調(diào)控USP8基因抑制神經(jīng)炎癥

朱麗紅，趙佳儀，藍　欣，袁　羽，陸大祥(暨南大學(xué)醫(yī)學(xué)院，廣東廣州510632)

調(diào)控USP8基因抑制神經(jīng)炎癥

朱麗紅△，趙佳儀，藍欣，袁羽，陸大祥
(暨南大學(xué)醫(yī)學(xué)院，廣東廣州510632)

目的:探討調(diào)控泛素特異性修飾酶8(USP8)的表達對小膠質(zhì)細胞活化的影響。方法:采用脂多糖(LPS)誘導(dǎo)BV2小鼠小膠質(zhì)細胞為活化的細胞模型，分別應(yīng)用分子生物學(xué)技術(shù)構(gòu)建pGCMV/IRES/EGFP-USP8載體研究上調(diào)USP8基因和RNA干擾技術(shù)研究干擾USP8基因?qū)PS誘導(dǎo)BV2小膠質(zhì)細胞一氧化氮(NO)和前列腺素E2(PGE2)的含量、一氧化氮合酶(iNOS)和環(huán)氧合酶2(COX-2)的表達以及核因子抑制蛋白(IκBα)降解的影響。結(jié)果:高表達USP 8可明顯抑制LPS刺激BV2小膠質(zhì)細胞NO和PGE2的釋放，可明顯減少LPS刺激BV2小膠質(zhì)細胞iNOS和COX-2表達以及IκBα蛋白的降解。高表達USP8可減少炎癥因子的釋放。USP8 siRNA可明顯增加LPS刺激BV2小膠質(zhì)細胞NO和PGE2的釋放，可明顯增加LPS刺激BV2小膠質(zhì)細胞iNOS和COX-2表達以及IκBα蛋白的降解。結(jié)論: USP8的高活性可調(diào)節(jié)促炎癥細胞因子的釋放，進而抑制小膠質(zhì)細胞的激活，抑制神經(jīng)炎癥和減輕炎癥反應(yīng)。

Exogenous EETs or sEH inhibition offers inhibitory effects on obesity progression，which is associated with reduced adipocyte differentiation and adipogenesis，and increased energy expenditure.Furthermore，CYP epoxygenase gene delivery and sEH inhibition markedly decreased plasma cholesterol and triglyceride levels due to reduced lipid synthesis.CYP epoxygenase overexpression or sEH inhibition attenuated liver steatosis，which was associated with decreased inflammatory response and lipid synthesis.

High-fat diet (HFD) treatment as little as 3 d induced fatty liver，insulin resistance and adipose inflammation.n3 PUFAs and their metabolites eicosanoids mediate protective effects on several metabolic disorders.However，the functions of n3 PUFA metabolites are largely unknown.Early in the course of HFD feeding for 4 d，we found significant lipid accumulation in mouse liver which was reversed by an n3-enriched diet (3% w/w) with decreased lipogenesis and increased beta-oxidation-related gene expression.Next，LCMS/MS was used to determine the plasma eicosanoids profile.In those mice，the liver lipid accumulation was positively associated with hydroxyeicosapentaenoic acids (HEPEs) and epoxyeicosatetraenoic acids (EEQs) levels.However，HEPEs and EEQs treatment did not ameliorate palmitate-induced steatosis in primary hepatocyte，suggesting an exitence of an indirect effect.Indeed，n3 PUFA supplementation significantly improved HFD-induced macrophage infiltration in adipose tissue and decreased the proinflammatory cytokine levels in plasma.Furthermore，the expression of proinflammatory cytokines and the activation of JNK pathway induced by palmitate was suppressed by HEPEs and EEQs in macrophages.In conclusion，n3 PUFA supplementation ameliorates HFD-induced inflammatory effect in adipose tissue and consequently hepatic steatosis by increasing EEQs and HEPEs.

△Corresponding author AI Ding E-mail: edin2000cn@gmail.com; ZHU Yi E-mail: zhuyi@tijmu.edu.cn

▲These authors contribute equally to this work

The current study aims to explore the signaling pathway involved in hyperhomocysteinemia (HHcy) -induced hepatic steatosis.First，we performed a meta-analysis involving 2 057 subjects and revealed that plasma homocysteine (Hcy) levels was associated with an increased risk of nonalcoholic fatty liver disease (P＜0. 05).Next，C57BL/6 mice were fed a high-methionine diet (HMD) (2%，wt/wt) for 8 weeks to establish a HHcy mouse model with hepatic steatosis and elevated CD36 expression in the liver.The increased CD36 expression was associated with activation of aryl hydrocarbon receptor (AHR).Furthermore，mass spectrometry analysis showed that hepatic content of lipoxin 4A，a well-known ligand of AHR，was significantly elevated in HHcy mice.In primary hepatocytes，the Hcy-induced CD36 expression and subsequent lipid uptake were significantly attenuated by AHR siRNA.Transient transfection assays showed that the activity of AHR response element was dramatically increased in a ligand-dependent manner by Hcy.In addition，Hcy treatment promoted the bingding of AHR to CD36 promoter.Finally，AHR antagonist CH223191 reversed lipid accumulation caused by HHcy via inhibiting AhR-CD36 pathway.In conclusion，HHcy activates AHR-CD36 pathway by increasing hepatic lipoxin 4A content，which results in hepatic steatosis.

△Corresponding author AI Ding E-mail: edin2000cn@gmail.com; ZHU Yi E-mail: zhuyi@tijmu.edu.cn

Hydroxysteroid sulfotransferase 2B1 (SULT2B1) sulfates cholesterol and oxysterols.Hepatic oval cells (HOCs)，thought to be progenitor cells，can be triggered in chemical-injured livers.The present study focuses on the role of SULT2B1 in hepatic oval cell proliferation after liver injury.Wild-type (WT) and SULT2B1－/－mice were fed with a 3，5-diethoxycarbonyl-1，4-dihydrocollidine (DDC) -containing diet.Our experiments revealed that the expression of SULT2B1 increased dramatically in chemical-induced liver injury model，which mainly occurred in HOCs.In vivo，enhanced expression of SULT2B1 shows positive correlation with the number of HOCs during DDC-induced liver injury and negative correlation with liver function.In vitro，HOCs derived from SULT2B1－/－mice showed lower proliferation capability than those from WT mice.SULT2B1 overexpression/knockdown by Ad-SULT2B1/SULT2B1-siRNA could promoted/inhibited WB-F344 cell growth.The upregulated SULT2B1 might promote hepatic oval cell proliferation and aggravate liver injury，which might be mediated by the inactivation of LXR.Moreover，we demonstrated that SULT2B1 might further activate IL-6-gp130-STAT3 signaling pathway，eventually promote hepatic oval cell proliferation and aggravate liver injury.In conclusion，our data indicate that the upregulated SULT2B1 plays a harmful role during chemical-induced liver injuries by promoting hepatic oval cell proliferation.

△Corresponding author Fax: 86-21-54237623; YIN Lian-hua E-mail: lhyin@shmu.edu.cn; LI Xiao-bo E-mail: xbli@fudan.edu.cn

Role of cytochrome P450 epoxygenase and EETs in regulating metabolism-related diseases

WANG Dao-wen
(Department of Internal Medicine and Gene Therapy Center，Tongji Medical College of Huazhong University of Science and Tochnology，Wuhan 430030，China.Tel: 027-83663280; E-mail: dwwang@tjh.tjmu.edu.cn)

Hydroxyeicosapentaenoic acids and epoxyeicosatetraenoic acids derived from n3 polyunsaturated fatty acid attenuate early occurrence of nonalcoholic fatty liver disease: targeted metabolomics-based research

WANG Chun-jiong▲，LIU Wen-li▲，YAO Liu，ZHANG Xu，AI Ding△，ZHU Yi△
(Department of Physiology and Pathophysiology，Tianjin Medical University，Tianjin 300070，China)

Hyperhomocysteinemia activates aryl hydrocarbon receptor-CD36 pathway to promote hepatic steatosis in mice liver

YAO Liu，WANG Chun-jiong，LIU Wen-li，ZHANG Xue-jiao，AI Ding△，ZHU Yi△

(Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology，Tianjin Medical University，Tianjin 300070，China)

SULT2B1 promotes hepatic oval cell proliferation by suppressing LXR activation inDDC-induced mouse liver injury

WANG Zheng-yang1，YANG Xiao-ming2，CHEN Liang1，ZHI Xiu-ling1，LU Han-yu1，NING Yan-xia1，Pohsheng Yeong3，4，CHEN Si-feng1，YIN Lian-hua1△，LI Xiao-bo1△

(1Department of Physiology and Pathophysiology，School of Basic Medical Sciences，F(xiàn)udan University，Shanghai 200032，China;
2Ningxia Medical University，Yinchuan 750004，China;3Department of Pathology，Singapore General Hospital，Singapore;
4Singapore Immunology Network，Agency for Science，Technology and Research，Biopolis，Singapore 138648，Singapore)

△E-mail: lhzhu@jnu.edu.cn