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非酒精性脂肪性肝炎的血浆脂质沉积特征:N-3 和 N-6多不饱和脂肪酸及它们脂氧合酶产物的特定水平

 

来源：国际肝病作者：发布时间：2007-11-6阅读：368

P. Puri1; M. M. Wiest2; M. Patnaik2; O. Cheung1; C. C. Sargeant1; F. Mirshahi1; S. M. Watkins2; A. J. Sanyal1

1. Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA.
2. Lipomics Technologies, Inc., West Sacramento, CA, USA.
 
BACKGROUND: Nonalcoholic steatohepatitis (NASH) is characterized by increased hepatic triacylglycerol, free cholesterol (FC):phosphatidylcholine (PC) and n-6:n-3 polyunsaturated fatty acid (PUFA) ratio (Puri et al, Hepatol, 2007 in press). The plasma lipidomic signature and its diagnostic utility in NASH are unknown.

AIMS: To define (1) the plasma lipidomic profile in subjects with NASH and compare it to nonalcoholic fatty liver (NAFL) and lean normal controls, (2) the basis for changes in plasma PUFAs, and (3) the diagnostic utility of these changes for NASH.

METHODS: NAFL and NASH were identified by liver biopsy and clinical assessment. Plasma lipid classes and their fatty acid composition were measured by GC-FID and inflammatory lipids including products of cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome p-450 (Cyp) activities were measured by LC-MS.

RESULTS: A total of 52 subjects were studied (normal:NAFL:NASH 12:10:30). Lipidomic profile: NASH was associated with significantly decreased PC (2165:1838:1787 nmole/g, p< 0.001) and higher FC:PC ratio (0.6:0.6:0.7, p< 0.02) relative to normal. Total n-3 PUFA (nmole/g) were specifically depleted in NASH (428:491:340, p< 0.02 NASH vs normal and NAFL) resulting in increased n-6:n-3 ratio in NASH (10.7:9.5:12.8, p< 0.04). PUFA metabolism: The linoleic acid (LA):α-linolenic acid (ALA) ratio in free fatty acid was significantly increased in NASH (11.7:13:14.9, p<0.0005 NASH vs normal). Although ALA was decreased, mead acid was not increased indicating an absence of dietary deficiency. N-6 changes: Arachidonic acid (AA):dihomogammalinolenic acid (DGLA) was decreased in NASH suggesting decreased Δ5-desaturase activity or increased utilization. Pro-inflammatory LOX products of AA (hydroxyeicosatetranoic acids (HETE): 5HETE, 8HETE, 9HETE, 11HETE, 15HETE) were increased (p< 0.05 for all) in NASH; COX products were unchanged and 8,9 diHETE, a Cyp product of AA was increased. N-3 changes: ALA levels were decreased in NASH while eicosapentanoic acid was unchanged. Docosahexanoic acid (DHA), a downstream n-3 PUFA, was decreased significantly in all lipid classes in NASH. 19,20 diHDPA, a Cyp product of DHA, was also decreased in NASH. Diagnostic utility: An n-6:n-3 ratio ≥ 12.5 separated NASH from other groups (AUROC 0.77, + likelihood ratio 11.4, p< 0.0001).

CONCLUSIONS: NASH is associated with increased FC:PC and n-6:n-3 PUFA in plasma. NASH is associated with (1) increased pro-inflammatory n-6 metabolites via the LOX pathway and (2) decreased n-3 PUFA, specifically DHA. The changes in plasma n-6:n-3 ratio may be useful as a diagnostic tool for NASH.

背景：非酒精性脂肪性肝炎(NASH)的特征是肝甘油三酯、游离胆固醇(FC)、磷酸卵磷酯(PC)和n-6:n-3多不饱和脂肪酸(PUFA)比率增加(Puri et al, Hepatol, 2007 in press)。在NASH中，血浆脂质沉积特征和它在诊断中的作用还不清楚。
 
目的：(1)在NASH病例中确定血浆脂质沉积的特征，并且与非酒精性脂肪肝(NAFL)和无脂肪肝的正常对照比较，(2)血浆多不饱和脂肪酸（PUFAs）改变的基础，(3)这些改变对 NASH诊断的作用。
 
方法：根据肝脏解剖学和临床诊断区分NAFL 和NASH。血浆脂类类别和脂肪酸组成使用GC-FID检测，炎性脂质包括环氧合酶(COX)产物，脂肪氧化酶(LOX)和细胞色素p-450 (Cyp)活性使用LC-MS检测。
 
结果：共研究52名受试者(正常:NAFL:NASH 12:10:30)。脂质沉积特征：NASH与PC的显著减少有关(2165:1838:1787 nmole/g, p< 0.001)，对于正常对照来说，FC:PC的比率更高 (0.6:0.6:0.7, p< 0.02)。总体的n-3 PUFA (nmole/g)在NASH中显著减少 (428:491:340, p< 0.02 NASH vs 正常 and NAFL)，导致n-6:n-3比率增加(10.7:9.5:12.8, p< 0.04)。PUFA代谢：NASH患者的亚油酸(LA) ：α-亚油酸(ALA)比率在游离脂肪酸中显著增加(11.7:13:14.9, p<0.0005 NASH vs normal)。虽然ALA减少，但蜂蜜酸不增加表明不存在饮食缺乏。N-6改变：在NASH患者花生四烯酸(AA)：双高亚麻油酸(DGLA)减少提示Δ5-去饱和酶活性减少或使用增加。NASH患者中，花生四烯酸的前炎症性LOX产物羟基廿碳四烯酸(HETE)：5HETE, 8HETE, 9HETE, 11HETE, 15HETE增加(对所有产物p< 0.05 )；环氧化酶（COX）产物没有变化，而且AA的8,9环磷酰胺产物diHETE增加；N-3改变：在NASH患者廿碳四烯酸不发生变化时，ALA水平降低。n-3 PUFA下游区的二十二碳六烯酸(DHA)在所有NASH脂质组中显著减少。DHA的环磷酰胺产物19,20 diHDPA在NASH患者中也减少。诊断作用：n-6:n-3 比率 ≥ 12.5可以将NASH与其他组区分开来(AUROC 0.77, +似然比11.4, p< 0.0001)。

结论：NASH与FC:PC和 n-6:n-3 PUFA在血浆中的增加有关。与NASH相关的因素有：(1)通过LOX通路，前炎症性n-6代谢增加 (2) n-3 PUFA, 特别是DHA减少。血浆中n-6:n-3比率的改变可能成为诊断NASH的有力工具。

内容标签：肝炎,NASH
 
 
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