Intestinal and hepatic cholesterogenesis in hypercholesterolemic dyslipidemia of experimental diabetes in dogs.
We previously reported that dog diabetes results in hypercholesterolemia and the accumulation of a high-density lipoprotein (HDL) subclass, HDL1. Hypercholesterolemic diabetic rodents exhibit hyperphagia, intestinal hypertrophy, and increased intestinal cholesterol synthesis and absorption; intestinal 3-hydroxy-3-methylglutaryl (HMG) CoA reductase activity is increased, whereas hepatic activity is unchanged or reduced. To determine whether similar mechanisms operate in the hypercholesterolemic diabetic dog, we measured hepatic and intestinal cholesterologenesis. Streptozocin-alloxan-induced diabetic dogs allowed access to food ad libitum were hyperphagic and hypercholesterolemic (10.1 vs. 4.47 mM) but normotriglyceridemic. Plasma HDL1 concentrations were markedly increased. Differences in renal and hepatic function were not statistically significant, except serum alkaline phosphatase, which was elevated 4-fold (P = 0.0003). Urinary mevalonate, an index of whole-body cholesterol synthesis, was increased 6-fold. Intestinal and hepatic weights were both increased, and direct measurements showed crypt and villus thickening. The activity of HMG CoA reductase per gram organ weight was increased 1.7-fold in liver and 2.1-fold in intestine. Calculated whole-organ activity in intestine was nearly twice that in liver. These observations provide strong evidence that intestinal cholesterogenesis is involved in the pathogenesis of hypercholesterolemia in dog diabetes and support the conclusion that increased cholesterol synthesis plays a role in the hypercholesterolemia of diabetes.
Kwong
L K
LK
Veterans Affairs Medical Center, Salt Lake City, UT 84148.
Feingold
K R
KR
Peric-Golia
L
L
Le
T
T
Karkas
J D
JD
Alberts
A W
AW
Wilson
D E
DE
D000818:Animals; D001835:Body Weight; D002784:Cholesterol / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D004285:Dogs; D005260:Female; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D006937:Hypercholesterolemia / Q000209:etiology / Q000503:physiopathology*; D007328:Insulin / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism* / Q000473:pathology; D008074:Lipoproteins / Q000097:blood* / Q000302:isolation & purification; D008099:Liver / Q000378:metabolism*; D008297:Male; D008798:Mevalonic Acid / Q000652:urine; D008954:Models, Biological; D009929:Organ Size
D007328:Insulin; D008074:Lipoproteins; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid