Endothelial cell dysfunction or activation elicited by oxidatively modified low density lipoprotein (Ox-LDL) has been
implicated in the pathogenesis of atherosclerosis. Vascular endothelial cells internalize and degrade Ox-LDL through a
putative receptor-mediated pathway that does not involve macrophage scavenger receptors. To identify
genes encoding Ox-LDL receptors, Sawamura et al. (1997) transfected mammalian cells with a cDNA expression library
derived from bovine aortic endothelial cells and assayed for uptake of labeled Ox-LDL. They recovered a cDNA encoding
an Ox-LDL receptor, which they designated lectin-like Ox-LDL receptor-1 (LOX1). Immunofluorescence studies showed that
bovine LOX1 is expressed on the cell surface. Northern blot analysis revealed
that human LOX1 is expressed as a 2.8-kb mRNA in various tissues, with the most abundant expression in placenta.
NCBI Summary:
This gene encodes a low density lipoprotein receptor that belongs to the C-type lectin superfamily. This gene is regulated through the cyclic AMP signaling pathway. The encoded protein binds, internalizes and degrades oxidized low-density lipoprotein. This protein may be involved in the regulation of Fas-induced apoptosis. This protein may play a role as a scavenger receptor. Mutations of this gene have been associated with atherosclerosis, risk of myocardial infarction, and may modify the risk of Alzheimer's disease. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Feb 2010]
General function
Receptor, Cell death/survival, Apoptosis
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Cellular localization
Plasma membrane
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Ovarian function
Steroid metabolism, Luteinization
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Inactivation of the LOX-1 pathway promotes the Golgi apparatus during cell differentiation of mural granulosa cells. Weitzel JM 2014 et al.
In female mammals, granulosa cells of the ovarian follicle differentiate into the corpus luteum after ovulation of the pregnable oocyte into the fallopian tube. During these differentiation processes several morphological alterations have to occur and the molecular basis is not fully understood. As an endpoint estradiol production from granulosa cells has to switch off in favor for progesterone production from the proceeding corpus luteum to sustain the developing embryo. Previously, we demonstrated that the multiligand receptor LOX-1 plays a critical role in steroid hormone synthesis of granulosa cells via intracellular calcium release from endoplasmic (ER)-dependent and ER-independent calcium pools. In the present study, we show that inhibition of LOX-1 leads to a rearrangement of ceramide from the basal membrane toward the Golgi apparatus. This activity is accomplished by a calcium-dependent phosphorylation of aromatase, the key step in estradiol production. Phosphorylated aromatase increased estradiol production in a dose-dependent manner. Our data indicate that the ceramide cascade is essential for proper granulosa cell function and ceramide redistribution serves as a first step in order to proceed with the prosperous differentiation into a corpus luteum. J. Cell. Physiol. 2014 Wiley Periodicals, Inc.
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LOX-1
is a receptor specific for Ox-LDL, and enhanced uptake of Ox-LDL via this novel receptor on
vascular endothelial cells may play an important role in endothelial activation in atherogenesis (Kume et al 1998) .
PMID: 21595015
Expression regulated by
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Ovarian localization
Granulosa
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Resveratrol and desferoxamine protect human oxLDL-treated granulosa cell subtypes from degeneration. Schube U 2013 et al.
Context: Obese women suffer from anovulation and infertility, which are driven by oxidative stress caused by increased levels of lipid peroxides and circulating oxidised low-density lipoprotein (oxLDL). OxLDL binds to lectin-like oxLDL receptor 1 (LOX-1), CD36, and toll-like receptor 4 (TLR4) and causes cell death in human granulosa cells (GCs). Objective: To reveal whether treatment with antioxidants: resveratrol (RES) and/or desferoxamine (DFO) protect GCs from oxLDL-induced damage. Design and Setting: Basic research at the Institute of Anatomy and the Clinic of Reproductive Medicine. Patients: Women undergoing in vitro fertilization (IVF) therapy. Main Outcome Measures: Granulosa cell cultures were treated with oxLDL alone or with resveratrol (RES) or desferoxamine (DFO) under serum-free conditions for up to 36 h. Dead cells were determined by propidium iodide uptake, cleaved caspase-3 expression, and electron microscopy. Mitosis was detected by Ki-67 immunostaining. LOX-1, TLR4, CD36 and Hsp60 were examined by Western blots. Measurement of oxidative stress markers (8-iso-PGF2a, advanced glycation end products, protein carbonyl-content) was conducted by ELISA-Kits. Results: Different subtypes of human GCs exposed to RES or DFO were protected as evidenced by lack of cell death, enhanced mitosis, reduced expression of LOX-1, TLR4, CD36, and Hsp-60, induction of protective autophagy, and reduction of oxidative stress markers. Importantly, RES could restore steroid-biosynthesis in cytokeratin-positive GCs which exhibited significant induction of steroidogenic acute regulatory protein. Conclusions: RES and DFO exert a protective effect on human GCs. Thus, RES and DFO may help improving the treatment of obese women or PCOS patients undergoing IVF-therapy.
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The variable expression of lectin-like oxidized low-density lipoprotein receptor (LOX-1) and signs of autophagy and apoptosis in freshly harvested human granulosa cells depend on gonadotropin dose, age, and body weight. Vilser C et al. OBJECTIVE: To extend our recent observations on lectin-like oxidized low-density lipoprotein receptor (LOX-1) expression in human granulosa cell cultures with freshly harvested granulosa cells. DESIGN: Clinical research. SETTING: Institute of Anatomy and Clinic for Reproductive Medicine. PATIENT(S): Women undergoing IVF therapy were classified by total FSH dose, age, and body mass index. MAIN OUTCOME MEASURE(S): Purified granulosa cells were studied by Western blot and morphology for the presence of LOX-1, microtubule-associated light-chain protein 3 (LC3) and autophagosomes, which are both autophagic markers, cleaved caspase-3 for apoptosis, and apoptosis-inducing factor (AIF) for caspase-independent apoptosis. INTERVENTION(S): None. RESULTS: Active LOX-1 was found in all samples, being at its maximum in the younger obese group with a total FSH dose <2,000 IU. The LC3 II/LC3 I ratio, indicative of reparative autophagy, was at its maximum in younger normal-weight patients and increased under total FSH dose >2,000 IU. Autophagosomes in ultrathin sections were indicative of reparative autophagy. Cleaved caspase-3 was absent in all groups. The apoptotic AIF form was up-regulated in older patients. Unpurified granulosa cells consisted of approximately 20% dead cells in the younger normal-weight group compared with up to 50% in the older obese group. CONCLUSION(S): The regulation of LOX-1 and of cell death in granulosa cells depends on oxidative stress. It becomes excessive during aging and obesity, because the power of reparative autophagy fades and antioxidant efficiency declines.
Follicle stages
Comment
LOX-1 Receptor Mediated Autophagy in Human Granulosa Cells as an Alternative of Programmed Cell Death. Duerrschmidt N et al. The LOX-1 receptor, identified on endothelial cells, mediates the uptake of oxLDL (oxidized low-density lipoprotein). The oxLDL dependent LOX-1 activation causes endothelial cell apoptosis. We here investigated the presence of LOX-1 in granulosa cells from patients under in vitro fertilization (IVF) therapy. We were interested in the oxLDL dependent LOX-1 receptor biology, in particular in the induction of apoptosis. In the human ovary, LOX-1 was localized in regressing antral follicles. In granulosa cell cultures, oxLDL induced mRNA expression of LOX-1 in a time- and dose-dependent manner. The LOX-1 inhibitors (anti-LOX-1 antibody and kappa-carrageenan) abrogated the up-regulation of LOX-1. The oxLDL (100 microg/ml) treatment caused the autophagy form of programed cell death: (1) reorganisation of the actin cytoskeleton at the 6-h-time point, (2) uptake of YO-PRO(c), a marker for the early step of programed cell death, before propidium iodide (PI) staining to signify necrosis, (3) absence of apoptotic bodies and of cleaved caspase-3, (4) abundant vacuole formation at the ultrastructural level, (5) decrease of the autophagosome marker protein MAP LC3-I at the 6-h-time point indicative of autophagosome formation. We conclude: Follicular atresia is not under the exclusive control of apoptosis. The LOX-1-dependent autophagy represents an alternate form of programed cell death. Obese women with high blood levels of oxLDL may display an increased rate of autophagic granulosa cell death.