Cholesteryl ester transfer protein (CETP) is important clinically and is the current target for new drug development. Its structure and mechanism of action has not been well understood. We have combined current new structural and functional methods to compare with relevant prior data. These analyses have led us to propose several steps in CETP's function at the molecular level, in the context of its interactions with lipoproteins, e.g., sensing, penetration, docking, selectivity, ternary complex formation, lipid transfer, and HDL dissociation. These new molecular insights improve our understanding of CETP's mechanisms of action.
"The observed increase in both LDL-1 and large HDL fractions following insulin therapy may be attributed to the reduction in circulating triglycerides. CETP mediates the transfer of TG from VLDL to HDL and/or LDL in exchange for cholesteryl ester (CE)
. It is important to note that CETP does not drive triglycerides or cholesterol esters in one direction or another but is simply a shuttle protein for whatever lipids are available
[Show abstract][Hide abstract] ABSTRACT: Background
Insulin treatment can lead to good glycemic control and result in improvement of lipid parameters in type 2 diabetic patients. This study was designed to evaluate the effect of insulin analog initiation therapy on low-density lipoprotein (LDL)/ high-density lipoprotein (HDL) sub-fractions and HDL associated enzymes in type 2 diabetic patients during early phase.
Twenty four type 2 diabetic patients with glycosylated hemoglobin (HbA1c) levels above 10% despite ongoing combination therapy with sulphonylurea and metformin were selected. Former treatment regimen was continued for the first day followed by substitution of sulphonylurea therapy with different insulin analogs (0.4 U/kg/day) plus metformin. Glycemic profiles were determined over 72 hours by continuous glucose monitoring system (CGMS) and blood samples were obtained from all patients at 24 and 72 hours. Plasma levels of cholesteryl ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), apolipoprotein B (apoB) and apolipoprotein A-1 (apoA-I) were determined by enzyme-linked immunosorbent assay (ELISA). Measurement of CETP and LCAT activity was performed via fluorometric analysis. Paraoxonase (PON1) enzyme activity was assessed from the rate of enzymatic hydrolysis of phenyl acetate to phenol formation. LDL and HDL subfraction analysis was done by continuous disc polyacrylamide gel electrophoresis.
Mean blood glucose, total cholesterol (TC), triglyceride (TG) and very low-density lipoprotein cholesterol (VLDL-C) levels were significantly decreased while HDL-C levels were significantly increased after insulin treatment. Although LDL-C levels were not significantly different before and after insulin initiation therapy a significant increase in LDL-1 subgroup and a significant reduction in atherogenic LDL-3 and LDL-4 subgroups were observed. Insulin analog initiation therapy caused a significant increase in HDL-large, HDL- intermediate and a significant reduction in HDL-small subfractions. CETP protein level and activity was significantly increased while apoB levels were significantly decreased following insulin analog initiation therapy. No significant difference was found in LCAT mass, LCAT activity, apoA-I and PON-1 arylesterase levels following insulin initiation therapy.
These findings indicate that insulin analog initiation therapy activates lipid metabolism via up-regulating CETP and shows anti-atherogenic effects by increasing HDL-large and decreasing LDL-3 and LDL-4 subfractions in a short time period.
Lipids in Health and Disease 04/2013; 12(1):54. DOI:10.1186/1476-511X-12-54 · 2.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Familial hyperlipidemia is an inherited metabolic disorder characterized by elevated lipid and/or lipoprotein levels in the blood. Despite improvements in lipid-lowering therapy during the last decades, it still remains a substantial contributor to the incidence of cardiovascular disease since patients on current conventional therapies do not achieve their target LDL-cholesterol levels. With a view to lower LDL-cholesterol levels, a number of new therapeutic strategies have been developed over recent years. In this review, we provide an overview of these treatment options that are currently in clinical development and may offer alternative or adjunctive therapies for this high-risk population.
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