HEPATOCELLULAR AND HEPATIC PEROXISOMAL ALTERATIONS IN MICE WITH A DISRUPTED PEROXISOMAL FATTY ACYL-COENZYME-A OXIDASE GENE

Peroxisomal genetic disorders, such as Zellweger syndrome, are charact erized by defects in one or more enzymes involved in the peroxisomal b eta-oxidation of very long chain fatty acids and are associated with d efective peroxisomal biogenesis. The biologic role of peroxisomal beta -oxidation system, which consists of three enzymes: fatty acyl-CoA oxi dase (ACOX), enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (HD), and thiolase, has been examined in mice by disrupting ACOX gene, whic h encodes the first and rate-limiting enzyme of this system, Homozygou s (ACOX -/-) mice lacked the expression of ACOX protein and accumulate very long chain fatty acids in blood. However, these homozygous mice are viable, but growth-retarded and infertile. During the first 3-4 mo nths of age, the livers of ACOX -/- mice reveal severe microvesicular fatty metamorphosis of hepatocytes. In such steatotic cells, peroxisom e assembly is markedly defective; as a result, they contain few or no peroxisomes. Few hepatocytes in 1-3-month-old ACOX -/- mice contain nu merous peroxisomes, and these peroxisome-rich hepatocytes show no fatt y change. At this stage, the basal mRNA levels of HD, thiolase, and ot her peroxisome proliferator-induced target genes were elevated in ACOX -/- mouse liver, but these mice, when treated with a peroxisome proli ferator, showed no increases in the number of hepatic peroxisomes and in the mRNAs levels of these target genes. Between 4 and 5 months of a ge, severe steatosis resulted in scattered cell death, steatohepatitis , formation of lipogranulomas, and focal hepatocellular regeneration. In 6-7-month-old animals, the newly emerging hepatocytes, which progre ssively replaced steatotic cells, revealed spontaneous peroxisome prol iferation. These livers showed marked increases in the mRNA levels of the remaining two genes of the beta-oxidation system, suggesting that ACOX gene disruption leads to increased endogenous ligand-mediated tra nscription levels. These observations demonstrate links among peroxiso mal beta-oxidation, development of severe microvesicular fatty liver, peroxisome assembly, cell death, and cell proliferation in liver.