¹Department of Pathology, School of Medicine, Saint Louis University, St Louis, MO, USA

Correspondence: A Chen, PhD, Department of Pathology, School of Medicine, Saint Louis University, 1100 South Grand Boulevard, Room 215, Edward A Doisy Research Center, St Louis, MO 63104, USA. E-mail: achen5@slu.edu

Received 4 June 2009; Revised 30 July 2009; Accepted 10 August 2009; Published online 19 October 2009.

Abstract

Hyperinsulinemia associated with type II diabetes mellitus (T2DM) is a risk factor for non-alcoholic steatohepatitis (NASH) and hepatic fibrosis. Hepatic stellate cells (HSCs) are the major effectors in collagen production during hepatic fibrogenesis. Elevated levels of insulin stimulate HSC activation. In addition to its anti-diabetic effects, the antioxidant curcumin, the yellow pigment in curry from turmeric, suppresses HSC activation and protects the liver from fibrogenesis in vitro and in vivo. This study aims at evaluating the effect of curcumin on insulin-induced HSC activation and further elucidating the underlying mechanisms. We report that curcumin dose-dependently eliminates insulin-induced HSC activation by suppressing expression of type I collagen gene and other key genes relevant to HSC activation. Additional experiments indicate that curcumin interrupts insulin signaling in HSCs by reducing the phosphorylation level of insulin receptor (InsR) and suppressing gene expression of InsR. Furthermore, curcumin attenuates insulin-induced oxidative stress in HSCs by inducing gene expression of glutamate-cysteine ligase (GCL), leading to de novo synthesis of glutathione and the suppression of gene expression of InsR. These results support our initial hypothesis that curcumin inhibits the effects of insulin on stimulating HSC activation by interrupting insulin signaling and attenuating oxidative stress. Our results provide novel insights into the mechanisms by which curcumin inhibits the insulin-induced HSC activation.