Journal of Lipid Research, Vol 34, 23-36, Copyright © 1993 by Lipid Research, Inc.
Lipoprotein lipase regulation in the cyclophosphamide-treated rabbit: dependence on nutritional status
A Lespine, C Azema, M Gafvels, J Manent, N Dousset, H Chap and B Perret
INSERM Unite 326, Hopital Purpan, Toulouse, France.
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)
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