Decreased Lipoprotein Clearance Is Responsible for Increased Cholesterol in LDL Receptor Knockout Mice With Streptozotocin-Induced Diabetes

Abstract

OBJECTIVE-Patients with diabetes often have dyslipidemia and increased postprandial lipidmia. Induction of diabetes in LDL receptor (Ldlr Ϫ/Ϫ ) knockout mice also leads to marked dyslipidemia. The reasons for this are unclear. RESEARCH DESIGN AND METHODS-We placed LdlrϪ/Ϫ and heterozygous LDL receptor knockout (Ldlr ϩ/Ϫ ) mice on a high-cholesterol (0.15%) diet, induced diabetes with streptozotocin (STZ), and assessed reasons for differences in plasma cholesterol. RESULTS-STZ-induced diabetic LdlrϪ/Ϫ mice had plasma cholesterol levels more than double those of nondiabetic controls. Fast-performance liquid chromatography and ultracentrifugation showed an increase in both VLDL and LDL. Plasma VLDL became more cholesterol enriched, and both VLDL and LDL had a greater content of apolipoprotein (apo)E. In LDL the ratio of apoB48 to apoB100 was increased. ApoB production, assessed using [ 35 S]methionine labeling in Triton WR1339 -treated mice, was not increased in fasting STZ-induced diabetic mice. Similarly, postprandial lipoprotein production was not increased. Reduction of cholesterol in the diet to normalize the amount of cholesterol intake by the control and STZ-induced diabetic animals reduced plasma cholesterol levels in STZ-induced diabetic mice, but plasma cholesterol was still markedly elevated compared with nondiabetic controls. LDL from STZ-induced diabetic mice was cleared from the plasma and trapped more rapidly by livers of control mice. STZ treatment reduced liver expression of the proteoglycan sulfation enzyme, heparan sulfate N-deacetylase/Nsulfotrasferase-1, an effect that was reproduced in cultured hepatocytyes by a high glucose-containing medium.CONCLUSIONS-STZ-induced diabetic, cholesterol-fed mice developed hyperlipidemia due to a non-LDL receptor defect in clearance of circulating apoB-containing lipoproteins. Diabetes

Hepatic FoxO1 Ablation Exacerbates Lipid Abnormalities during Hyperglycemia

“…To this end, we used tail-vein injection of Triton WR 1339 to block lipoprotein clearance from the circulation, and measured accumulation of serum TG and apolipoprotein B (apoB), the apoprotein required for hepatic VLDL assembly. Using similar methods, several previous studies have found that STZ treatment alone causes minimal changes in TG and apoB production (21)(22)(23). We found that hyperglycemic L-FoxO1 mice secreted significantly more TG than hyperglycemic control animals (Fig.…”

Insulin-dependent Diabetes Mellitus in Mice Does Not Alter Liver Heparan Sulfate

“…Subsequent studies suggested that reduced sulfation correlated with diminished GlcNAc Ndeacetylase activity (7,8,10,11,13,14). Although we have not measured Ndst1 expression or enzyme activity, the compositional studies demonstrate clearly that no change in sulfation occurred.…”

“…One of mutants lacked the enzyme N-acetylglucosamine N-deacetylase/N-sulfotransferase 1 (Ndst1), a biosynthetic enzyme that regulates the overall level of sulfation of heparan sulfate glycosaminoglycans. In vivo studies have suggested that IDDM causes reduced expression of Ndst1 (6,10,11,13,14,18), leading to the hypothesis that hypertriglyceridemia was caused by undersulfated heparan sulfate in the liver.In this work, we show that mice with IDDM exhibit reduced [ 35 S]sulfate incorporation into hepatic heparan sulfate. However, the reduction was caused by changes in plasma sulfate concentration after the onset of diabetes rather than any change in heparan sulfate biosynthesis.…”

Diabetes with poor glycaemic control does not promote atherosclerosis in genetically modified hypercholesterolaemic minipigs

“…Thus, the regulatory link between insulin and LDL receptor levels may be effectively disrupted, which may explain the lack of diabetes-induced hypercholesterolaemia in D374Y-PCSK9 + minipigs. A reduced binding of apoB48-containing remnants to hepatic proteoglycans has been suggested to cause cholesterol accumulation in diabetic LDL-receptor-deficient mice [39], but this mechanism is probably of less relevance in pigs (or humans), where the bulk of the cholesterol is carried in apoB100-containing LDL/VLDL particles. Furthermore, diabetic hyperphagia [39,40], with an increased dietary cholesterol intake in animals fed ad libitum, has been shown to contribute to diabetic hypercholesterolaemia [41,42].…”