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Liver X Receptor α Activation Increases Cholesterol Abundance In Mouse Milk
GRINMAN DIEGO; RUDOLPH M; CAREAGA V; MAIER MARTA; KORDON, E; MACLEAN P; PECCI ADALI
Simposio; Gordon Research Conferences in Mammary Gland Biology; 2017
Gordon Research Conferences
During lactation, the mammary gland is endowed with an enormous capacity to synthesize and secrete lipid in the form of triglycerides and cholesterol. Although several efforts have been made to understand the underlying mechanisms of milk lipid production and transport there are still many gaps to fill. Most of the members of the nuclear receptor family control glucose and lipid homeostasis. Particularly, LXRs are transcription factors activated by cholesterol metabolites whose target genes participate in the de novo triglycerides synthesis and cholesterol transport in many tissues. Two different LXR isoforms has been described: LXRα and LXRβ and their roles were characterized in liver, adipocytes, macrophages and intestinal epithelium among others. By using different in vitro and in vivo murine models and a variety of experimental approaches, this work aims to elucidate the LXR contribution in mouse mammary lipid production. Here, we report that LXRs are expressed in a mouse mammary epithelial cell line, its mRNA abundance increases throughout differentiation and LXRα?s expression levels are higher than those of LXRβ. Upon pharmacological activation, LXRs upregulate the expression of several target genes involved in lipid synthesis and transport and also enhance citoplasmic lipid droplets area Correspondingly, we have found that LXRα protein levels increase through lactation compare to pregnancy in mouse mammary epithelial enriched fractions (MECs) and, when treated with a commercial LXR agonist, mice exhibited increased milk cholesterol percentage during lactation accompanied with an increase in mRNA levels of SREBP1c, another master regulator of lipid metabolism, in MECs. Overall, these results suggest that LXRα would be a relevant player in the mammary epithelium by regulating cholesterol transport into the milk. Deepen into the mechanisms of action of this receptor during lactation may provide relevant data on milk fat production that would allow future approaches and therapies for nursing mothers with nutritional imbalances. Also the potential capability to modify milk lipid composition would be of great interest for dairy industry.