LXR-dependent regulation of macrophage-specific reverse cholesterol transport is impaired in a model of genetic diabesity

Teresa L. Errico, Karen Alejandra Méndez-Lara, David Santos, Núria Cabrerizo, Lucía Baila-Rueda, Jari Metso, Ana Cenarro, Eva Pardina, Albert Lecube, Matti Jauhiainen, Julia Peinado-Onsurbe, Joan Carles Escolà-Gil, Francisco Blanco-Vaca, Josep Julve

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3 Citations (Scopus)

Abstract

© 2017 Elsevier Inc. Diabesity and fatty liver have been associated with low levels of high-density lipoprotein cholesterol, and thus could impair macrophage-specific reverse cholesterol transport (m-RCT). Liver X receptor (LXR) plays a critical role in m-RCT. Abcg5/g8 sterol transporters, which are involved in cholesterol trafficking into bile, as well as other LXR targets, could be compromised in the livers of obese individuals. We aimed to determine m-RCT dynamics in a mouse model of diabesity, the db/db mice. These obese mice displayed a significant retention of macrophage-derived cholesterol in the liver and reduced fecal cholesterol elimination compared with nonobese mice. This was associated with a significant downregulation of the hepatic LXR targets, including Abcg5/g8. Pharmacologic induction of LXR promoted the delivery of total tracer output into feces in db/db mice, partly due to increased liver and small intestine Abcg5/Abcg8 gene expression. Notably, a favorable upregulation of the hepatic levels of ABCG5/G8 and NR1H3 was also observed postoperatively in morbidly obese patients, suggesting a similar LXR impairment in these patients. In conclusion, our data show that downregulation of the LXR axis impairs cholesterol transfer from macrophages to feces in db/db mice, whereas the induction of the LXR axis partly restores impaired m-RCT by elevating the liver and small intestine expressions of Abcg5/g8.
Original languageEnglish
Pages (from-to)19-35.e5
JournalTranslational Research
Volume186
DOIs
Publication statusPublished - 1 Aug 2017

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    Errico, T. L., Méndez-Lara, K. A., Santos, D., Cabrerizo, N., Baila-Rueda, L., Metso, J., Cenarro, A., Pardina, E., Lecube, A., Jauhiainen, M., Peinado-Onsurbe, J., Escolà-Gil, J. C., Blanco-Vaca, F., & Julve, J. (2017). LXR-dependent regulation of macrophage-specific reverse cholesterol transport is impaired in a model of genetic diabesity. Translational Research, 186, 19-35.e5. https://doi.org/10.1016/j.trsl.2017.05.004