Milner Kerry-Lee, van der Poorten David, Xu Aimin, Bugianesi Elisabetta, Kench James G, Lam Karen S L, Chisholm Donald J, George Jacob
Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia.
Hepatology. 2009 Jun;49(6):1926-34. doi: 10.1002/hep.22896.
Several circulating cytokines are increased with obesity and may combine with the influence of visceral fat to generate insulin resistance, inflammation, and fibrosis in nonalcoholic fatty liver disease (NAFLD). Little information exists in NAFLD about three recently recognized tissue-derived cytokines that are all lipid-binding and involved in inflammation, namely adipocyte fatty acid-binding protein (AFABP), lipocalin-2, and retinol-binding protein 4 (RBP4). We examined the association of these three peptides with hepatic steatosis, inflammation, and fibrosis plus indices of adiposity, insulin resistance, and dyslipidaemia in 100 subjects with NAFLD and 129 matched controls. Levels of AFABP and lipocalin-2, but not RBP4, were significantly elevated in NAFLD versus control (AFABP, 33.5 +/- 14.4 versus 23.1 +/- 12.1 ng/mL [P < 0.001]; lipocalin-2, 63.2 +/- 26 versus 48.6 +/- 20 ng/mL [P < 0.001]) and correlated with indices of adiposity. AFABP correlated with indices of subcutaneous rather than visceral fat. AFABP alone distinguished steatohepatitis from simple steatosis (P= 0.02). Elevated AFABP independently predicted increasing inflammation and fibrosis, even when insulin resistance and visceral fat were considered; this applied to lobular inflammation and ballooning (odds ratio 1.4, confidence interval 1.0-1.8) and fibrosis stage (odds ratio 1.3, confidence interval 1.0-1.7) (P < or = 0.05 for all). None of the cytokines correlated with steatosis grade. AFABP levels correlated with insulin resistance (homeostasis model assessment of insulin resistance) in controls and NAFLD, whereas lipocalin-2 and RBP4 only correlated positively with insulin resistance in controls.
Circulating AFABP, produced by adipocytes and macrophages, and lipocalin-2, produced by multiple tissues, are elevated and may contribute to the metabolic syndrome in NAFLD. AFABP levels, which correlate with subcutaneous, but not visceral fat, independently predict inflammation and fibrosis in NAFLD and may have a direct pathogenic link to disease progression.
几种循环细胞因子在肥胖时会增加，并可能与内脏脂肪的影响相结合，在非酒精性脂肪性肝病（NAFLD）中产生胰岛素抵抗、炎症和纤维化。在NAFLD中，关于最近发现的三种均与脂质结合且参与炎症反应的组织源性细胞因子，即脂肪细胞脂肪酸结合蛋白（AFABP）、lipocalin-2和视黄醇结合蛋白4（RBP4）的信息很少。我们在100例NAFLD患者和129例匹配的对照中，研究了这三种肽与肝脂肪变性、炎症、纤维化以及肥胖、胰岛素抵抗和血脂异常指标之间的关联。与对照组相比，NAFLD患者中AFABP和lipocalin-2水平显著升高，但RBP4水平未升高（AFABP，33.5±14.4对23.1±12.1 ng/mL [P < 0.001]；lipocalin-2，63.2±26对48.6±20 ng/mL [P < 0.001]），且与肥胖指标相关。AFABP与皮下脂肪而非内脏脂肪指标相关。仅AFABP就能区分脂肪性肝炎和单纯性脂肪变性（P = 0.02）。即使考虑胰岛素抵抗和内脏脂肪，AFABP升高也能独立预测炎症和纤维化的加重；这适用于小叶炎症和气球样变（比值比1.4，置信区间1.0 - 1.8）以及纤维化分期（比值比1.3，置信区间1.0 - 1.7）（所有P均≤0.05）。这些细胞因子均与脂肪变性分级无关。在对照组和NAFLD患者中，AFABP水平与胰岛素抵抗（胰岛素抵抗稳态模型评估）相关，而lipocalin-2和RBP4仅在对照组中与胰岛素抵抗呈正相关。
由脂肪细胞和巨噬细胞产生的循环AFABP以及由多种组织产生的lipocalin-2水平升高，可能在NAFLD的代谢综合征中起作用。与皮下脂肪而非内脏脂肪相关的AFABP水平，可独立预测NAFLD中的炎症和纤维化，并且可能与疾病进展存在直接的致病联系。
