Curcumin inhibits gene expression of receptor for advanced glycation end‐products (RAGE) in hepatic stellate cells in vitro by elevating PPARγ activity and attenuating oxidative stress

• Published in: British journal of pharmacology Vol. 166; no. 8; pp. 2212 - 2227
• Main Authors: Lin, Jianguo, Tang, Youcai, Kang, Qiaohua, Feng, Yunfeng, Chen, Anping
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2012; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Curcumin - pharmacology; diabetes; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gastroenterology. Liver. Pancreas. Abdomen; gene expression; Gene Expression Regulation - drug effects; Gene Knockdown Techniques; Glutathione - metabolism; hepatic fibrosis; hepatic stellate cells; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; hyperglycaemia; Lipid Peroxidation; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Mice; Mice, Inbred C57BL; Nitro Compounds - pharmacology; Other diseases. Semiology; Oxidative Stress; Pharmacology. Drug treatments; phytochemical; PPAR gamma - genetics; PPAR gamma - metabolism; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Receptor for Advanced Glycation End Products; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Research Papers with Commentaries; RNA - genetics; RNA - metabolism; RNA, Small Interfering; Thiazoles - pharmacology; Endocrinopathy; Phytochemical compound; Hepatic fibrosis; Oxidative stress; hepatic stellate cells; Tyrosine kinase inhibitor; Diabetes mellitus; RAGE receptor; Hepatic disease; Gene expression; PPAR-γ receptor; In vitro; Hyperglycemia; Digestive diseases; hyperglycaemia; Ito cell; Curcumin; diabetes; phytochemical
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2012.01910.x

BACKGROUND AND PURPOSE Diabetes is characterized by hyperglycaemia, which facilitates the formation of advanced glycation end‐products (AGEs). Type 2 diabetes mellitus is commonly accompanied by non‐alcoholic steatohepatitis, which could lead to hepatic fibrosis. Receptor for AGEs (RAGE) mediates effects of AGEs and is associated with increased oxidative stress, cell growth and inflammation. The phytochemical curcumin inhibits the activation of hepatic stellate cells (HSCs), the major effectors during hepatic fibrogenesis. The aim of this study was to explore the underlying mechanisms of curcumin in the elimination of the stimulating effects of AGEs on the activation of HSCs. We hypothesize that curcumin eliminates the effects of AGEs by suppressing gene expression of RAGE. EXPERIMENTAL APPROACH Gene promoter activities were evaluated by transient transfection assays. The expression of rage was silenced by short hairpin RNA. Gene expression was analysed by real‐time PCR and Western blots. Oxidative stress was evaluated. KEY RESULTS AGEs induced rage expression in cultured HSCs, which played a critical role in the AGEs‐induced activation of HSCs. Curcumin at 20 µM eliminated the AGE effects, which required the activation of PPARγ. In addition, curcumin attenuated AGEs‐induced oxidative stress in HSCs by elevating the activity of glutamate‐cysteine ligase and by stimulating de novo synthesis of glutathione, leading to the suppression of gene expression of RAGE. CONCLUSION AND IMPLICATIONS Curcumin suppressed gene expression of RAGE by elevating the activity of PPARγ and attenuating oxidative stress, leading to the elimination of the AGE effects on the activation of HSCs. LINKED ARTICLE This article is commented on by Stefanska, pp. 2209–2211 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476‐5381.2012.01959.x