A metabolomic analysis of omega-3 fatty acid-mediated attenuation of western diet-induced nonalcoholic steatohepatitis in LDLR-/- mice.
A metabolomic analysis of omega-3 fatty acid-mediated attenuation of western diet-induced nonalcoholic steatohepatitis in LDLR-/- mice.
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DOI：
10.1371/journal.pone.0083756
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Jump DB
中科院分区：
文献类型：
--
作者：
Depner CM;Traber MG;Bobe G;Kensicki E;Bohren KM;Milne G;Jump DB
非酒精性脂肪性肝炎（NASH）是一种进行性非酒精性脂肪性肝病，是肝硬化、肝细胞癌和肝功能衰竭的危险因素。在此之前，我们报道了二十二碳六烯酸（DHA, 22:6,n-3）比二十碳五烯酸（EPA, 20:5,n-3）在逆转西方饮食（WD）诱导的LDLR-/-小鼠NASH方面更有效。利用我们之前研究的肝脏，我们开展了一项全球非靶向代谢组学方法来量化饮食引起的肝脏代谢变化。WD +橄榄油（WD + O）喂养小鼠的肝脏表现出与NASH一致的组织学和基因表达特征。对320种代谢物的代谢组学分析表明，WD和n-3多不饱和脂肪酸（PUFA）的补充对所有主要代谢途径都有广泛的影响。WD + o喂养小鼠的肝脏富含饱和脂肪酸（SFA）和单不饱和脂肪酸（MUFA）、棕榈酰鞘磷脂、胆固醇、n-6 PUFA、含n-6 PUFA的磷酸甘油脂、n-6 PUFA衍生的氧化脂（12-HETE），而缺乏含C20-22 n-3 PUFA的磷酸甘油脂、C20-22 n-3 PUFA衍生的氧化脂（18-HEPE、17、18-DiHETE）和s -乳酰谷胱甘肽（一种甲基乙二醛解毒产物）。WD + DHA比WD + EPA更有效地减弱WD + o诱导的NASH基因表达标志物、n-6 PUFA和氧化脂质、柠檬酸盐和s -乳糖基谷胱甘肽的变化。饮食引起的肝脏MUFA和鞘脂含量的变化与参与MUFA和鞘脂合成的酶的表达变化有关。然而，肝脏氧化脂肪酸和s -乳酸谷胱甘肽的变化与肝脏n-3和n-6 C20-22 PUFA含量相关。肝脏C20-22 n-3 PUFA含量与肝脏α-生育酚和抗坏血酸含量呈负相关，与尿液F2-和f3异前列腺素呈正相关，揭示了饮食对全身氧化应激的影响。DHA对肝脏SFA、MUFA、PUFA、鞘磷脂、PUFA衍生的氧化脂质和s -乳酸谷胱甘肽的调节可能解释了DHA对LDLR-/-小鼠wd诱导的NASH的保护作用。
Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease and a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. Previously, we reported that dietary docosahexaenoic acid (DHA, 22:6,n-3) was more effective than eicosapentaenoic acid (EPA, 20:5,n-3) at reversing western diet (WD) induced NASH in LDLR-/- mice. Using livers from our previous study, we carried out a global non-targeted metabolomic approach to quantify diet-induced changes in hepatic metabolism. Livers from WD + olive oil (WD + O)-fed mice displayed histological and gene expression features consistent with NASH. The metabolomic analysis of 320 metabolites established that the WD and n-3 polyunsaturated fatty acid (PUFA) supplementation had broad effects on all major metabolic pathways. Livers from WD + O-fed mice were enriched in saturated (SFA) and monounsaturated fatty acids (MUFA), palmitoyl-sphingomyelin, cholesterol, n-6 PUFA, n-6 PUFA-containing phosphoglycerolipids, n-6 PUFA-derived oxidized lipids (12-HETE) and depleted of C20-22 n-3 PUFA-containing phosphoglycerolipids, C20-22 n-3 PUFA-derived oxidized lipids (18-HEPE, 17,18-DiHETE) and S-lactoylglutathione, a methylglyoxal detoxification product. WD + DHA was more effective than WD + EPA at attenuating WD + O-induced changes in NASH gene expression markers, n-6 PUFA and oxidized lipids, citrate and S-lactosyl glutathione. Diet-induced changes in hepatic MUFA and sphingolipid content were associated with changes in expression of enzymes involved in MUFA and sphingolipid synthesis. Changes in hepatic oxidized fatty acids and S-lactoylglutathione, however, correlated with hepatic n-3 and n-6 C20-22 PUFA content. Hepatic C20-22 n-3 PUFA content was inversely associated with hepatic α-tocopherol and ascorbate content and positively associated with urinary F2- and F3-isoprostanes, revealing diet effects on whole body oxidative stress. DHA regulation of hepatic SFA, MUFA, PUFA, sphingomyelin, PUFA-derived oxidized lipids and S-lactoylglutathione may explain the protective effects of DHA against WD-induced NASH in LDLR-/- mice.
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影响因子：
7.7
作者：
Cani, Patrice D.;Amar, Jacques;Burcelin, Remy
通讯作者：
Burcelin, Remy
影响因子：
3.8
作者：
Lam, Brian P.;Younossi, Zobair M.
通讯作者：
Younossi, Zobair M.
影响因子：
4.2
作者：
Depner, Christopher M.;Torres-Gonzalez, Moises;Jump, Donald B.
通讯作者：
Jump, Donald B.
DOI：
10.1186/1476-9255-7-15
发表时间：
2010-03-30
期刊：
Journal of inflammation (London, England)
影响因子：
--
作者：
Harte AL;da Silva NF;Creely SJ;McGee KC;Billyard T;Youssef-Elabd EM;Tripathi G;Ashour E;Abdalla MS;Sharada HM;Amin AI;Burt AD;Kumar S;Day CP;McTernan PG
通讯作者：
McTernan PG
影响因子：
4.2
作者：
Depner, Christopher M.;Philbrick, Kenneth A.;Jump, Donald B.
通讯作者：
Jump, Donald B.