Peroxisome proliferator chemicals are classic @entity3257 . These agents cause @entity96 when chronically administered to @entity35 and @entity19 . Peroxisome proliferators include the widely prescribed lipid and @entity165 lowering fibrate drugs. In contrast to the results in rodents, there is no evidence that fibrates are associated with elevated risk of @entity96 or any other @entity5 in @entity1 thus indicating a species difference in the hepatocarcinogenic response. The biological effects of peroxisome proliferators are mediated by the peroxisome proliferator-activated receptor (PPAR)alpha. @entity3229 -null @entity19 are resistant to all of the pleiotropic effects of peroxisome proliferators, including cell proliferation and hepatocarcinogenesis. The mechanism of hepatocellular proliferation involves downregulation of the microRNA let-7c gene by @entity3229 . Let-7c controls levels of proliferative c-myc by destabilizing its mRNA. Thus, upon suppression of let-7c, c-myc mRNA and protein are elevated resulting in enhanced hepatocellular proliferation. In contrast, @entity3229 -humanized @entity19 , that respond to @entity21372 by lower serum @entity1674 and induction of genes encoding @entity844 metabolizing enzymes, are resistant to peroxisome proliferator-induced cell proliferation and @entity5 . These @entity19 do not exhibit downregulation of let-7c gene expression thus forming the basis for the resistance to hepatocellular @entity105 .

XXXX : mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators.

@entity1 :: ('9606', 'Species') :: ['humans'] @entity844 :: ('CHEBI:35366', 'Chemical') :: ['fatty acid'] @entity3229 :: ('19013(Tax:10090)', 'Gene') :: ['PPARalpha', 'Pparalpha'] @entity96 :: ('MESH:D008113', 'Disease') :: ['liver cancers', 'liver cancer'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity5 :: ('MESH:D009369', 'Disease') :: ['cancer', 'neoplasms'] @entity1674 :: ('MESH:D014280', 'Chemical') :: ['triglycerides'] @entity105 :: ('MESH:D063646', 'Disease') :: ['carcinogenesis'] @entity35 :: ('10116', 'Species') :: ['rats'] @entity3257 :: ('MESH:C580335', 'Disease') :: ['non-genotoxic carcinogens'] @entity165 :: ('MESH:D002784', 'Chemical') :: ['cholesterol'] @entity21372 :: ('MESH:C006253', 'Chemical') :: ['Wy-14,643']
@entity3229 :: (19013(Tax:10090),Gene) :: ['PPARalpha']
