Administration of the potent PPARalpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice.

摘要: Administration of a methionine and choline deficient (MCD) diet to rodents causes progressive fibrosing steatohepatitis pathologically similar human metabolic steatohepatitis. We have previously shown that the peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist, Wy-14,643, prevented development MCD diet-induced now tested whether Wy-14,643 ameliorates established fibrosis. Male C57BL6 mice were fed for 51 days induce severe They then treated with together 5 or 12 days; positive controls continued on days. After treatment, alanine aminotransferase (ALT) levels significantly decreased, less severe, hepatic lipoperoxides reduced. days, triglycerides normalized there was near resolution histological changes. dietary feeding associated increased expression vascular cell adhesion molecule (VCAM)-1, numbers activated macrophages in liver. Treatment reduced VCAM-1 macrophage numbers. diet-fed developed fibrosis collagen alpha1(I), tissue inhibitor metalloproteinases (TIMP)-1, TIMP-2, matrix metalloproteinase (MMP)-13 mRNA levels. treatment these genes manner paralleled reduction stellate cells liver In conclusion, present study shows can be reversed by Wy-14,643. It is likely activation PPARalpha reverses indirectly reducing stimuli, such as lipid peroxides, responsible promoting