Growth hormone reduces plasma cholesterol in LDL receptor-deficient mice.
Growth hormone (GH) has pleiotropic effects on cholesterol and lipoprotein metabolism. Pituitary GH is important for the normal regulation of hepatic LDL receptors (LDLR), for the enzymatic activity of bile acid regulatory cholesterol 7alpha-hydroxylase (C7alphaOH), and for the maintenance of resistance to dietary cholesterol. The present study aimed to determine whether GH has beneficial effects on plasma lipids and hepatic cholesterol metabolism in mice devoid of LDLR. Compared with wild-type controls, LDLR-deficient mice had approximately 250% elevated plasma total cholesterol and approximately 50% increased hepatic cholesterol levels; hepatic HMG CoA reductase activity was reduced by 70%, whereas C7alphaOH activity was increased by 40%. In LDLR mice, GH infusion reduced plasma cholesterol and triglycerides up to 40%, whereas HMG CoA reductase and C7alphaOH activities were stimulated by approximately 50% and 110% respectively. GH also stimulated HMG CoA reductase and C7alphaOH activities in control mice, whereas hepatic LDLR and plasma lipoproteins were unchanged. The effects of cholestyramine and atorvastatin on C7alphaOH in LDLR-deficient mice were potentiated by GH, and this was associated with a further reduction in plasma cholesterol. GH treatment reduces plasma cholesterol and triglycerides and stimulates C7alphaOH activity in mice devoid of LDLR, particularly in combination with resin or statin treatment. The potential of GH therapy in patients with homozygous familial hypercholesterolemia should be evaluated.
Rudling
M
M
Metabolism Unit, Center for Metabolism and Endocrinology, Department of Medicine, Novum, Karolinska Institute at Huddinge University Hospital, S-141 86, Stockholm, Sweden. mats.rudling@cnt.ki.se
Angelin
B
B
D000818:Animals; D000069059:Atorvastatin; D002784:Cholesterol / Q000097:blood*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000032:analysis; D002792:Cholestyramine Resin / Q000494:pharmacology; D013006:Growth Hormone / Q000494:pharmacology*; D006538:Heptanoic Acids / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000032:analysis; D008075:Lipoproteins, HDL / Q000737:chemistry; D008077:Lipoproteins, LDL / Q000737:chemistry; D008079:Lipoproteins, VLDL / Q000737:chemistry; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011758:Pyrroles / Q000494:pharmacology; D011973:Receptors, LDL / Q000172:deficiency*; D014280:Triglycerides
D006538:Heptanoic Acids; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D011758:Pyrroles; D011973:Receptors, LDL; D014280:Triglycerides; D002792:Cholestyramine Resin; D013006:Growth Hormone; D002784:Cholesterol; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase