Molecular Mechanism of Reverse Cholesterol Transport: Reaction of Pre-β-Migrating High-Density Lipoprotein with Plasma Lecithin/Cholesterol Acyltransferase†

Biochemistry ◽  
2004 ◽  
Vol 43 (46) ◽  
pp. 14811-14820 ◽  
Author(s):  
Yasushi Nakamura ◽  
Leila Kotite ◽  
Yonghong Gan ◽  
Thomas A. Spencer ◽  
Christopher J. Fielding ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
Molecular Mechanism ◽  
Reverse Cholesterol Transport ◽  
Cholesterol Acyltransferase ◽  
Density Lipoprotein ◽  
High Density ◽  
Cholesterol Transport ◽  
Transport Reaction ◽  
Lecithin Cholesterol Acyltransferase

scholarly journals MEDI6012: Recombinant Human Lecithin Cholesterol Acyltransferase, High‐Density Lipoprotein, and Low‐Density Lipoprotein Receptor–Mediated Reverse Cholesterol Transport

2021 ◽  
Author(s):  
Richard T. George ◽  
Liron Abuhatzira ◽  
Susan M. Stoughton ◽  
Sotirios K. Karathanasis ◽  
Dewei She ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
High Density Lipoprotein Cholesterol ◽  
Reverse Cholesterol Transport ◽  
Low Density Lipoprotein ◽  
Cholesterol Acyltransferase ◽  
Density Lipoprotein ◽  
High Density ◽  
Cholesterol Transport ◽  
Low Density ◽  
Lecithin Cholesterol Acyltransferase

Background MEDI6012 is recombinant human lecithin cholesterol acyltransferase, the rate‐limiting enzyme in reverse cholesterol transport. Infusions of lecithin cholesterol acyltransferase have the potential to enhance reverse cholesterol transport and benefit patients with coronary heart disease. The purpose of this study was to test the safety, pharmacokinetic, and pharmacodynamic profile of MEDI6012. Methods and Results This phase 2a double‐blind study randomized 48 subjects with stable coronary heart disease on a statin to a single dose of MEDI6012 or placebo (6:2) (NCT02601560) with ascending doses administered intravenously (24, 80, 240, and 800 mg) and subcutaneously (80 and 600 mg). MEDI6012 demonstrated rates of treatment‐emergent adverse events that were similar to those of placebo. Dose‐dependent increases in high‐density lipoprotein cholesterol were observed with area under the concentration‐time curves from 0 to 96 hours of 728, 1640, 3035, and 5318 should be: mg·h/mL in the intravenous dose groups and 422 and 2845 mg·h/mL in the subcutaneous dose groups. Peak mean high‐density lipoprotein cholesterol percent change was 31.4%, 71.4%, 125%, and 177.8% in the intravenous dose groups and 18.3% and 111.2% in the subcutaneous dose groups, and was accompanied by increases in endogenous apoA1 (apolipoprotein A1) and non‐ATP‐binding cassette transporter A1 cholesterol efflux capacity. Decreases in apoB (apolipoprotein B) were observed across all dose levels and decreases in atherogenic small low‐density lipoprotein particles by 41%, 88%, and 79% at the 80‐, 240‐, and 800‐mg IV doses, respectively. Conclusions MEDI6012 demonstrated an acceptable safety profile and increased high‐density lipoprotein cholesterol, endogenous apoA1, and non‐ATP‐binding cassette transporter A1 cholesterol efflux capacity while reducing the number of atherogenic low‐density lipoprotein particles. These findings are supportive of enhanced reverse cholesterol transport and a functional high‐density lipoprotein phenotype. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02601560.

Smoking prevents the intravascular remodeling of high-density lipoprotein particles: implications for reverse cholesterol transport

Metabolism ◽  
2004 ◽  
Vol 53 (7) ◽  
pp. 858-862 ◽  
Author(s):  
Águeda C.M Zaratin ◽  
Eder C.R Quintão ◽  
Andrei C Sposito ◽  
Valéria S Nunes ◽  
Ana Maria Lottenberg ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
Reverse Cholesterol Transport ◽  
Density Lipoprotein ◽  
High Density ◽  
Cholesterol Transport ◽  
Lipoprotein Particles

scholarly journals Agonistic Human Antibodies Binding to Lecithin-Cholesterol Acyltransferase Modulate High Density Lipoprotein Metabolism

2015 ◽  
Vol 291 (6) ◽  
pp. 2799-2811 ◽  
Author(s):  
Ruwanthi N. Gunawardane ◽  
Preston Fordstrom ◽  
Derek E. Piper ◽  
Stephanie Masterman ◽  
Sophia Siu ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
Cholesterol Acyltransferase ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
High Density ◽  
Human Antibodies ◽  
Lecithin Cholesterol Acyltransferase

The association between lecithin–cholesterol acyltransferase activity and fatty liver index

2019 ◽  
Vol 56 (5) ◽  
pp. 583-592 ◽  
Author(s):  
Jelena Janac ◽  
Aleksandra Zeljkovic ◽  
Zorana Jelic-Ivanovic ◽  
Vesna Dimitrijevic-Sreckovic ◽  
Milica Miljkovic ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
Fatty Liver ◽  
Cholesterol Acyltransferase ◽  
Density Lipoprotein ◽  
High Density ◽  
Paraoxonase 1 ◽  
Acyltransferase Activity ◽  
Lecithin Cholesterol Acyltransferase ◽  
Liver Index ◽  
Fatty Liver Index

Background Non-alcoholic fatty liver disease is a frequent ailment with known complications, including those within the cardiovascular system. Associations between several indicators of high-density lipoprotein metabolism and function with clinical and laboratory parameters for the assessment of fatty liver index, a surrogate marker of non-alcoholic fatty liver disease, were evaluated. Methods The study comprised 130 patients classified according to fatty liver index values: fatty liver index < 30, fatty liver index 30–59 (the intermediate group) and fatty liver index ⩾ 60. Lecithin–cholesterol acyltransferase and cholesteryl ester transfer protein activities were determined. Paraoxonase 1 concentration and its activity, paraoxonase 3 concentration and high-density lipoprotein subclass distribution were assessed. Results Increased lecithin–cholesterol acyltransferase activity correlated with increased fatty liver index ( P < 0.001). Paraoxonase 3 concentration was lower in the fatty liver index ⩾ 60 group compared with the fatty liver index < 30 group ( P < 0.05). Cholesteryl ester transfer protein activity, paraoxonase 1 concentration and its activity did not significantly differ across the fatty liver index groups. The relative proportion of small-sized high-density lipoprotein 3 subclass was higher in the fatty liver index ⩾ 60 group compared with the other two fatty liver index groups ( P < 0.01). Lecithin–cholesterol acyltransferase activity positively associated with the fatty liver index ⩾ 60 group and remained significant after adjustment for other potential confounders. Only the triglyceride concentration remained significantly associated with lecithin–cholesterol acyltransferase activity when the parameters that constitute the fatty liver index equation were examined. Conclusions Higher lecithin–cholesterol acyltransferase activity is associated with elevated fatty liver index values. Significant independent association between triglycerides and lecithin–cholesterol acyltransferase activity might indicate a role of hypertriglyceridaemia in alterations of lecithin–cholesterol acyltransferase activity in individuals with elevated fatty liver index.

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