We employed homologous recombination in embryonic stem cells to produce mice lacking functional LDL receptor genes. Homozygous male and female mice lacking LDL receptors (LDLR-/- mice) were viable and fertile. Total plasma cholesterol levels were twofold higher than those of wild-type litter-mates, owing to a seven- to ninefold increase in intermediate density lipoproteins (IDL) and LDL without a significant change in HDL. Plasma triglyceride levels were normal. The half-lives for intravenously administered 125I-VLDL and 125I-LDL were prolonged by 30-fold and 2.5-fold, respectively, but the clearance of 125I-HDL was normal in the LDLR-/- mice. Unlike wild-type mice, LDLR-/- mice responded to moderate amounts of dietary cholesterol (0.2% cholesterol/10% coconut oil) with a major increase in the cholesterol content of IDL and LDL particles. The elevated IDL/LDL level of LDLR-/- mice was reduced to normal 4 d after the intravenous injection of a recombinant replication-defective adenovirus encoding the human LDL receptor driven by the cytomegalovirus promoter. The virus restored expression of LDL receptor protein in the liver and increased the clearance of 125I-VLDL. We conclude that the LDL receptor is responsible in part for the low levels of VLDL, IDL, and LDL in wild-type mice and that adenovirus-encoded LDL receptors can acutely reverse the hypercholesterolemic effects of LDL receptor deficiency.

/pdf/hypercholesterolemia-in-low-density-lipoprotein-receptor-168sq23gaq.pdf

Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery.

Metabolic origins and clinical significance of LDL heterogeneity.

Insulin resistance is a key feature of the metabolic syndrome and often progresses to type 2 diabetes. Both insulin resistance and type 2 diabetes are characterized by dyslipidemia, which is an important and common risk factor for cardiovascular disease. Diabetic dyslipidemia is a cluster of potentially atherogenic lipid and lipoprotein abnormalities that are metabolically interrelated. Recent evidence suggests that a fundamental defect is an overproduction of large very low-density lipoprotein (VLDL) particles, which initiates a sequence of lipoprotein changes, resulting in higher levels of remnant particles, smaller LDL, and lower levels of high-density liporotein (HDL) cholesterol. These atherogenic lipid abnormalities precede the diagnosis of type 2 diabetes by several years, and it is thus important to elucidate the mechanisms involved in the overproduction of large VLDL particles. Here, we review the pathophysiology of VLDL biosynthesis and metabolism in the metabolic syndrome. We also review recent research investigating the relation between hepatic accumulation of lipids and insulin resistance, and sources of fatty acids for liver fat and VLDL biosynthesis. Finally, we briefly discuss current treatments for lipid management of dyslipidemia and potential future therapeutic targets.

Overproduction of Very Low–Density Lipoproteins Is the Hallmark of the Dyslipidemia in the Metabolic Syndrome

The apolipoprotein B containing lipoproteins VLDL, IDL, and LDL exhibit variation in their structure, function, and metabolism. These major lipoprotein classes can be fractionated into apparently discrete components by density gradient centrifugation or affinity chromatography. Examination of the behavior of subfractions in vivo reveals the presence of metabolic channels within the VLDL-LDL delipidation cascade so that the pedigree of a lipoprotein in part determines its metabolic fate. Evidence from VLDL and LDL apoB turnovers together with epidemiological data allows the construction of a quantitative model for the generation of small, dense LDL. This lipoprotein subspecies is one component of the dyslipidemic syndrome known as the atherogenic lipoprotein phenotype, a common disorder in those at risk for coronary heart disease. Understanding lipoprotein heterogeneity is an essential step in the further discovery of the pathogenesis of atherosclerosis and in the tailoring of pharmacologic treatment for subjects at risk.

Lipoprotein Heterogeneity and Apolipoprotein B Metabolism

Abnormalities of plasma lipid and lipoprotein concentrations are common in both insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus. In general, individuals with IDDM who are untreated or inadequately treated have elevations in both postprandial and fasting triglyceride levels in association with reduced activity of lipoprotein lipase. Low-density lipoprotein (LDL) cholesterol levels can rise when insulin deficiency impacts on LDL-receptor function. When patients with IDDM are treated and plasma glucose levels well controlled, plasma very-low-density lipoprotein (VLDL) triglyceride and LDL cholesterol levels are usually normal. In addition, plasma high-density lipoprotein (HDL) cholesterol levels are normal or elevated in well-controlled IDDM subjects. In NIDDM, increased VLDL triglyceride and reduced HDL cholesterol concentrations are common and are only partially related to glycemic control. Overproduction of VLDL leads to hypertriglyceridemia, which can be exacerbated if lipoprotein lipase activity is also reduced. The regulation of LDL levels is complex; catabolism can be reduced if significant insulin deficiency exists or increased if significant hypertriglyceridemia is present. The reduced levels of HDL cholesterol in NIDDM appear to be related to increased exchange of HDL cholesteryl esters for VLDL triglycerides, although other mechanisms may exist. The roles of insulin resistance, obesity, and independently inherited abnormalities of lipoprotein metabolism in the etiology of dyslipidemia of NIDDM are complex and require further investigation. Finally, the effects of diabetes on glycosylation of apoproteins; on other lipid enzymes, particularly hepatic triglyceride lipase; on lipoprotein surface lipids; and on hepatic uptake of remnants have only just begun to be defined. In view of the marked increase in atherosclerotic cardiovascular disease in individuals with diabetes mellitus, prompt attention to and aggressive therapy for dyslipidemia should be a central component of care for these patients.

Lipoprotein Physiology in Nondiabetic and Diabetic States: Relationship to Atherogenesis

A noncompetitive enzyme-linked immunosorbent assay (ELISA) for apolipoprotein A-II (ApoA-II) was developed. Microtiter plates were coated with affinity purified antibodies to ApoA-II. After incubation with human plasma, the amount of ApoA-II bound to the coated plate was determined with peroxidase-labeled antibodies to ApoA-II. When pure ApoA-II or delipidated reference plasma was used as standard, a single step delipidation was required in order to unmask some antigenic sites of ApoA-II. However, the underestimated ApoA-II values in untreated samples were shown to be corrected by using intact reference plasma as secondary standard. The average concentration of ApoA-II in normolipidemic plasma was 0.376 g/l.

Quantitative determination of human plasma apolipoprotein A-II by a non competitive enzyme-linked immunosorbent assay.

Apolipoprotein B metabolism in homozygous familial hypercholesterolemia.

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Quantitative determination of human plasma apolipoprotein A-II by a non competitive enzyme-linked immunosorbent assay.

Apolipoprotein B metabolism in homozygous familial hypercholesterolemia.