Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

被引：72

作者：

Zhang, Da-Gang ^{[1
]}

Zhang, Cheng ^{[2
]}

Wang, Jun-Xian ^{[1
]}

Wang, Bi-Wei ^{[2
]}

Wang, Hua ^{[2
]}

Zhang, Zhi-Hui ^{[2
]}

Chen, Yuan-Hua ^{[2
]}

Lu, Yan ^{[3
]}

Tao, Li ^{[3
]}

Wang, Jian-Qing ^{[3
]}

Chen, Xi ^{[1
]}

Xu, De-Xiang ^{[2
]}

机构：

[1] Anhui Med Univ, Affiliated Hosp 1, Hefei 230022, Peoples R China

[2] Anhui Med Univ, Dept Toxicol, Hefei 230032, Peoples R China

[3] Anhui Med Univ, Affiliated Hosp 2, Hefei 230601, Peoples R China

来源：

TOXICOLOGY AND APPLIED PHARMACOLOGY | 2017年 / 314卷

基金：

高等学校博士学科点专项科研基金; 中国国家自然科学基金;

关键词：

Obeticholic acid; Farnesoid X receptor (FXR); Carbon tetrachloride (CCl4); Acute liver injury; Inflammation; FARNESOID-X-RECEPTOR; NECROSIS-FACTOR-ALPHA; HEPATOCYTE APOPTOSIS; NONALCOHOLIC STEATOHEPATITIS; HEPATIC INFLAMMATION; STELLATE CELLS; AGONIST; MECHANISMS; FIBROSIS; FAILURE;

D O I：

10.1016/j.taap.2016.11.006

中图分类号：

R9 [药学];

学科分类号：

100702 [药剂学];

摘要：

The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl4)-induced acute liver injury. Mice were intraperitoneally injected with CCl4 (0.15 ml/kg). In CCl4 + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl4. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl4-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl4-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl4-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl4-induced hepatic pro-inflammatory gene Tnf-alpha and Il-1 beta. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic I kappa B phosphorylation and blocked nuclear translocation of NF-kappa B p65 and p50 subunits during CCl4-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl4-induced acute liver injury. These results suggest that OCA protects against CCl4-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. (C) 2016 Elsevier Inc All rights reserved.

引用

页码：39 / 47

页数：9

共 59 条

[1]

CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis [J].

Abdelmegeed, Mohamed A. ;

Banerjee, Atrayee ;

Jang, Sehwan ;

Yoo, Seong-Ho ;

Yun, Jun-Won ;

Gonzalez, Frank J. ;

Keshavarzian, Ali ;

Song, Byoung-Joon .

FREE RADICAL BIOLOGY AND MEDICINE, 2013, 65 :1238-1245

[2]

The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis [J].

Barreyro, Fernando J. ;

Holod, Silvia ;

Finocchietto, Paola V. ;

Camino, Alejandra M. ;

Aquino, Jorge B. ;

Avagnina, Alejandra ;

Carreras, Maria C. ;

Poderoso, Juan J. ;

Gores, Gregory J. .

LIVER INTERNATIONAL, 2015, 35 (03) :953-966

[3]

The glucocorticoid mometasone furoate is a novel FXR ligand that decreases inflammatory but not metabolic gene expression [J].

Bijsmans, Ingrid T. G. W. ;

Guercini, Chiara ;

Pittol, Jose M. Ramos ;

Omta, Wienand ;

Milona, Alexandra ;

Lelieveld, Daphne ;

Egan, David A. ;

Pellicciari, Roberto ;

Gioiello, Antimo ;

van Mil, Saskia W. C. .

SCIENTIFIC REPORTS, 2015, 5

[4]

Vitamin D3 inhibits lipopolysaccharide-induced placental inflammation through reinforcing interaction between vitamin D receptor and nuclear factor kappa B p65 subunit [J].

Chen, Yuan-Hua ;

Yu, Zhen ;

Fu, Lin ;

Wang, Hua ;

Chen, Xue ;

Zhang, Cheng ;

Lv, Zheng-Mei ;

Xu, De-Xiang .

SCIENTIFIC REPORTS, 2015, 5

[5]

C-C Motif Chemokine Receptor 9 Positive Macrophages Activate Hepatic Stellate Cells and Promote Liver Fibrosis in Mice [J].

Chu, Po-sung ;

Nakamoto, Nobuhiro ;

Ebinuma, Hirotoshi ;

Usui, Shingo ;

Saeki, Keita ;

Matsumoto, Atsuhiro ;

Mikami, Yohei ;

Sugiyama, Kazuo ;

Tomita, Kengo ;

Kanai, Takanori ;

Saito, Hidetsugu ;

Hibi, Toshifumi .

HEPATOLOGY, 2013, 58 (01) :337-350

[6]

FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats [J].

Cipriani, Sabrina ;

Mencarelli, Andrea ;

Palladino, Giuseppe ;

Fiorucci, Stefano .

JOURNAL OF LIPID RESEARCH, 2010, 51 (04) :771-784

[7]

Acute Hepatitis E Infection Accounts for Some Cases of Suspected Drug-Induced Liver Injury [J].

Davern, Timothy J. ;

Chalasani, Naga ;

Fontana, Robert J. ;

Hayashi, Paul H. ;

Protiva, Petr ;

Kleiner, David E. ;

Engle, Ronald E. ;

Hanh Nguyen ;

Emerson, Suzanne U. ;

Purcell, Robert H. ;

Tillmann, Hans L. ;

Gu, Jiezhun ;

Serrano, Jose ;

Hoofnagle, Jay H. .

GASTROENTEROLOGY, 2011, 141 (05) :1665-U215

[8]

Ferlini A, 2012, METHODS MOL BIOL, V867, P189, DOI 10.1007/978-1-61779-767-5_12

[9]

Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis [J].

Fiorucci, S ;

Clerici, C ;

Antonelli, E ;

Orlandi, S ;

Goodwin, B ;

Sadeghpour, BM ;

Sabatino, G ;

Russo, G ;

Castellani, D ;

Willson, TM ;

Pruzanski, M ;

Pellicciari, R ;

Morelli, A .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 313 (02) :604-612

[10]

Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease [J].

Gadaleta, Raffaella M. ;

van Erpecum, Karel J. ;

Oldenburg, Bas ;

Willemsen, Ellen C. L. ;

Renooij, Willem ;

Murzilli, Stefania ;

Klomp, Leo W. J. ;

Siersema, Peter D. ;

Schipper, Marguerite E. I. ;

Danese, Silvio ;

Penna, Giuseppe ;

Laverny, Gilles ;

Adorini, Luciano ;

Moschetta, Antonio ;

van Mil, Saskia W. C. .

GUT, 2011, 60 (04) :463-472

← 1 2 3 4 5 6 →