The genetic background modifies the effects of the obesity mutation, 'fatty', on apolipoprotein gene regulation in rat liver

BACKGROUND: Obesity is associated with disorders of plasma lipid transport in many, but not in all obese subjects. The effects of obesity on the regul ation of genes involved in plasma lipid transport may depend an specific mu tations causing or contributing to obesity and/or on interactions of a spec ific obesity mutation with the genetic background. The 'fatty' (Glu269Pro) leptin receptor mutation causes severe obesity associated with hypertriglyc eridaemia and altered hepatic apolipoprotein gene regulation in Zucker fatt y rats. OBJECTIVE: To determine whether the effects of the obesity mutation 'fatty' on apolipoprotein gene regulation in rat liver depend on the genetic backg round. METHODS: We studied hepatic apolipoprotein (apo) A-IV, A-I, and C-lll gene expression in obese rats carrying the 'fatty' mutation on the background of the Zucker or Wistar strain. RESULTS: Basal apoA-IV gene expression was increased in fatty rats of both strains, whereas apoA-I and apoC-III gene expression differed between Wista r and Zucker fatty rats: apoA-I gene transcription was reduced to half and apoC-III mRNA was increased two-fold in Wistar fatty, but: not in Zucker fa tty rats vs lean controls. A fish oil diet suppressed apoA-IV, but not apoA -I gene transcription in Wistar fatty rats, whereas in Zucker fatty rats ap oA-IV transcription was unaffected, but apoA-I transcription was suppressed . CONCLUSIONS: Interactions of the 'fatty' leptin receptor mutation with the genetic background significantly affect the basal and diet-induced regulati on of the apoA-IV, C-III and A-I genes in rat liver. The genetic background may therefore be a major determinant of the consequences of a specific obe sity mutation for plasma lipid transport.