D-chiro-inositol effectively attenuates cholestasis in bile duct ligated rats by improving bile acid secretion and attenuating oxidative stress

• Published in: Acta pharmacologica Sinica Vol. 39; no. 2; pp. 213 - 221
• Main Authors: Zhao, Shuang-shuang, Li, Na-ren, Zhao, Wu-li, Liu, Hong, Ge, Mao-xu, Zhang, Yi-xuan, Zhao, Long-yin, You, Xue-fu, He, Hong-wei, Shao, Rong-guang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2018; Nature Publishing Group
• Subjects: Acids; Alanine; Alanine transaminase; Alanine Transaminase - blood; Animal tissues; Animals; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - metabolism; Aspartate aminotransferase; Aspartate Aminotransferases - blood; ATP Binding Cassette Transporter, Subfamily B, Member 11 - genetics; ATP Binding Cassette Transporter, Subfamily B, Member 11 - metabolism; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Bile; Bile Acids and Salts - metabolism; Bile ducts; Bile Ducts - surgery; Biomedical and Life Sciences; Biomedicine; Cholestasis; Cholestasis - prevention & control; Cirrhosis; Diabetes mellitus; Disease Models, Animal; Drinking water; Fibrosis; Gene Expression - drug effects; Genomes; Immunology; Immunosuppressive agents; Inositol; Inositol - administration & dosage; Inositol - therapeutic use; Internal Medicine; Ligation; Liver; Liver - pathology; Liver cirrhosis; Liver Cirrhosis - prevention & control; Liver diseases; Liver transplantation; Male; Medical Microbiology; NF-kappa B - metabolism; NF-κB protein; Oligonucleotides; Oral administration; Original; original-article; Oxidation; Oxidative stress; Oxidative Stress - drug effects; Pharmacology/Toxicology; Polycystic ovary syndrome; Protective Agents - administration & dosage; Protective Agents - therapeutic use; Rats; Rats, Sprague-Dawley; Rodents; Secretion; Serum levels; Stereoisomerism; Superoxide dismutase; Superoxide Dismutase - metabolism; Surgery; Transplantation; Vaccine; Viscera; 氧化应力;胆汁酸;分泌物;老鼠;稀释;绑扎;肝移植;DCl; bile duct ligation; liver fibrosis; d; inflammation; inositol; cholestatic liver diseases; bile acid transporters; oxidative stress
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2017.98

Cholestatic liver diseases are important causes of liver cirrhosis and liver transplantation, but few drugs are available for treatment. D-chiro-inositol （DCI）, an isomer of inositol found in many Leguminosae plants and in animal viscera, is used clinically for the treatment of polycystic ovary syndrome （PCOS） and diabetes mellitus. In this study, we investigated whether DCI exerted an anti-cholestatic effect and its underlying mechanisms. A cholestatic rat model was established via bile duct ligation （BDL）. After the surgery, the rats were given DCl （150 mg·kg^-1·d^-1） in drinking water for 2 weeks. Oral administration of DCI significantly decreased the serum levels of alanine aminotransferase （ALT） and aspartate aminotransferase （AST）, and attenuated bile duct proliferation, parenchymal necrosis and fibrosis in BDL rats. Furthermore, DCI treatment significantly increased the serum and bile levels of total bite acid （TBA）, and decreased TBA levels in the liver. Moreover, DCl treatment significantly increased expression of the genes encoding bile acid transporters BSEP （Abcb11） and MRP2 （Abcc2） in liver tissues. DCI treatment also markedly decreased hepatic CD68 and NF-kappaB （NF-KB） levels, significantly decreased the serum and hepatic MDA levels, markedly increased superoxide dismutase activity in both serum and liver tissues. Using whole-genome oligonucleotide microarray, we revealed that DCl treatment altered the expression profiles of oxidation reduction-related genes in liver tissues. Collectively, DCl effectively attenuates BDL-induced hepatic bile acid accumulation and decreases the severity of injury and fibrosis by improving bile acid secretion, repressing inflammation and decreasing oxidative stress. The results suggest that DCl might be beneficial for patients with cholestatic disorders.