EXTRAHEPATIC LIPOGENESIS CONTRIBUTES TO HYPERLIPIDEMIA IN THE ANALBUMINEMIC RAT

Hepatic lipid and apolipoprotein synthesis is increased in the nephrot ic syndrome. Catabolism of triglyceride-rich lipoproteins is impaired in nephrotic syndrome but not in rats with hereditary analbuminemia (N A), suggesting that lipid synthesis should be increased by analbuminem ia in the absence of proteinuria. In this study the rate of cholestero l and fatty acid synthesis in liver and extrahepatic tissue was measur ed in female NA and control Sprague-Dawley (SD) rats to determine whet her lipid synthesis was indeed increased in isolated analbuminemia and to identify the site(s) of increased lipogenesis. We also measured th e concentrations of apolipoproteins (apo) AI, B, and E in plasma, as w ell as the levels of the respective mRNAs in liver. Plasma cholesterol , triglycerides, and apo AI, B, and E were all increased severalfold i n the NA rat (P < 0.001). Although liver apolipoprotein mRNA content w as significantly increased (P < 0.001) for apo AI (643%), B (273%), an d E (299%), 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity i n liver microsomes and hepatic cholesterol synthesis were not signific antly increased in the NA rats. Hepatic fatty acid synthesis and intes tinal cholesterol synthesis were not increased in the NA rats. Surpris ingly, intestinal fatty acid synthesis was elevated by 60% (P < 0.01). The NA rats demonstrated approximately fourfold increases in the inco rporation of (H2O)-H-3 into circulating cholesterol and fatty acids (P < 0.001). A 56% increase in the synthesis of total nonsaponifiable li pid was found in the extravisceral carcass (P < 0.01). Thus, although apolipoprotein mRNAs encoding the principal apolipoprotein are increas ed in the liver of the NA rat, suggesting that the liver is an importa nt site of increased apolipoprotein synthesis, the liver is not the si te of increased lipogenesis. Major increases in cholesterol and fatty acid synthesis occur at extrahepatic sites in analbuminemia.