Plasma apolipoprotein E, high density lipoprotein1 (HDL1) and urinary mevalonate excretion in pancreatectomized diabetic dogs: effects of insulin and lovastatin.
Hypercholesterolemia and increased concentrations of an apolipoprotein E (apoE)-containing HDL subclass, high density lipoprotein1 (HDL1) have been observed in streptozocin-alloxan diabetic dogs consuming normal amounts of dietary cholesterol. The aim of this study was to characterize the response of HDL1 and its targeting ligand, apoE, to insulin and HMG-CoA reductase inhibitor treatment in pancreatectomized diabetic dogs. Following induction of diabetes, plasma total cholesterol, HDL1, and apoE concentrations were all increased. Urinary mevalonate excretion, an index of cholesterol synthesis in humans, was 6-fold that of nondiabetic controls. Lipoprotein fractionation by Pevikon block electrophoresis and gel filtration chromatography showed that the increased cholesterol and apoE were associated with alpha 2-migrating particles corresponding to HDL1. Insulin treatment, resulting in near normal fasting blood glucose concentrations in the group as a whole (average 5.1 mM, 92 mg/dl), led to variable reductions in apoE, total plasma cholesterol, and HDL1. Uncorrected dyslipidemia during intensified insulin treatment appeared to be related to failure to achieve euglycemia. Despite unremitting hyperglycemia, treatment with lovastatin resulted in pronounced decreases in plasma cholesterol, HDL1 and apoE to concentrations below those observed in nondiabetic animals. Mevalonate excretion also fell, but remained twice normal. Thus neither modality corrected all of the abnormalities in canine diabetic dyslipidemia. Since apoE-containing HDL1 may mediate cholesterol traffic between the periphery and the liver (reverse cholesterol transport), the present observations suggest that increased cholesterol synthesis is accompanied by parallel abnormalities in cholesterol flux through the reverse transport pathway in the canine model.
Gleeson
J M
JM
Veterans Affairs Medical Center, Salt Lake City, UT 84148.
Hejazi
J S
JS
Kwong
L
L
Chan
I F
IF
Le
T
T
Alberts
A W
AW
Wilson
D E
DE
D000818:Animals; D001055:Apolipoproteins B / Q000097:blood*; D001786:Blood Glucose / Q000032:analysis; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000652:urine; D004285:Dogs; D007328:Insulin / Q000494:pharmacology*; D008075:Lipoproteins, HDL / Q000097:blood*; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D008798:Mevalonic Acid / Q000652:urine*; D010180:Pancreatectomy
D001055:Apolipoproteins B; D001786:Blood Glucose; D007328:Insulin; D008075:Lipoproteins, HDL; C035392:high density lipoprotein-1; D002784:Cholesterol; D008148:Lovastatin; D008798:Mevalonic Acid