Inhibition of elevated hepatic glutathione abolishes copper deficiency cholesterolemia.
Dietary copper deficiency causes hypercholesterolemia and increased hepatic 3-hydroxy-3-methyl-glutaryl coenzyme A (MHG-CoA) reductase activity and increased hepatic glutathione (GSH) in rats. We hypothesized that inhibition of GSH production by L-buthionine sulfoximine (BSO), a specific GSH synthesis inhibitor, would abolish the cholesterolemia and increased HMG-CoA reductase activity of copper deficiency. In two experiments, two groups of 20 weanling male rats were fed diets providing 0.4 and 5.8 micrograms Cu/g, copper-deficient (Cu-D) and copper-adequate (Cu-A), respectively. At 35 days plasma cholesterol was significantly elevated by 30 to 43% in Cu-D and 10 animals in each of the Cu-D and Cu-A groups were randomly assigned to receive 10 mM BSO solution in place of drinking water and continued on the same diets for another 2 wk. At necropsy Cu-D animals had a significant 52 to 58% increase in plasma cholesterol. BSO administration abolished the cholesterolemia in Cu-D rats, but had no influence on plasma cholesterol of Cu-A rats. Hepatic GSH was increased 39 to 82% in Cu-D rats and BSO abolished this increase. BSO was without effect on cardiac hypertrophy, plasma and liver copper, and hematocrit indices of copper status. Liver microsome HMG-CoA reductase activity was significantly increased 85 to 288% in Cu-D rats and BSO administration abolished this increase in activity in Cu-D rats. The results suggest that copper deficiency cholesterolemia and elevated HMG-CoA reductase activity are a consequence of elevated hepatic GSH, and provide evidence for GSH regulation of cholesterol metabolism in intact animals.
Kim
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Department of Food Science and Human Nutrition, Colorado State University, Fort Collins 80523.
Chao
P Y
PY
Allen
K G
KG
D000818:Animals; D019328:Buthionine Sulfoximine; D002784:Cholesterol / Q000378:metabolism; D003300:Copper / Q000172:deficiency*; D005978:Glutathione / Q000378:metabolism*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D003300:Copper; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D005978:Glutathione