Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis.
Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis.
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DOI：
10.1016/j.jhep.2018.03.031
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发表时间：
2018-08
影响因子：
25.7
通讯作者：
Schnabl B
中科院分区：
文献类型：
--
作者：
Brandl K;Hartmann P;Jih LJ;Pizzo DP;Argemi J;Ventura-Cots M;Coulter S;Liddle C;Ling L;Rossi SJ;DePaoli AM;Loomba R;Mehal WZ;Fouts DE;Lucey MR;Bosques-Padilla F;Mathurin P;Louvet A;Garcia-Tsao G;Verna EC;Abraldes JG;Brown RS Jr;Vargas V;Altamirano J;Caballería J;Shawcross D;Stärkel P;Ho SB;Bataller R;Schnabl B
胆汁淤积的程度是酒精性肝炎的重要疾病驱动因素，酒精性肝炎是一种严重的临床疾病，需要新的生物标志物和靶向治疗。与胆汁淤积相关的机制和生物标志物在很大程度上是未知的。在这里，我们分析了一组酒精性肝炎患者的特征，以及与血清胆汁酸和成纤维细胞生长因子19（FGF 19）（胆汁酸合成的主要调节因子）相关的临床和组织学参数和结局。我们发现，总胆汁酸和结合胆汁酸在酒精性肝炎患者与对照组相比显着增加。酒精性肝炎患者的血清FGF 19水平显著升高，并且在胆管上皮细胞和导管细胞中诱导FGF 19基因表达。酒精性肝炎患者的从头胆汁酸合成（CYP 7A 1基因表达和C4血清水平）显著降低。重要的是，总胆汁酸和结合胆汁酸与FGF 19和疾病严重程度（MELD）呈正相关。FGF 19与结合胆酸（CA）的相关性最好，MELD与牛磺酸结合鹅去氧胆酸（T-CDCA）的相关性最好。单因素分析显示，在所有酒精性肝炎患者中，FGF 19与胆红素以及γ-谷氨酰转移酶（GGT）之间存在显著相关性，与纤维化分期以及多形核白细胞（PMN）浸润之间存在负相关性。酒精性肝炎患者血清FGF 19和胆汁酸显著增加，而从头胆汁酸合成受到抑制。调节胆汁酸代谢或信号传导可能是治疗人类酒精性肝炎的一个有前途的靶点。了解驱动酒精性肝炎的潜在机制对于开发新的生物标志物和靶向治疗非常重要。在这里，我们描述了一种在酒精性肝炎患者中增加的分子，调节这种途径可能会导致有希望的酒精性肝炎治疗靶点。
The degree of cholestasis is an important disease driver in alcoholic hepatitis, a severe clinical condition that needs new biomarkers and targeted therapies. The mechanisms and biomarkers linked to cholestasis are largely unknown. Here, we analyzed a well characterized cohort of patients with alcoholic hepatitis and correlated clinical and histological parameters and outcomes with serum bile acids and fibroblast growth factor 19 (FGF19), a major regulator of bile acids synthesis. We found that total and conjugated bile acids were significantly increased in patients with alcoholic hepatitis compared with controls. Serum FGF19 levels were strongly increased and gene expression of FGF19 was induced in biliary epithelial cells and ductular cells of patients with alcoholic hepatitis. De novo bile acid synthesis (CYP7A1 gene expression and C4 serum levels) was significantly decreased in alcoholic hepatitis patients. Importantly, total and conjugated bile acids correlated positively with FGF19 and with disease severity (MELD). FGF19 correlated best with conjugated cholic acid (CA), and MELD best with taurine-conjugated chenodeoxycholic acid (T-CDCA). Univariate analysis demonstrated significant associations between FGF19 and bilirubin as well as gamma-glutamyl-transferase (GGT), and negative correlations between FGF19 and fibrosis stage as well as polymorphonuclear leukocyte (PMN) infiltration in all alcoholic hepatitis patients. Serum FGF19 and bile acids are significantly increased in patients with alcoholic hepatitis, while de novo bile acid synthesis is suppressed. Modulation of bile acid metabolism or signaling could represent a promising target for treatment of alcoholic hepatitis in humans. Understanding underlying mechanisms that drive alcoholic hepatitis is important for the development of new biomarkers and targeted therapies. Here we describe a molecule that is increased in patients with alcoholic hepatitis and modulating this pathway might lead to promising targets for the treatment of alcoholic hepatitis.
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影响因子：
29.4
作者：
Naugler WE;Tarlow BD;Fedorov LM;Taylor M;Pelz C;Li B;Darnell J;Grompe M
通讯作者：
Grompe M
影响因子：
9.8
作者：
Dominguez, Marlene;Rincon, Diego;Bataller, Ramon
通讯作者：
Bataller, Ramon
肠道 FXR 激动剂可促进脂肪组织褐变，减少肥胖和胰岛素抵抗。
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
4.8
作者：
Bohan, A;Chen, WS;Boyer, JL
通讯作者：
Boyer, JL
影响因子：
29.4
作者：
Altamirano J;Miquel R;Katoonizadeh A;Abraldes JG;Duarte-Rojo A;Louvet A;Augustin S;Mookerjee RP;Michelena J;Smyrk TC;Buob D;Leteurtre E;Rincón D;Ruiz P;García-Pagán JC;Guerrero-Marquez C;Jones PD;Barritt AS 4th;Arroyo V;Bruguera M;Bañares R;Ginès P;Caballería J;Roskams T;Nevens F;Jalan R;Mathurin P;Shah VH;Bataller R
通讯作者：
Bataller R