Oltipraz regenerates cirrhotic liver through CCAAT/enhancer binding protein‐mediated stellate cell inactivation

Abstract

Liver cirrhosis (LC) is a chronic disease with high mortality rate. In the United States and Western world as well as Asian countries, LC is the major leading cause of death by disease. Yet, no effective therapeutic agent is available for LC treatment. Laboratory cirrhotic rats produced by dimethylnitrosamine administrations simulate the clinical features of human LC such as mortality, ascites, hepatic parenchymal cell destruction, and formation of connective tissue and nodular regeneration, providing a preclinical model to evaluate therapeutic efficacy of drugs and the underlying mechanisms. Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione] has been used clinically and is of little toxicity. Comprehensive mechanistic and phase IIa clinical studies supported the notion that oltipraz exerts chemopreventive effects against chemical carcinogenesis. We report here that oltipraz within the clinical dose range regenerates cirrhotic liver in the established LC rats as a result of reduction of the intensities of cirrhotic nodules, elimination of accumulated extracellular matrix, and inactivation of stellate cells, thereby improving survival rate. We also reveal that activation of CCAAT/enhancer binding protein by oltipraz inhibits transforming growth factor b1 gene expression in stellate cells, which provides a molecular target for pharmacological treatment of LC. Oltipraz is the first therapeutic agent that regenerates cirrhotic liver.

Nrf2 pathway activation contributes to anti-fibrosis effects of ginsenoside Rg1 in a rat model of alcohol- and CCl4-induced hepatic fibrosis

“…Increased expression of α-SMA, a marker of transdifferentiation, is one of the major phenotypic changes that activated HSCs display [53][54][55] . In the present study, compared to the CCl 4 group, Rg1 decreased the number of α-SMA positive cells in the liver.…”

Transactivation of the PPAR-Responsive Enhancer Module in Chemopreventive Glutathione S -Transferase Gene by the Peroxisome Proliferator-Activated Receptor-γ and Retinoid X Receptor Heterodimer

“…3T3-L1 preadipocytes were differentiated to adipocytes by incubating in the medium containing 10% FCS, 1 M dexamethasone, 1 g/ml insulin, and 0.5 mM 3-isobutyl-1-methylxanthine, as described previously (35). Hepatic stellate cells and primary hepatocytes were isolated from male Sprague Dawley rats according to the method published previously with slight modifications (36).…”

Identification of a novel class of dithiolethiones that prevent hepatic insulin resistance via the adenosine monophosphate–activated protein kinase–p70 ribosomal S6 kinase-1 pathway

“…The finding that oltipraz inhibits TGF-␤1 and has the ability to regenerate cirrhotic liver 8 provided the basis for its phase IIa trial for cirrhosis therapy. Its pharmacological effect is explained in part by PI3K-dependent gene regulation.…”