Abstract Recent studies have shown that pharmacological increases in HDL cholesterol concentrations do not necessarily translate into clinical benefits for patients, raising concerns about its predictive value for cardiovascular events. Here we hypothesize that the size-modulated lipid distribution within HDL particles is compromised in metabolic disorders that have abnormal HDL particle sizes, such as type 2 diabetes mellitus (DM2). By using NMR spectroscopy combined with a biochemical volumetric model we determined the size and spatial lipid distribution of HDL subclasses in a cohort of 26 controls and 29 DM2 patients before and after two drug treatments, one with niacin plus laropiprant and another with fenofibrate as an add-on to simvastatin. We further characterized the HDL surface properties using atomic force microscopy and fluorescent probes to show an abnormal lipid distribution within smaller HDL particles, a subclass particularly enriched in the DM2 patients. The reduction in the size, force cholesterol esters and triglycerides to emerge from the HDL core to the surface, making the outer surface of HDL more hydrophobic. Interestingly, pharmacological interventions had no effect on this undesired configuration, which may explain the lack of clinical benefits in DM2 subjects.

Fenofibrate

Niacin

10.1038/srep19249

Cite

Citations (31)

Front Cover: Nicotinamide Protects Against Diet‐Induced Body Weight Gain, Increases Energy Expenditure, and Induces White Adipose Tissue Beiging

Molecular Nutrition & Food Research (2021)

Karen Alejandra Méndez‐Lara Elisabeth Rodríguez‐Millán David Sebastián Rosi Blanco‐Soto Mercedes Camacho

Mol. Nutr. Food Res. 2021, 65, 2100111 DOI: 10.1002/mnfr.202100111 Artwork of representative resonance magnetic images illustrating reduced fat depots in diet-induced obese mice treated with nicotinamide. Nicotinamide supplementation increased uncoupling protein 1 abundance, NAD+ content and mitochondrial activity in white adipose tissue of treated mice. This is reported by Karen Alejandra Méndez-Lara and co-workers in article 2100111. Cover is illustrated by Òscar Julve.

Front cover

White (mutation)

Thermogenin

10.1002/mnfr.202170027

Cite

Citations (0)

Effects of site‐directed mutagenesis on the serine residues of human lecithin: Cholesterol acyltransferase

Lipids (1994)

Shi‐Jing Qu Hui‐Zhen Fan Francisco Blanco‐Vaca Henry J. Pownall

Abstract Lecithin:cholesterol acyltransferase (LCAT) is a serine protease‐type enzyme that esterifies cholesterol in human plasma and is activated by apolipoprotein A‐I in high‐density lipoproteins. LCAT contains 22 serine residues, including Ser 181, which is thought to be part of the catalytic site. In order to determine the importance of these serine residues in LCAT, we prepared six LCAT mutants: LCAT (Ser19→Ala), LCAT (Ser181→Gly), LCAT (Ser208→Ala), LCAT (Ser216→Ala), LCAT (Ser225→Ala) and LCAT (Ser383→Ala). We also replaced the adjacent asparagine residues in two additional mutants, LCAT (Ser19→Ala, Asn20→Thr) and LCAT (Ser383→Ala, Asn384→Thr), in order to ascertain the effect of the serines on N ‐glycosylation. The mutant complementary DNA (cDNA) were subcloned into a eukaryotic expression vector (pSG5) and expressed in COS‐6 cells. By polymerase chain reaction analysis, LCAT‐specific messenger RNA (mRNA) was found in all mutant and wild‐type transfectants. Western blot analysis revealed LCAT‐specific bands in media and lysates of the transfected cells. With two exceptions, the amounts of LCAT mass secreted by the transfectants were similar to that of the wild type (mean, 90% mass of wild type; range, 34–138%). Except for LCAT (Ser181→Gly), which was inactive, the specific activities of the remainder of the mutant enzymes were also similar (mean, 95% activity of wild type; range, 65–169%). These results indicate that Ser181 is part of the catalytic site and that stereoconservative substitutions for serines have minor effects on the synthesis, secretion and specific activities of human LCAT.

Acyltransferases

Wild type

Site-directed mutagenesis

Sterol O-acyltransferase

10.1007/bf02536246

Cite

Citations (10)

Serum soluble transferrin receptor concentrations are increased in central obesity. Results from a screening programme for hereditary hemochromatosis in men with hyperferritinemia

Clinica Chimica Acta (2008)

Núria Freixenet Ángel F. Remacha Eugenio Berlanga Assumpta Caixàs Olga Giménez‐Palop

Hereditary hemochromatosis

Soluble transferrin receptor

10.1016/j.cca.2008.10.019

Cite

Citations (36)

Apo(B)-dependent dyslipidemic phenotypes in type 1 diabetic patients

European Journal of Internal Medicine (2001)

Ana M. Wägner Jordi Ordóñez‐Llanos Marta Hernández José Luís Sánchez-Quesada Francisco Blanco‐Vaca

Clinical phenotype

10.1016/s0953-6205(01)00178-9

Cite

Citations (1)

Impaired HDL (High-Density Lipoprotein)-Mediated Macrophage Cholesterol Efflux in Patients With Abdominal Aortic Aneurysm—Brief Report

Arteriosclerosis Thrombosis and Vascular Biology (2018)

Diego Martínez-López Lídia Cedó Jari Metso Elena Burillo Annabel García‐León

Objective— The ability of HDL (high-density lipoprotein) to promote macrophage cholesterol efflux is considered the main HDL cardioprotective function. Abdominal aortic aneurysm (AAA) is usually characterized by cholesterol accumulation and macrophage infiltration in the aortic wall. Here, we aim to evaluate the composition of circulating HDL particles and their potential for promoting macrophage cholesterol efflux in AAA subjects. Approach and Results— First, we randomly selected AAA and control subjects from Spain. The AAA patients in the Spanish cohort showed lower plasma apoA-I levels concomitantly associated with low levels of plasma HDL cholesterol and the amount of preβ-HDL particles. We determined macrophage cholesterol efflux to apoB-depleted plasma, which contains mature HDL, preβ-HDL particles and HDL regulatory proteins. ApoB-depleted plasma from AAA patients displayed an impaired ability to promote macrophage cholesterol efflux. Next, we replicated the experiments with AAA and control subjects derived from Danish cohort. Danish AAA patients also showed lower apoA-I levels and a defective HDL-mediated macrophage cholesterol efflux. Conclusions— AAA patients show impaired HDL-facilitated cholesterol removal from macrophages, which could be mechanistically linked to AAA.

Efflux

Reverse cholesterol transport

High-density lipoprotein

10.1161/atvbaha.118.311704

Cite

Citations (20)

LDL Receptor Regulates the Reverse Transport of Macrophage-Derived Unesterified Cholesterol via Concerted Action of the HDL-LDL Axis Insight From Mouse Models

WOS (2020)

Lídia Cedó Jari Metso David Santos Annabel García‐León Núria Plana

Rationale: The HDL (high-density lipoprotein)-mediated stimulation of cellular cholesterol efflux initiates macrophage-specific reverse cholesterol transport (m-RCT), which ends in the fecal excret...

Reverse cholesterol transport

Source

Cite

Citations (1)