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

Int J Mol Sci. 2019 Feb 2;20(3):655. doi: 10.3390/ijms20030655.

Abstract

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.

Keywords: HDL functions; hepatic steatosis; metabolic syndrome; obesity; reverse cholesterol transport.

MeSH terms

  • Animals
  • Apolipoprotein A-I / genetics*
  • Biological Transport
  • Body Weight
  • Cholesterol / metabolism*
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus / metabolism*
  • Disease Models, Animal
  • Fatty Liver / genetics
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Gene Expression Profiling
  • Gene Expression*
  • Humans
  • Macrophages / metabolism*
  • Mice

Substances

  • APOA1 protein, human
  • Apolipoprotein A-I
  • Cholesterol