The prolyl 4-hydroxylase inhibitor HOE 077 prevents activation of Ito cells, reducing procollagen gene expression in rat liver fibrosis induced by choline-deficient l-amino acid-defined diet

Abstract

No effective therapy has yet developed for liver fibro-Among the different causes of liver cirrhosis, one sis by directory inhibiting the accumulation of extracel-common feature is an increased deposition of extracellular matrix. The effect of a newly synthesized prolyl lular matrix, which consists mainly of collagen, in the 4-hydroxylase (PH) inhibitor, HOE 077 (pyridine-2,4-di-liver, 1 leading to portal hypertension, esophageal varicarboxylic-di(2-methoxyethyl)amide), was examined us-ces, and liver failure. ing the model of choline-deficient L-amino acid (CDAA)A key enzyme in collagen synthesis is prolyl 4-hydefined diet-induced liver fibrosis in 16-week-old male droxylase, 2,3 which catalyzes the hydroxylation of pepWistar rats. HOE 077 at doses up to 200 ppm prevented tide-bound proline residues to 4-hydroxyproline. Hyfibrosis in a dose-dependent manner, as indicated by redrogen bonds, including those of hydroxyl groups, play duced hydroxyproline content in liver as well as inhibia crucial role in stabilizing the triple helix of collagetion of increased serum fibrotic markers (PIIIP, 7S, hyaluronic acid). HOE 077 at 200 ppm reduced expression of nous proteins. Newly synthesized procollagen motype III procollagen a 1 messenger RNA (mRNA) in the leclues that have not undergone hydroxylation are unliver, with a good correlation with serum PIIIP and hy-able to form a stable triple helix, resulting in their droxyproline content of the liver. Histologically, HOE rapid degradation at physiological temperature. Thus, 077 at 200 ppm also reduced proliferation of myofi-prolyl 4-hydroxylase is an excellent target enzyme in broblastlike cells (activated Ito cells). These results indi-efforts to prevent fibrogenesis. cate that a PH inhibitor can prevent fibrosis by inhib-The new prolyl 4-hydroxylase inhibitor, HOE 077 iting not only the hydroxylation of proline but also the (Hoechst Pharmaceutical Co., Frankfurt, Germany), is activation of Ito cells, which are considered the main a proinhibitor that is absorbed well from the gastroin- in hepatocytes to a competitive inhibitor of prolyl 4-hydroxylase. 4,5 In the present study, we induced the development of Liver cirrhosis is very common disease in Japan as liver cirrhosis in male Wistar rats by administering a well as in other countries and results from chronic hepcholine-deficient L-amino acid (CDAA) defined diet 6,7 atitis (type B or type C), ethanol abuse, or other condiinstead of a semipurified choline-deficient diet. 8,9 The tions. Interferon alfa and beta have been studied as replacement of protein with same equivalent of Lpossible therapeutic agents for the eradication of virus amino acids (a CDAA diet) had a more necrogenic effect in patients with chronic viral hepatitis resulting in the caused by a lack of oligopeptides and antioxidant minprevention of liver fibrosis. However, the results of erals resulting in more active fibrosis compared with these studies have been generally unsatisfactory.a semipurified choline-deficient (CD) diet. 7 Using this model, we inve...

miR-122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression

“…Proline hydroxylation plays an important role in stabilizing the triple helix of the collagen molecule. Inhibition of prolyl 4-hydroxylase produces unstable collagen associated with decreased collagen production [26]. Several inhibitors of prolyl 4-hydroxylase have been developed and examined as new therapeutics for the treatment of liver fibrosis [27,28].…”

Selective inhibition of activated stellate cells and protection from carbon tetrachloride-induced liver injury in rats by a new PPARγ agonist KR62776

“…These chemicals include HOE-077 (Sakaida et al, 1996), halofuginone (Pines et al, 1997; Bruck et al, 2001) and pirfenidone (Tada et al, 2001; Garcia et al, 2002), and appear to act by inhibiting collagen α1(I) biosynthesis. PPARγ, a nuclear receptor with transcriptional activity, has been shown to play an important role in the cellular physiology and metabolism for modulating the glucose and lipid metabolism/homeostasis (Berger and Moller, 2002; Rangwala and Lazar, 2004).…”

Endogenous hydrogen sulfide is associated with angiotensin II type 1 receptor in a rat model of carbon tetrachloride-induced hepatic fibrosis

“…HSCs have a crucial role in the onset of hepatic fibrosis. HSCs express AGTR1 ( 15 ), and are activated by the binding of angiotensin II to AGTR1, which in turn leads to the secretion of extracellular matrix components resulting in the development of hepatic fibrosis ( 24 ). Activated HSCs also express numerous cytokines, which accelerate hepatic inflammation ( 24 ).…”