Disruption of phospholipid and bile acid homeostasis in mice with nonalcoholic steatohepatitis.
Disruption of phospholipid and bile acid homeostasis in mice with nonalcoholic steatohepatitis.
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DOI：
10.1002/hep.25630
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发表时间：
2012-07
期刊：
影响因子：
--
通讯作者：
Gonzalez FJ
中科院分区：
文献类型：
--
作者：
Tanaka N;Matsubara T;Krausz KW;Patterson AD;Gonzalez FJ
非酒精性脂肪性肝炎(NASH)是一种进行性的非酒精性脂肪性肝病，可发展为肝硬化、肝功能衰竭和肝细胞癌。尽管NASH的几条代谢途径被破坏，内源性代谢物可能发生变化，但NASH发展过程中血清代谢物的变化仍不清楚。为了深入了解该病的发病机制，采用超高效液相色谱-电喷雾电离-四极杆飞行时间质谱仪的代谢组学方法和蛋氨酸和胆碱缺乏(MCD)饮食诱导的常规小鼠NASH模型，对血清代谢物的变化进行了评估。NASH小鼠血清棕榈酰基、硬脂酰基和油酰基溶血磷脂酰胆碱(LPC)显著降低，牛磺胆酸(Tauro-β)、牛磺胆酸盐和12-羟基二十碳四烯酸(12-HETE)显著升高。与这些代谢物的变化相一致的是，参与低密度脂蛋白降解(溶血磷脂酰胆碱酰基转移酶1-4)、胆汁酸排泄(三磷酸腺苷结合盒C亚家族成员1/4/5和有机溶质转运体β)和12-HETE合成(花生四烯酸12-脂氧合酶)的肝脏mRNAs显著上调。相反，负责向肝细胞转运胆汁酸的溶质载体家族10成员1(SLc10a1)和溶质载体有机阴离子转运体家族成员(Slco)1a1和1b2的表达明显受到抑制。MCD饲料中添加蛋氨酸的结果表明，血清代谢产物和相关基因表达的变化源于脂肪性肝炎，而不是膳食中胆碱缺乏或脂肪变性。此外，肿瘤坏死因子-α和转化生长因子-β1可诱导原代肝细胞Lpcat2/4和Abcc1/4的表达，下调SLc10a1和sLco1a1的表达，提示血清LPC和胆汁酸的变化与促炎细胞因子有关。最后，D-氨基半乳糖注射诱导肥胖/肥胖小鼠肝炎后，血清代谢产物和相关基因表达也发生了类似的变化。NASH患者磷脂和胆汁酸代谢紊乱，可能是由于肝脏炎症信号增强所致。
Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease that can develop into cirrhosis, hepatic failure, and hepatocellular carcinoma. Although several metabolic pathways are disrupted and endogenous metabolites may change in NASH, the alterations in serum metabolites during NASH development remain unclear. To gain insight into the disease mechanism, serum metabolite changes were assessed using metabolomics with ultraperformance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry and a conventional mouse NASH model induced by a methionine- and choline-deficient (MCD) diet. Significant decreases in serum palmitoyl-, stearoyl-, and oleoyl-lysophosphatidylcholine (LPC) and marked increases in tauro-β-muricholate, taurocholate and 12-hydroxyeicosatetraenoic acid (12-HETE) were detected in mice with NASH. In agreement with these metabolite changes, hepatic mRNAs encoding enzymes and proteins involved in LPC degradation (lysophosphatidylcholine acyltransferase [Lpcat] 1–4), basolateral bile acid excretion (ATP-binding cassette subfamily C member [Abcc] 1/4/5 and organic solute transporter β), and 12-HETE synthesis (arachidonate 12-lipoxygenase) were significantly up-regulated. In contrast, the expression of solute carrier family 10 member 1 (Slc10a1) and solute carrier organic anion transporter family member (Slco) 1a1 and 1b2, responsible for transporting bile acids into hepatocytes, were markedly suppressed. Supplementation of the MCD diet with methionine revealed that the changes in serum metabolites and the related gene expression were derived from steatohepatitis, but not dietary choline deficiency or steatosis. Furthermore, tumor necrosis factor-α and transforming growth factor-β1 induced the expression of Lpcat2/4 and Abcc1/4 and down-regulated Slc10a1 and Slco1a1 in primary hepatocytes, suggesting an association between the changes in serum LPC and bile acids and proinflammatory cytokines. Finally, induction of hepatitis in ob/ob mice by D- galactosamine injection led to similar changes in serum metabolites and related gene expression. Phospholipid and bile acid metabolism is disrupted in NASH, likely due to enhanced hepatic inflammatory signaling.(HEPATOLOGY 2012;56:118-129)
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影响因子：
24.5
作者：
Feldstein AE;Charatcharoenwitthaya P;Treeprasertsuk S;Benson JT;Enders FB;Angulo P
通讯作者：
Angulo P
影响因子：
4.1
作者：
Chen, Chi;Krausz, Kristopher W.;Shah, Yatrik M.;Idle, Jeffrey R.;Gonzalez, Frank J.
通讯作者：
Gonzalez, Frank J.
影响因子：
4.1
作者：
BAISTED, DJ;ROBINSON, BS;VANCE, DE
通讯作者：
VANCE, DE
DOI：
10.1152/ajpgi.00301.2011
发表时间：
2012-01-01
影响因子：
4.5
作者：
Kakisaka, Keisuke;Cazanave, Sophie C.;Gores, Gregory J.
通讯作者：
Gores, Gregory J.
影响因子：
29.4
作者：
Day, CP
通讯作者：
Day, CP