Administration of the potent PPARalpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice.
Administration of a methionine and choline deficient (MCD) diet to rodents causes progressive fibrosing steatohepatitis pathologically similar to human metabolic steatohepatitis. We have previously shown that the peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist, Wy-14,643, prevented the development of MCD diet-induced steatohepatitis. We have now tested whether Wy-14,643 ameliorates established steatohepatitis and fibrosis. Male C57BL6 mice were fed the MCD diet for 51 days to induce severe steatohepatitis. They were then treated with Wy-14,643 together with the MCD diet for 5 or 12 days; positive controls continued on the MCD diet for 5 or 12 days. After 5 days of Wy-14,643 treatment, alanine aminotransferase (ALT) levels were significantly decreased, steatohepatitis less severe, and hepatic lipoperoxides significantly reduced. After 12 days, hepatic triglycerides were normalized and there was near resolution of histological changes. MCD dietary feeding was associated with increased expression of vascular cell adhesion molecule (VCAM)-1, and increased numbers of activated macrophages in the liver. Treatment with Wy-14,643 reduced VCAM-1 expression and macrophage numbers. MCD diet-fed mice developed hepatic fibrosis with increased hepatic collagen alpha1(I), tissue inhibitor of metalloproteinases (TIMP)-1, TIMP-2, and matrix metalloproteinase (MMP)-13 mRNA levels. After treatment with Wy-14,643, expression of these genes was reduced in a manner that paralleled the reduction in activated hepatic stellate cells and near resolution of liver fibrosis. In conclusion, the present study shows that MCD diet-induced fibrosing steatohepatitis can be reversed by treatment with Wy-14,643. It is likely that activation of PPARalpha reverses fibrosis indirectly by reducing stimuli, such as lipid peroxides, and activation of cells responsible for promoting hepatic fibrosis.
Ip
Emilia
E
Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, NSW, Australia.
Farrell
Geoff
G
Hall
Pauline
P
Robertson
Graham
G
Leclercq
Isabelle
I
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D004041:Dietary Fats / Q000494:pharmacology; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014280:Triglycerides / Q000378:metabolism
C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D015815:Cell Adhesion Molecules; D004041:Dietary Fats; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008054:Lipid Peroxides; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014280:Triglycerides; D055513:Connective Tissue Growth Factor; C006253:pirinixic acid