Side Chain Structure Determines Unique Physiologic and Therapeutic Properties of norUrsodeoxycholic Acid in Mdr2-/- Mice

被引：122

作者：

Halilbasic, Emina ^{[1
]}

Fiorotto, Romina ^{[2
]}

Fickert, Peter ^{[1
]}

Marschall, Hanns-Ulrich ^{[3
]}

Moustafa, Tarek ^{[1
]}

Spirli, Carlo ^{[2
]}

Fuchsbichler, Andrea ^{[4
]}

Gumhold, Judith ^{[1
]}

Silbert, Dagmar ^{[1
]}

Zatloukal, Kurt ^{[4
]}

Langner, Cord ^{[4
]}

Maitra, Uday ^{[5
]}

Denk, Helmut ^{[4
]}

Hofmann, Alan F. ^{[6
]}

Strazabosco, Mario ^{[2
,7
,8
]}

Trauner, Michael ^{[1
]}

机构：

[1] Med Univ Graz, Lab Expt & Mol Hepatol, Dept Gastroenterol & Hepatol, Univ Clin Internal Med, A-8036 Graz, Austria

[2] Yale Univ, Sch Med, Dept Internal Med, Sect Digest Dis, New Haven, CT 06510 USA

[3] Karolinska Univ, Huddinge Hosp, Stockholm, Sweden

[4] Med Univ Graz, Inst Pathol, A-8036 Graz, Austria

[5] Indian Inst Sci, Dept Organ Chem, Bangalore 560012, Karnataka, India

[6] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA

[7] Osped Riuniti Bergamo, I-24100 Bergamo, Italy

[8] Univ Milano Bicocca, Dept Clin Med & Prevent, Milan, Italy

来源：

HEPATOLOGY | 2009年 / 49卷 / 06期

基金：

美国国家卫生研究院; 瑞典研究理事会;

关键词：

BILE-ACIDS; SCLEROSING CHOLANGITIS; URSODEOXYCHOLIC ACID; KNOCKOUT MICE; TRANSPORTER EXPRESSION; HEPATIC TRANSPORT; LIVER-DISEASE; SECRETION; FIBROSIS; CHOLESTASIS;

D O I：

10.1002/hep.22891

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

24-norursodeoxycholic acid (norUDCA), a side chain-modified ursodeoxycholic acid derivative, has dramatic therapeutic effects in experimental cholestasis and may be a promising agent for the treatment of cholestatic liver diseases. We aimed to better understand the physiologic and therapeutic properties of norUDCA and to test if they are related to its side chain length and/or relative resistance to amidation. For this purpose, Mdr2(-/-) mice, a model for sclerosing cholangitis, received either a standard diet or a norUDCA-, tauronorursodeoxycholic acid (tauronor-UDCA)-, or dinorursodeoxycholic acid (dinorUDCA) -enriched diet. Bile composition, serum biochemistry, liver histology, fibrosis, and expression of key detoxification and transport systems were investigated. Direct choleretic effects were addressed in isolated bile duct units. The role of Cftr for norUDCA-induced choleresis was explored in Cftr(-/-) mice. norUDCA had pharmacologic features that were not shared by its derivatives, including the increase in hepatic and serum bile acid levels and a strong stimulation of biliary HCO3--output. norUDCA directly stimulated fluid secretion in isolated bile duct units in a HCO3--dependent fashion to a higher extent than the other bile acids. Notably, the norUDCA significantly stimulated HCO3--output also in Cftr(-/-) mice. In Mdr2(-/-) mice, cholangitis and fibrosis strongly improved with norUDCA, remained unchanged with tauro-norUDCA, and worsened with dinorUDCA. Expression of Mrp4, Cyp2b10, and Sult2a1 was increased by norUDCA and dinorUDCA, but was unaffected by tauro-norUDCA Conclusion: The relative resistance of norUDCA to amidation may explain its unique physiologic and pharmacologic properties. These include the ability to undergo cholehepatic shunting and to directly stimulate cholangiocyte secretion, both resulting in a HCO3--rich hypercholeresis that protects the liver from cholestatic injury. (HEPATOLOGY 2009;49:1972-1981.)

引用

页码：1972 / 1981

页数：10

共 29 条

[1]

Secretin activation of the apical Na+-dependent bile acid transporter is associated with cholehepatic shunting in rats [J].