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

AuthorsMéndez-Lara, Karen; Farré, Núria; Santos, David; Rivas-Urbina,Andrea; Metso, Jari; Sánchez-Quesada, José Luís; Llorente-Cortés, Vicenta; Errico, Teresa L.; Lerma, Enrique; Jauhiainen, Matti; Martín-Campos, Jesús M.; Alonso, Núria; Escolà-Gil, Joan Carles; Blanco-Vaca, Francisco
KeywordsHDL functions
Reverse cholesterol transport
Metabolic syndrome
Hepatic steatosis
Issue Date2-Feb-2019
PublisherMolecular Diversity Preservation International
CitationInternational Journal of Molecular Sciences 20(3): 655 (2019)
AbstractHuman 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.
Publisher version (URL)http://dx.doi.org/10.3390/ijms20030655
Identifiersdoi: 10.3390/ijms20030655
e-issn: 1422-0067
issn: 1661-6596
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