Lipoprotein lipase regulation in the cyclophosphamide-treated rabbit: dependence on nutritional status.

Abstract

Cyclophosphamide injection into the fasted rabbit induces a hypertriglyceridemia (4.6 mM vs. 0.8 mM in controls) and a defect of lipoprotein lipase (LPL), as measured in post-heparin plasma (PHP). In contrast, administration of the drug into fed animals tends to increase PHP-LPL. The effects of cyclophosphamide on LPL activity and synthesis, depending on the nutritional state, were thus studied in two sites: periepididymal adipose tissue and heart. In adipose tissue, fasting decreased LPL activity to 45.2 mIU/g (P < 0.001) compared to 667.9 mIU/g in fed animals. PHP-LPL activity was also decreased by 45% upon starvation. These modulations appeared to be related to plasma insulin levels. The relative rate of synthesis of fat tissue LPL was decreased from 0.32% total protein synthesis in fed animals to 0.10% in fasted rabbits, concordant with a reduction in the expression of LPL specific mRNA. Cyclophosphamide administration to the fed rabbit led to decreases of LPL activity and synthesis in the adipose tissue, similar to those observed upon starvation. However, when injected into fasted animals, the drug did not further depress fat tissue LPL. Fasting did not change heart LPL activity (288.3 mIU/g vs. 239.3 in fed animals) nor its relative rate of synthesis (0.21% of total protein synthesis). However, cyclophosphamide induced opposite effects, depending on the nutritional state: after injection into fed animals, heart LPL activity increased up to 477.2 mIU/g (P < 0.01) with a concomitant increase in the LPL synthesis rate. Conversely, drug administration into fasted rabbits led to a decrease of heart LPL activity to 133.9 mIU/g. Similar qualitative variations were recorded in postheparin plasma. Hence, although insensitive to nutritional modulations, heart LPL responded differently to cyclophosphamide, depending on the nutritional state. In spite of those different modulations of heart and adipose tissue LPL, the enzyme isolated from these two sources displayed similar molecular mass, immunoreactivity, and catalytic properties. The effects of cyclophosphamide injection on very low density lipoprotein (VLDL)-triacylglycerol (TG) synthesis were also investigated, as a possible determinant of hypertriglyceridemia. The drug stimulated TG synthesis in both nutritional states, and maximally by 45% in fed animals. Hence, a defect of heart and postheparin plasma LPL appears as a major determinant of hypertriglyceridemia in cyclophosphamide-treated fasted rabbits.(ABSTRACT TRUNCATED AT 400 WORDS)