Peroxisomal fatty acyl-coa oxidase gene disruption causes defective peroxisome assembly in hepatocytes with severe microvesicular steatosis, cell death and hepatocellular proliferation in mouse liver

Peroxisomal genetic disorders such as Zellweger syndrome, are characterized by defects in one or more enzymes involved in the peroxisomal β-oxidation of very long chain fatty acids and are associated with defective peroxisomal biogenesis. The biologic role of peroxisomal β-oxidation system has been examined in mice by disrupting fatty acyl-CoA oxidase (ACOX), the first and rate limiting enzyme of this system. Homozygous (ACOX -/-) mice are viable, but infertile, accumulate very long chain fatty acids in blood, develop severe micro vesicular fatty metamorphosis of hepatocytes, and weigh 40- 50% less than the age-matched wild-type (+/+) controls. Peroxisome assembly is markedly defective in hepatocytes with severe fatty change, resulting in the presence of few or no peroxisomes in such hepatocytes. In these hepatocytes, peroxisomal marker enzyme cataîase is localized in the cytosol and crystalloid cores containing urate oxidase are recognizable in peroxisome membrane ghosts. Few hepatocytes in 1 to 3 month old ACOX -/- mice, contain numerous peroxisomes and these peroxisome-rich hepatocytes show no fatty change. By 5 months of age, severe steatosis results in scattered cell death due to steatohepatitis, formation of lipogranulomas and focal hepatocellular proliferation. The newly emerging hepatocytes also contain abundant peroxisomes, and are resistant to fatty change. Peroxisome defective steatotic hepatocytes fail to display peroxisome proliferative response when treated with peroxisome proliferators. These observations demonstrate links among peroxisomal β-oxidation, development of severe microvesicular fatty liver, peroxisome assembly, cell death and cell proliferation in liver.