Temporal Dynamics of High-Density Lipoprotein Proteome in Diet-Controlled Subjects with Type 2 Diabetes.

Karim G Kheniser,Takhar Kasumov,Serguei Ilchenko,Abdullah Osme,Sangeeta R Kashyap,Chunki Kim

doi:10.3390/biom10040520

Karim G Kheniser, Takhar Kasumov + Show 4 more

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https://doi.org/10.3390/biom10040520

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Journal: Biomolecules	Publication Date: Mar 30, 2020
Citations: 13	License type: CC BY 4.0

Affiliation: Cleveland Clinic, Northeast Ohio Medical University

Abstract

We examined the effect of mild hyperglycemia on high-density lipoprotein (HDL) metabolism and kinetics in diet-controlled subjects with type 2 diabetes (T2D). 2H2O-labeling coupled with mass spectrometry was applied to quantify HDL cholesterol turnover and HDL proteome dynamics in subjects with T2D (n = 9) and age- and BMI-matched healthy controls (n = 8). The activities of lecithin–cholesterol acyltransferase (LCAT), cholesterol ester transfer protein (CETP), and the proinflammatory index of HDL were quantified. Plasma adiponectin levels were reduced in subjects with T2D, which was directly associated with suppressed ABCA1-dependent cholesterol efflux capacity of HDL. The fractional catabolic rates of HDL cholesterol, apolipoprotein A-II (ApoA-II), ApoJ, ApoA-IV, transthyretin, complement C3, and vitamin D-binding protein (all p < 0.05) were increased in subjects with T2D. Despite increased HDL flux of acute-phase HDL proteins, there was no change in the proinflammatory index of HDL. Although LCAT and CETP activities were not affected in subjects with T2D, LCAT was inversely associated with blood glucose and CETP was inversely associated with plasma adiponectin. The degradation rates of ApoA-II and ApoA-IV were correlated with hemoglobin A1c. In conclusion, there were in vivo impairments in HDL proteome dynamics and HDL metabolism in diet-controlled patients with T2D.

Highlights

Cardiovascular disease (CVD) is one of the major complications of type 2 diabetes (T2D) and the most common causes of mortality in patients with T2D [1]
The results show that the FCR of high-density lipoprotein (HDL) cholesterol and several HDL proteins including apolipoprotein A-II (ApoA-II), ApoJ, and ApoA-IV were increased in patients with diet-controlled T2D
When we applied this method to diet-controlled subjects with T2D, we found that hyperglycemia resulted in increased apolipoprotein A-I (ApoA-I) degradation, the principal HDL protein largely responsible for reverse cholesterol transport [28]

Summary

Introduction

Cardiovascular disease (CVD) is one of the major complications of type 2 diabetes (T2D) and the most common causes of mortality in patients with T2D [1]. Patients with T2D are characterized by reduced levels of high-density lipoprotein (HDL) cholesterol, a known risk factor for CVD. Recent pharmacological approaches aiming to improve HDL cholesterol levels had a negligible impact on CVD risk. Clinical trials that increased HDL levels via niacin treatment failed to improve CVD outcomes [2]. Other trials that investigated the effects of cholesterol ester transfer protein (CETP) inhibitors did not result in reduced CVD risk [3]. The genetic studies echoed this prevailing sentiment by demonstrating that genetic polymorphism associated with the augmented levels of HDL was not associated with reduced CVD risk [4]. The aforementioned studies suggest that HDL functionality and HDL quantity are important determinants of CVD risk because there is a clear interplay between the two [5]

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