1. Academic Validation
  2. Liver X receptor-α activation enhances cholesterol secretion in lactating mammary epithelium

Liver X receptor-α activation enhances cholesterol secretion in lactating mammary epithelium

  • Am J Physiol Endocrinol Metab. 2019 Jun 1;316(6):E1136-E1145. doi: 10.1152/ajpendo.00548.2018.
Diego Y Grinman 1 Valeria P Careaga 2 3 Elizabeth A Wellberg 4 María V Dansey 2 5 Edith C Kordon 1 5 Steven M Anderson 4 Marta S Maier 2 3 Gerardo Burton 2 3 Paul S MacLean 6 Michael C Rudolph 6 Adali Pecci 1 5
Affiliations

Affiliations

  • 1 Instituto de Fisiología, Biología Molecular y Neurociencias, CONICET, Universidad de Buenos Aires , Buenos Aires , Argentina.
  • 2 Unidad De Microanálisis Y Métodos Físicos Aplicados a la Química Orgánica, CONICET, Universidad de Buenos Aires , Buenos Aires , Argentina.
  • 3 Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales , Universidad de Buenos Aires, Buenos Aires , Argentina.
  • 4 Department of Pathology, University of Colorado, Anschutz Medical Campus, Denver, Colorado.
  • 5 Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires , Buenos Aires , Argentina.
  • 6 Division of Endocrinology, Metabolism, and Diabetes, University of Colorado, Anschutz Medical Campus, Denver, Colorado.
Abstract

Liver X receptors (LXRs) are ligand-dependent transcription factors activated by Cholesterol metabolites. These receptors induce a suite of target genes required for de novo synthesis of triglycerides and Cholesterol transport in many tissues. Two different isoforms, LXRα and LXRβ, have been well characterized in liver, adipocytes, macrophages, and intestinal epithelium among Others, but their contribution to Cholesterol and fatty acid efflux in the lactating mammary epithelium is poorly understood. We hypothesize that LXR regulates lipogenesis during milk fat production in lactation. Global mRNA analysis of mouse mammary epithelial cells (MECs) revealed multiple LXR/RXR targets upregulated sharply early in lactation compared with midpregnancy. LXRα is the primary isoform, and its protein levels increase throughout lactation in MECs. The LXR Agonist GW3965 markedly induced several genes involved in Cholesterol transport and lipogenesis and enhanced cytoplasmic lipid droplet accumulation in the HC11 MEC cell line. Importantly, in vivo pharmacological activation of LXR increased the milk Cholesterol percentage and induced sterol regulatory element-binding protein 1c (Srebp1c) and ATP-binding cassette transporter a7 (Abca7) expression in MECs. Cumulatively, our findings identify LXRα as an important regulator of Cholesterol incorporation into the milk through key nodes of de novo lipogenesis, suggesting a potential therapeutic target in women with difficulty initiating lactation.

Keywords

LXR; cholesterol pathway; lactation; mammary epithelial cells; milk lipid.

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