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Open AccessArticle

Human ApoA-I Overexpression Enhances Macrophage-Specific Reverse Cholesterol Transport but Fails to Prevent Inherited Diabesity in Mice

1
Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau i Institut d’Investigació Biomèdica Sant Pau, IIB-Sant Pau, 08025 Barcelona, Spain
2
Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
3
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, 28029 Madrid, Spain
4
Minerva Foundation Institute for Medical Research, Biomedicum 2U and National Institute for Health and Welfare, Genomics and Biomarkers Unit, FIN-00290 Helsinki, Finland
5
CSIC-ICCC-IIB-Sant Pau i CSIC-Institut d’Investigacions Biomèdiques de Barcelona (IIBB), 08025 Barcelona, Spain
6
CIBER de Enfermedades Cardiovasculares, CIBERCV, 28029 Madrid, Spain
7
Servei de Bioquímica, Hospital de la Santa Creu i Sant Pau i Institut d’Investigació Biomèdica de l’Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08041 Barcelona, Spain
8
Departament de Patologia, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain
9
Departament de Ciències Morfològiques, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
10
Servei d’Endocrinologia, Hospital Universitari Germans Trias i Pujol, Badalona, 08916 Barcelona, Spain
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
These authors are co-principal and co-corresponding authors on this work.
Int. J. Mol. Sci. 2019, 20(3), 655; https://doi.org/10.3390/ijms20030655
Received: 20 December 2018 / Revised: 26 January 2019 / Accepted: 29 January 2019 / Published: 2 February 2019
Human apolipoprotein A-I (hApoA-I) overexpression improves high-density lipoprotein (HDL) function and the metabolic complications of obesity. We used a mouse model of diabesity, the db/db mouse, to examine the effects of hApoA-I on the two main functional properties of HDL, i.e., macrophage-specific reverse cholesterol transport (m-RCT) in vivo and the antioxidant potential, as well as the phenotypic features of obesity. HApoA-I transgenic (hA-I) mice were bred with nonobese control (db/+) mice to generate hApoA-I-overexpressing db/+ offspring, which were subsequently bred to obtain hA-I-db/db mice. Overexpression of hApoA-I significantly increased weight gain and the incidence of fatty liver in db/db mice. Weight gain was mainly explained by the increased caloric intake of hA-I-db/db mice (>1.2-fold). Overexpression of hApoA-I also produced a mixed type of dyslipidemia in db/db mice. Despite these deleterious effects, the overexpression of hApoA-I partially restored m-RCT in db/db mice to levels similar to nonobese control mice. Moreover, HDL from hA-I-db/db mice also enhanced the protection against low-density lipoprotein (LDL) oxidation compared with HDL from db/db mice. In conclusion, overexpression of hApoA-I in db/db mice enhanced two main anti-atherogenic HDL properties while exacerbating weight gain and the fatty liver phenotype. These adverse metabolic side-effects were also observed in obese mice subjected to long-term HDL-based therapies in independent studies and might raise concerns regarding the use of hApoA-I-mediated therapy in obese humans. View Full-Text
Keywords: HDL functions; reverse cholesterol transport; metabolic syndrome; obesity; hepatic steatosis HDL functions; reverse cholesterol transport; metabolic syndrome; obesity; hepatic steatosis
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Méndez-Lara, K.A.; Farré, N.; Santos, D.; Rivas-Urbina, A.; Metso, J.; Sánchez-Quesada, J.L.; Llorente-Cortes, V.; Errico, T.L.; Lerma, E.; Jauhiainen, M.; Martín-Campos, J.M.; Alonso, N.; Escolà-Gil, J.C.; Blanco-Vaca, F.; Julve, J. Human ApoA-I Overexpression Enhances Macrophage-Specific Reverse Cholesterol Transport but Fails to Prevent Inherited Diabesity in Mice. Int. J. Mol. Sci. 2019, 20, 655.

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