Human ApoA-I overexpression enhances macrophage-specific reverse cholesterol transport but fails to prevent inherited diabesity in mice

Karen Alejandra Méndez-Lara, Núria Farré, David Santos, Andrea Rivas-Urbina, Jari Metso, José Luis Sánchez-Quesada, Vicenta Llorente-Cortes, Teresa L. Errico, Enrique Lerma, Matti Jauhiainen, Jesús M. Martín-Campos, Núria Alonso, Joan Carles Escolà-Gil, Francisco Blanco-Vaca, Josep Julve

Research output: Contribution to journalArticleResearch

Abstract

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. 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.
Original languageEnglish
Article number655
JournalInternational Journal of Molecular Sciences
Volume20
DOIs
Publication statusPublished - 1 Feb 2019

Keywords

  • HDL functions
  • Hepatic steatosis
  • Metabolic syndrome
  • Obesity
  • Reverse cholesterol transport

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