Hyperlipidemia May Synergize with Hypomethylation in Establishing Trained Immunity and Promoting Inflammation in NASH and NAFLD.
Hyperlipidemia May Synergize with Hypomethylation in Establishing Trained Immunity and Promoting Inflammation in NASH and NAFLD.
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DOI：
10.1155/2021/3928323
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发表时间：
2021
影响因子：
4.1
通讯作者：
Yang X
中科院分区：
文献类型：
--
作者：
Drummer CIV;Saaoud F;Sun Y;Atar D;Xu K;Lu Y;Shao Y;Johnson C;Liu L;Shen H;Jhala NC;Jiang X;Wang H;Yang X
我们对人非酒精性脂肪性肝炎(NASH)基因芯片数据和各种非酒精性脂肪性肝病NASH/NAFLD小鼠模型的微阵列/RNA-SEQ数据进行了全景分析，共检测了4249个基因，发现：(1)人NASH和NAFLD小鼠模型均上调细胞因子和趋化因子：(2)通路分析表明，人NASH可分为代谢性和免疫性NASH；蛋氨酸和胆碱缺乏+高脂饮食、甘氨酸N-甲基转移酶缺乏、蛋氨酸腺苷转移酶1A缺乏和高脂-胆固醇饮食分别可分为炎症性、地塞米松蓄积型、胆固醇/甲戊酸和LXR/RXR-脂肪酸β氧化型；(3)典型和非典型炎症小体在NASH/NAFLD的发病机制中起着不同的作用；(4)训练性免疫(TI)酶在NASH/NAFLD中显著上调；HFCD比细胞因子、趋化因子和炎性小体调节因子更能激活TI酶；(V)MCD+HFD是一个促炎细胞因子和典型和非典型炎症小体上调的模型，而HFCD是一个TI酶和脂质过氧化酶上调的模型；(Vi)caspase-11和caspase-1作为上游主调控因子，部分上调细胞因子、趋化因子、典型和非典型炎症小体途径调节因子、TI酶和脂质过氧化酶的表达。我们的发现为高脂血症和低甲基化在NASH和NAFLD进展中建立TI和促进炎症的协同作用提供了新的见解，并为未来NASH和NAFLD、代谢性疾病、移植和癌症的治疗干预提供了新的靶点。
We performed a panoramic analysis on both human nonalcoholic steatohepatitis (NASH) microarray data and microarray/RNA-seq data from various mouse models of nonalcoholic fatty liver disease NASH/NAFLD with total 4249 genes examined and made the following findings: (i) human NASH and NAFLD mouse models upregulate both cytokines and chemokines; (ii) pathway analysis indicated that human NASH can be classified into metabolic and immune NASH; methionine- and choline-deficient (MCD)+high-fat diet (HFD), glycine N-methyltransferase deficient (GNMT-KO), methionine adenosyltransferase 1A deficient (MAT1A-KO), and HFCD (high-fat-cholesterol diet) can be classified into inflammatory, SAM accumulation, cholesterol/mevalonate, and LXR/RXR-fatty acid β-oxidation NAFLD, respectively; (iii) canonical and noncanonical inflammasomes play differential roles in the pathogenesis of NASH/NAFLD; (iv) trained immunity (TI) enzymes are significantly upregulated in NASH/NAFLD; HFCD upregulates TI enzymes more than cytokines, chemokines, and inflammasome regulators; (v) the MCD+HFD is a model with the upregulation of proinflammatory cytokines and canonical and noncanonical inflammasomes; however, the HFCD is a model with upregulation of TI enzymes and lipid peroxidation enzymes; and (vi) caspase-11 and caspase-1 act as upstream master regulators, which partially upregulate the expressions of cytokines, chemokines, canonical and noncanonical inflammasome pathway regulators, TI enzymes, and lipid peroxidation enzymes. Our findings provide novel insights on the synergies between hyperlipidemia and hypomethylation in establishing TI and promoting inflammation in NASH and NAFLD progression and novel targets for future therapeutic interventions for NASH and NAFLD, metabolic diseases, transplantation, and cancers.
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作者：
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通讯作者：
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