Nuclear receptors are intracellular proteins that act as transcription factors. Proteins with classic nuclear receptor domain structure lacking identified signaling ligands are designated orphan nuclear receptors. Two of these, steroidogenic factor-1 (NR5A1, also known as SF-1) and liver receptor homolog-1 (NR5A2, also known as LRH-1), bind to the same DNA sequences, with different and nonoverlapping effects on targets. Endogenous regulation of both is achieved predominantly by cofactor interactions. SF-1 is expressed primarily in steroidogenic tissues, LRH-1 in tissues of endodermal origin and the gonads. Both receptors modulate cholesterol homeostasis, steroidogenesis, tissue-specific cell proliferation, and stem cell pluripotency. LRH-1 is essential for development beyond gastrulation and SF-1 for genesis of the adrenal, sexual differentiation, and Leydig cell function. Ovary-specific depletion of SF-1 disrupts follicle development, while LRH-1 depletion prevents ovulation, cumulus expansion, and luteinization. Uterine depletion of LRH-1 compromises decidualization and pregnancy. In humans, SF-1 is present in endometriotic tissue, where it regulates estrogen synthesis. SF-1 is underexpressed in ovarian cancer cells and overexpressed in Leydig cell tumors. In breast cancer cells, proliferation, migration and invasion, and chemotherapy resistance are regulated by LRH-1. In conclusion, the NR5A orphan nuclear receptors are nonredundant factors that are crucial regulators of a panoply of biological processes, across multiple reproductive tissues.
In the ovary, the follicular granulosa cells express the nuclear receptor Nr5a2 (nuclear receptor subfamily 5 group A member 2), also known as liver receptor homolog-1, and after ovulation, Nr5a2 expression persists in the corpus luteum. Previous studies demonstrated that Nr5a2 is required for both ovulation and luteal steroid synthesis. Our objectives were to analyze the temporal sequence in the regulatory effects of Nr5a2 in the ovary, with focus on its contribution to luteal function. We developed a female mouse model of granulosa-specific targeted disruption from the formation of the antral follicles forward (genotype Nr5a2(Cyp19-/-)). Mice lacking Nr5a2 in granulosa cells of antral follicles are infertile. Although their cumulus cells undergo expansion after gonadotropin stimulation, ovulation is disrupted in those mice, at least in part, due to the down-regulation of the progesterone receptor (Pgr) gene. The depletion of Nr5a2 in antral follicles permits formation of luteal-like structures but not functional corpora lutea, as evidenced by reduced progesterone levels and failure to support pseudopregnancy. Progesterone synthesis is affected by depletion of Nr5a2 due to, among others, defects in the transport of cholesterol, evidenced by down-regulation of Scarb1, Ldlr, and Star. Comparison of this mouse line with the models in which Nr5a2 is depleted from the primary follicle forward (genotype Nr5a2(Amhr2-/-)) and after the ovulatory signal (genotype Nr5a2(Pgr-/-)) demonstrates that Nr5a2 differentially regulates female fertility across the trajectory of follicular development.
Obesity reaches an epidemic level worldwide, and this condition is associated with chronic low-grade inflammation and secondary comorbidities, largely driven by global changes in lifestyle and diet. Various dietary approaches are proposed for the obesity treatment and its associated metabolic disorders. Good taste, antioxidant functions, and vitamins have been attributed to virgin coconut oil (VCO). However, VCO contains a large amount of saturated fatty acids, and the consumption of this fat is associated with a number of secondary diseases. We evaluate the effects of VCO supplementation on biochemical, inflammatory, and oxidative stress parameters in rats fed with high-fat diet (HFD). After feeding with HFD for 12 weeks, the animals were supplemented with VCO for 30 days. HFD+VCO group increased in diet intake, weight gain, low-density lipoprotein cholesterol level, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. These findings were accompanied by increased in hepatic lipid profile and fat deposition in the liver. Adipocyte hypertrophy was observed in the HFD+VCO group, which was associated with elevated expression of tumor necrosis factor alpha (TNF-a) in adipose tissue. These results revealed that VCO associated with HFD induced important metabolic alterations, adipose inflammation, and hepatic lipid accumulation in rats.
This article is available online at http://www.jlr.org augmentation of the supply is by importation of lipoprotein-bound cholesterol ( 1 ). Low-density lipoproteins enter cells by receptor-mediated endocytosis of the LDL complex and the LDL receptor (LDLR) ( 2 ). High-density lipoproteins interact with a membrane protein known as scavenger receptor-B1 (SCARB1) to effect the selective uptake of cholesterol esters from the HDL molecule into cells and the bidirectional transfer of free cholesterol ( 3 ). The relative contribution of LDL and HDL to the steroidogenic substrate pool varies among species and may vary among tissues within a species. One of the most active steroidogenic tissues is the corpus luteum (CL), formed from the components of the follicle following ovulation ( 4 ). In humans, circulating LDL is believed to be the major source of cholesterol for luteal steroid synthesis, but it has been shown that luteinized human granulosa cells can derive cholesterol esters from selective uptake via the HDL pathway ( 5 ). The HDL pathway appears to predominate in the CL of rodents ( 1 ), and SCARB1 is expressed in theca and luteal cells of the rat ovary ( 6 ). SCARB1 expression in primary cultures of rat granulosa cells is tightly coupled with the uptake of cholesterol esters, again suggesting that it is the major pathway for importation in this tissue ( 7 ). There is a low level of expression of SCARB1 in mouse granulosa cells ( 8 ), and recent studies of luteinization in the pig demonstrated similar low expression of SCARB1 in the granulosa cells of the follicle ( 9 ). The latter study revealed extensive upregulation of SCARB1 in the CL following ovulation, with a high level of expression persisting through the luteal phase. In the macaque, the ovulatory stimulus causes a rapid increase in expression of both SCARB1 and LDLR, but only LDL can augment steroidogenesis after 24 h in vitro ( 10 ). The cholesterol substrate required for most tissues to accomplish steroidogenesis exceeds the capacity for de novo synthesis of this sterol, and the principal means of Abstract
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