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

Camilla H K Hughes,John W Newman,Joy L Pate,Remy Bosviel

doi:10.3389/fendo.2019.00662

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.

Highlights

The corpus luteum (CL) originates from the ovulatory follicle and has an incredibly high steroidogenic output
Free arachidonic acid was present in greater concentrations in the CL of the estrous cycle than in the CL of pregnancy on day 18 [1], perhaps providing precursor for the luteal synthesis of PGF2A that is required for luteal regression [3]
Seventy-nine lipids were measured in the CL, at four times, day 4, 11, 18 of the estrous cycle, and day 18 of pregnancy (Supplemental Table 5)

Summary

Introduction

The corpus luteum (CL) originates from the ovulatory follicle and has an incredibly high steroidogenic output. In the absence of a viable pregnancy, the bovine CL regresses rapidly, in response to prostaglandin (PG) F2A, ceasing progesterone production and allowing another ovulation to occur. Luteal rescue in the presence of a pregnancy is imperative for reproduction. The CL is a site of bioactive lipid synthesis. It contains high concentrations of arachidonic acid [1] and luteal tissue uptake of arachidonic acid in vitro was greater than the uptake of this prostaglandin precursor in skeletal muscle or ovarian cortex [2]. Free arachidonic acid was present in greater concentrations in the CL of the estrous cycle than in the CL of pregnancy on day 18 [1], perhaps providing precursor for the luteal synthesis of PGF2A that is required for luteal regression [3]. Intraluteal synthesis of PGEs and prostacyclin and uterine synthesis of PGEs have both been implicated in luteal rescue during early pregnancy [4,5,6,7], this mechanism is not entirely clear

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