Role of Liver X Receptor in Mastitis Therapy and Regulation of Milk Fat Synthesis

Hu, Xiaoyu; Zhang, Naisheng; Fu, Yunhe

doi:10.1007/s10911-018-9403-5

Cited by 6 publications

(7 citation statements)

References 157 publications

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“…Two major implications derive from these findings. On one hand, LXRs are potentially attractive druggable targets for the treatment of several diseases, i.e., atherosclerosis, cardiovascular diseases (14) and, more importantly, mastitis (9,15). Therefore, critical evaluation regarding the administration of LXR agonists should be made when designing therapies for those lactating mothers, since it could impact the milk cholesterol composition and consequently have implications in neonate's development while breastfeeding.…”

Section: Discussionmentioning

confidence: 99%

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

Grinman

Careaga

Wellberg

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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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.

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Section: Discussionmentioning

confidence: 99%

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

Grinman

Careaga

Wellberg

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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“…(2017) reported that LXRα agonist T0901317 and Platycodin D could suppress LPS-induced mastitis in mice and DCMECs. Overall, the evidence suggests that LXRα may serve as a new target for mastitis therapy and regulation of milk fat synthesis (Hu et al ., 2019). In the current research, our objective was to evaluate the role of LXRα in LPS-induced reduction of triglyceride synthesis in lactating DCMECs.…”

Section: Discussionmentioning

confidence: 99%

“…Besides cell viability and inflammatory response, the regulation of milk fat synthesis in DCMECs with LPS treatment also involves multiple transcription factors to control the milk fat enzymatic machinery. LXRα is a nuclear receptor and transcription factor that plays important role in milk fat synthesis and mastitis therapy in dairy cows (Hu et al ., 2019). Therefore, the transcription, translation, and translocation of LXR were detected in this study.…”

Section: Discussionmentioning

confidence: 99%

Liver X receptor α participates in LPS-induced reduction of triglyceride synthesis in bovine mammary epithelial cells

Wang

Lian

Song

et al. 2020

Journal of Dairy Research

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Lipopolysaccharides (LPS) could induce milk fat depression via regulating the body and blood fat metabolism. However, it is not completely clear how LPS might regulate triglyceride synthesis in dairy cow mammary epithelial cells (DCMECs). DCMECs were isolated and purified from dairy cow mammary tissue and treated with LPS. The level of triglyceride synthesis, the expression and activity of the liver X receptor α (LXRα), enzymes related to de novo fatty acid synthesis, and the expression of the fatty acid transporters were investigated. We found that LPS decreased the level of triglyceride synthesis via a down-regulation of the transcription, translation, and nuclear translocation level of the LXRα. The results also indicated that the transcription level of the LXRα target genes, sterol regulatory element binding protein 1 (SREBP1), fatty acid synthetase (FAS), acetyl-CoA carboxylase-1 (ACC1), were significantly down-regulated in DCMECs after LPS treatment. Our data may provide new insight into the mechanisms of milk fat depression caused by LPS.

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“…The fat content in milk is one of the main indicators of milk quality (Lu et al, 2016). Milk fat synthesis is affected by a variety of factors (Liu et al, 2018b); for example, when dairy cows suffer from mastitis, their milk fat synthesis levels are significantly reduced (Hu et al, 2019). Lipopolysaccharide is a key antigenic factor for dairy cow mastitis pathogens such as Escherichia coli (Brade et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide inhibits triglyceride synthesis in dairy cow mammary epithelial cells by upregulating miR-27a-3p, which targets the PPARG gene

Wang

Zhou

Cong

et al. 2021

Journal of Dairy Science

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The fat content of milk determines the quality of milk, and triglycerides are the major components of milk fat. Milk fat synthesis is regulated by many factors. Lipopolysaccharide (LPS) has been shown to inhibit milk fat synthesis in bovine mammary epithelial cells, but research on the underlying mechanisms has been limited. MicroRNA (miRNA) are involved in many physiological processes, but there have been few studies on their regulation in milk fat synthesis. In this study, we aimed to investigate whether LPS upregulates miR-27a-3p, which targets PPARG, thereby inhibiting the synthesis of triglycerides in a dairy cow mammary epithelial cell line (MAC-T). After LPS stimulation of MAC-T cells, PPARG gene expression and milk fat synthesis were inhibited. TargetScan software was used to predict miRNA targeting PPARG, and miR-27a-3p was selected as a candidate. A dual luciferase reporter assay further confirmed the targeting connection between miR-27a-3p and the PPARG gene. To investigate the functions of miR-27a-3p, miR-27a-3p mimic and inhibitors were transfected into MAC-T cells. The mRNA and protein levels of PPAR-γ were negatively correlated with the expression of miR-27a-3p. Lipid droplet accumulation and triglyceride synthesis were also negatively correlated with miR-27a-3p expression. Inhibition of miR-27a-3p partially reversed the LPSinduced decreases in PPARG expression and milk fat synthesis. In summary, our results reveal that LPS can inhibit MAC-T cell milk fat synthesis by upregulating miR-27a-3p, which targets the PPARG gene.

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Role of Liver X Receptor in Mastitis Therapy and Regulation of Milk Fat Synthesis

Cited by 6 publications

References 157 publications

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

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

Liver X receptor α participates in LPS-induced reduction of triglyceride synthesis in bovine mammary epithelial cells

Lipopolysaccharide inhibits triglyceride synthesis in dairy cow mammary epithelial cells by upregulating miR-27a-3p, which targets the PPARG gene

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