Luteal Lipids Regulate Progesterone Production and May Modulate Immune Cell Function During the Estrous Cycle and Pregnancy

Abstract

Although the corpus luteum (CL) contains high concentrations of lipid in the form of steroid hormone precursors and prostaglandins, little is known about the abundance or function of other luteal lipid mediators. To address this, 79 lipid mediators were measured in bovine CL, using ultra performance liquid chromatography-tandem mass spectrometry. CL from estrous cycle days 4, 11, and 18 were compared and, separately, CL from days 18 of the estrous cycle and pregnancy were compared. Twenty-three lipids increased as the estrous cycle progressed (P < 0.05), with nine increasing between days 4 and 11 and fourteen increasing between days 4 and 18. Overall, this indicated a general upregulation of lipid mediator synthesis as the estrous cycle progressed, including increases in oxylipins and endocannabinoids. Only 15-KETE was less abundant in the CL of early pregnancy (P < 0.05), with a tendency (P < 0.10) for four others to be less abundant. Notably, 15-KETE also increased between estrous cycle days 4 and 18. Ingenuity Pathway Analysis (IPA, Qiagen) indicated that functions associated with differentially abundant lipids during the estrous cycle included leukocyte activation, cell migration, and cell proliferation. To investigate changes in CL during maternal recognition of pregnancy, this lipid dataset was integrated with a published dataset from mRNA profiling during maternal recognition of pregnancy. This analysis indicated that lipids and mRNA that changed during maternal recognition of pregnancy may regulate some of the same functions, including immune cell chemotaxis and cell-cell communication. To assess effects of these lipid mediators, luteal cells were cultured with 5-KETE or 15-KETE. One ng/mL 5-KETE reduced luteal progesterone on day 1 of culture, only in the absence of luteinizing hormone (LH), while 1 ng/mL 15-KETE induced progesterone only in the presence of LH (10 ng/mL). On day 7 of culture, 0.1 ng/mL 15-KETE reduced prostaglandin (PG)F2A-induced inhibition of LH-stimulated progesterone production, while 1 ng/mL 15-KETE did not have this effect. Overall, these data suggest a role for lipid mediators during luteal development and early pregnancy, as regulators of steroidogenesis, immune cell activation and function, intracellular signaling, and cell survival and death.

Conception and early pregnancy in the mare: lipidomics the unexplored frontier

“…Despite indications that bioactive lipids have an important role in CL function ( Wiltbank & Ottobre 2003 , Hughes et al 2019 ), little is known about the function of specific luteal lipid mediators in this process, although luteal progesterone is clearly of utmost importance for pregnancy maintenance ( Allen 2001 ). Interestingly, pioneering studies first noted that circulating progesterone in mares, in comparison to many other species, was surprisingly low ( Short 1959 , Holtan et al 1979 ) and that 5α-reduced pregnanes including the sterol lipid 5α-dihydroprogesterone (DHP) were surprisingly high ( Holtan et al 1991 ).…”

“…In the cow, there have been reports that lipids ingested through dietary supplementation can alter the luteal response to PGF 2α ( Plewes et al 2018 ). A recent study in the dairy cow looked at in vitro lipidomic changes in the CL during MRP and suggested that lipids and mRNAs in the CL may regulate a suite of MRP-associated events, including immune cell chemotaxis and cell-cell communication ( Hughes et al 2019 ). Of particular interest was the eicosanoid 15-KETE, which is a major metabolite of AA.…”

“…In luteal cells, on day 1, a high concentration of 15-KETE induced progesterone production in the presence of LH, but after 7 days, a low concentration of 15-KETE reduced the ability of PGF 2α to inhibit LH-stimulated progesterone production. In cattle, the decline in 15-KETE during early pregnancy has been proposed to mediate an increased luteal resistance to PGF 2α ( Hughes et al 2019 ). Inspiration for better understanding equine biophysiology can be drawn from such studies.…”

Changes in Porcine Corpus Luteum Proteome Associated with Development, Maintenance, Regression, and Rescue during Estrous Cycle and Early Pregnancy

“…Using targeted analysis approach, tremendous work has been done on understanding molecular regulation of CL biology. Several mechanisms and factors regulating luteal growth and regression are known that involve lipid metabolism in CL [ 8 , 9 ], angiogenesis [ 10 , 11 ] and apoptosis [ 12 , 13 , 14 ], extracellular matrix remodeling [ 15 ], immune-endocrine cross-talk [ 16 , 17 ], role of tumor necrosis factor alpha and macrophages [ 18 , 19 , 20 ], and enzymes involved in steroidogenesis [ 1 ]. The CL during the estrous cycle undergoes tremendous changes in its structure and function.…”

Profile of uterine flush lipid mediators in cows with subclinical endometritis: pilot study

“…PGF 2α regulates development and function of the corpus luteum, and PGE 2 is increased during the late-luteal phase followed by a decrease during regression [ 3 ]. The production levels of lipid mediators such as 15-KETE and oxylipin in the corpus luteum of cows are altered as the estrous cycle progressed [ 16 ]. These studies indicate that PUFAs are involved in reproduction.…”