Puri Puneet, Wiest Michelle M, Cheung Onpan, Mirshahi Faridoddin, Sargeant Carol, Min Hae-Ki, Contos Melissa J, Sterling Richard K, Fuchs Michael, Zhou Huiping, Watkins Steven M, Sanyal Arun J
Division of Gastroenterology, Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, VA, USA
Hepatology. 2009 Dec;50(6):1827-38. doi: 10.1002/hep.23229.
Specific alterations in hepatic lipid composition characterize the spectrum of nonalcoholic fatty liver disease (NAFLD), which extends from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). However, the plasma lipidome of NAFLD and whether NASH has a distinct plasma lipidomic signature are unknown. A comprehensive analysis of plasma lipids and eicosanoid metabolites quantified by mass spectrometry was performed in NAFL (n = 25) and NASH (n = 50) subjects and compared with lean normal controls (n = 50). The key findings include significantly increased total plasma monounsaturated fatty acids driven by palmitoleic (16:1 n7) and oleic (18:1 n9) acids content (P < 0.01 for both acids in both NAFL and NASH). The levels of palmitoleic acid, oleic acid, and palmitoleic acid to palmitic acid (16:0) ratio were significantly increased in NAFLD across multiple lipid classes. Linoleic acid (8:2n6) was decreased (P < 0.05), with a concomitant increase in gamma-linolenic (18:3n6) and dihomo gamma-linolenic (20:3n6) acids in both NAFL and NASH (P < 0.001 for most lipid classes). The docosahexanoic acid (22:6 n3) to docosapentenoic acid (22:5n3) ratio was significantly decreased within phosphatidylcholine (PC), and phosphatidylethanolamine (PE) pools, which was most marked in NASH subjects (P < 0.01 for PC and P < 0.001 for PE). The total plasmalogen levels were significantly decreased in NASH compared with controls (P < 0.05). A stepwise increase in lipoxygenase (LOX) metabolites 5(S)-hydroxyeicosatetraenoic acid (5-HETE), 8-HETE, and 15-HETE characterized progression from normal to NAFL to NASH. The level of 11-HETE, a nonenzymatic oxidation product of arachidonic (20:4) acid, was significantly increased in NASH only.
Although increased lipogenesis, desaturases, and LOX activities characterize NAFL and NASH, impaired peroxisomal polyunsaturated fatty acid (PUFA) metabolism and nonenzymatic oxidation is associated with progression to NASH.
肝脏脂质组成的特定改变是非酒精性脂肪性肝病（NAFLD）的特征，其范围从非酒精性脂肪肝（NAFL）到非酒精性脂肪性肝炎（NASH）。然而，NAFLD的血浆脂质组以及NASH是否具有独特的血浆脂质组特征尚不清楚。对通过质谱定量的NAFL（n = 25）和NASH（n = 50）受试者的血浆脂质和类花生酸代谢物进行了全面分析，并与瘦正常对照（n = 50）进行了比较。主要发现包括，棕榈油酸（16:1 n7）和油酸（18:1 n9）含量驱动总血浆单不饱和脂肪酸显著增加（NAFL和NASH中这两种酸的P均<0.01）。在多种脂质类别中，NAFLD中棕榈油酸、油酸以及棕榈油酸与棕榈酸（16:0）的比值均显著升高。亚油酸（18:2n6）减少（P < 0.05），同时NAFL和NASH中γ-亚麻酸（18:3n6）和二高γ-亚麻酸（20:3n6）增加（大多数脂质类别中P < 0.001）。在磷脂酰胆碱（PC）和磷脂酰乙醇胺（PE）池中，二十二碳六烯酸（22:6 n3）与二十二碳五烯酸（22:5n3）的比值显著降低，在NASH受试者中最为明显（PC中P < 0.01，PE中P < 0.001）。与对照组相比，NASH中总缩醛磷脂水平显著降低（P < 0.05）。脂氧合酶（LOX）代谢物5（S）-羟基二十碳四烯酸（5-HETE）、8-HETE和15-HETE从正常到NAFL再到NASH呈逐步增加。11-HETE是花生四烯酸（20:4）的非酶氧化产物，仅在NASH中水平显著升高。
尽管脂肪生成增加、去饱和酶和LOX活性增强是NAFL和NASH的特征，但过氧化物酶体多不饱和脂肪酸（PUFA）代谢受损和非酶氧化与进展为NASH有关。
