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

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.

Identification and characterization of alternative splicing variants of buffalo LXRα expressed in mammary gland

“…LXR α has been shown to promote lipid synthesis in mammary gland by regulating the expression of multiple genes during the process of milk fat synthesis in buffalo and cattle, especially through the regulation of LXRE site in the core promoter region of its target genes 10 , 27 . Consistent with previous reports of increased expression levels of LXRα in murine mammary epithelial cells and bovine mammary gland tissues from non-lactation to lactation 28 , 29 , this study showed that the mRNA abundance of the three LXRα transcripts of buffalo in lactation stage were all significantly higher than those in the non-lactation period, indicating that LXR α is an important regulator of milk fat synthesis, which is also consistent with previous finding 10 . Notably, although there was a significant difference in the expression of LXRα2 and LXRα3 between lactation and non-lactation, the magnitude of the difference is very small.…”

Aberrant RET expression affects normal mammary gland post-lactation transition, enhancing cancer potential

“…1A). These findings are consistent with published data showing that the Ret gene is most highly expressed in lactating mammary glands (Bambhroliya et al, 2018;Clarkson et al, 2004;Grinman et al, 2019;Stein et al, 2004). Analysis of mammary tissue lysates by WB revealed that lactating exhibit high levels of active RET protein (phosphorylated RET) compared to glands from post-lactating animals (Fig.…”

The bovine cumulus proteome is influenced by maturation condition and maturational competence of the oocyte

“…Still, LXR/RXR activation was already identified as a player in human granulosa cells as well as in follicular fluid 37,68 . The system contributes to cholesterol homeostasis and lipid metabolism in many tissues 69 . Cholesterol is an important compound with a role as membrane component or precursor in steroid hormone production and lipid metabolism.…”