suppression of HDAC2 caused by CD36 deficiency, decreasing MCP-1 gene transcription and microphage migration.Innovation: Our results provide first evidence that decreased ROS production by CD36 deletion was also harmful for livers. The fine balance of CD36 plays an important role in maintaining balances of hepatic ROS and nuclear HDAC2, which could be a potential new therapeutic strategy for the prevention of NASH development.Conclusion: CD36 deficiency promoted the development of NASH by facilitating the transcription of MCP-1 in hepatocytes due to the reduction of ROS and nuclear HDAC2.