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Low Density Lipoprotein Receptor OKDB#: 841
 Symbols: LDLR Species: human
 Synonyms: FHC, FH| HYPERLIPOPROTEINEMIA, TYPE IIA| LDL RECEPTOR DISORDER| LOW DENSITY LIPOPROTEIN RECEPTOR, INCLUDED, LDLR, INCLUDED|  Locus: 19p13.2 in Homo sapiens
HPMR

For retrieval of Nucleotide and Amino Acid sequences please go to: OMIM Entrez Gene
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General Comment Russell, D. W et al isolated the cDNA for LDL receptor and showed its sequence homology with the epidermal growth factor precursor.
NCBI Summary: The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. Low density lipoprotein (LDL) is normally bound at the cell membrane and taken into the cell ending up in lysosomes where the protein is degraded and the cholesterol is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia.
General function Receptor
Comment
Cellular localization Plasma membrane
Comment
Ovarian function Steroid metabolism, Luteinization
Comment Tandeski TR, et al reported regulation of mRNA encoding low density lipoprotein receptor and high density lipoprotein-binding protein in ovine corpora lutea. Reaven E et al examined the development of the LDL receptor over time in cultured rat granulosa cells. Unstimulated granulosa cells show posttranslational increases in receptor activity with time in culture, but transcriptional changes in receptor follow stimulation with hCG or its second messenger, cAMP.
Expression regulated by FSH, LH, Growth Factors/ cytokines
Comment Veldhuis JD. Et al reported that Follicle-stimulating hormone regulates low density lipoprotein metabolism by swine granulosa cells. Golos TG, et al reported the regulation of low density lipoprotein receptor gene expression in cultured human granulosa cells and roles of human chorionic gonadotropin, 8-bromo-3',5'-cyclic adenosine monophosphate, and protein synthesis. Chaffin CL et al reported that monkey granulosa cell concentrations of low density lipoprotein receptor (LDL-R) and steroidogenic acute regulatory protein (StAR) mRNA increased transiently 12 h following HCG administration (P < 0.05) at which time steroid depletion tended to reduce StAR mRNA (P = 0.06). At 36 h post-HCG progesterone suppressed the LDL-R mRNA levels (P < 0.05). P450 side-chain cleavage (P450scc) mRNA decreased in a time-dependent fashion up to 24 h, whereas 3 beta-HSD mRNA increased within 12 h of HCG administration (P < 0.05) in a steroid-independent manner. LaVoie HA, et al. reported concerted regulation of low density lipoprotein receptor gene expression by follicle-stimulating hormone and insulin-like growth factor I in porcine granulosa cells.
Ovarian localization Granulosa, Theca, Luteal cells
Comment Argov N, et al 2004 reported the expression of mRNA of lipoprotein receptor related protein 8, low density lipoprotein receptor, and very low density lipoprotein receptor in bovine ovarian cells during follicular development and corpus luteum formation and regression. Lipoproteins in the plasma are the major source of cholesterol obtained by the ovarian theca and granulosa cells for steroidogenesis. In this study, we have identified mRNA expression in bovine theca and granulosa cells of two lipoprotein receptors, low density lipoprotein receptor (LDLr) and very low density lipoprotein receptor (VLDLr) in granulosa cells from small antral follicles through preovulatory follicles and in theca cells from large and medium sized antral follicles. In the corpus luteum (CL) both these receptors were found in the developing and differentiating stages whereas only mRNA for VLDLr was detected in the regression stage. This study also described for the first time, the presence of lipoprotein receptor related protein (LRP8) in granulosa cells from small antral follicles through preovulatory follicles and in theca cells from large and medium sized antral follicles. This may indicate a role of LRP8 in cholesterol delivery to steriodogenic cells. LRP8 was not detected in any of the CL stages. The roles of the LDLr superfamily in lipid transport to ovarian cells and its participation in follicular and CL development and regression is discussed. Changes in mouse granulosa cell gene expression during early luteinization. McRae RS et al. Changes in gene expression during granulosa cell luteinization have been measured using serial analysis of gene expression (SAGE). Immature normal mice were treated with pregnant mare serum gonadotropin (PMSG) or PMSG followed, 48 h later, by human chorionic gonadotropin (hCG). Granulosa cells were collected from preovulatory follicles after PMSG injection or PMSG/hCG injection and SAGE libraries generated from the isolated mRNA. The combined libraries contained 105,224 tags representing 40,248 unique transcripts. Overall, 715 transcripts showed a significant difference in abundance between the two libraries of which 216 were significantly down-regulated by hCG and 499 were significantly up-regulated. Among transcripts differentially regulated, there were clear and expected changes in genes involved in steroidogenesis as well as clusters of genes involved in modeling of the extracellular matrix, regulation of the cytoskeleton and intra and intercellular signaling. The SAGE libraries described here provide a base for functional investigation of the regulation of granulosa cell luteinization.
Follicle stages Antral, Preovulatory, Corpus luteum
Comment
Phenotypes
Mutations 4 mutations

Species: human
Mutation name: None
type: naturally occurring
fertility: unknown
Comment: Familial hypercholesterolemia is an autosomal dominant disorder characterized by elevation of serum cholesterol bound to low density lipoprotein (LDL). Mutations in the LDL receptor (LDLR) gene on chromosome 19 cause this disorder. Hobbs et al. (1990) reviewed the many mutations found in the LDLR gene.

Species: mouse
Mutation name: None
type: null mutation
fertility: fertile
Comment: Ishibashi et al. (1993) developed a new animal model for homozygous FH through targeted disruption of the LDLR gene in mice. Homozygous LDL receptor-deficient mice showed delayed clearance of VLDL, intermediate density lipoproteins (IDL), and LDL from plasma. As a result, total plasma cholesterol level rose from 108 mg/dl in wildtype mice to 236 mg/dl in homozygous deficient mice. Adult mice did not exhibit gross evidence of xanthomatosis, however, and the extent of aortic atherosclerosis was minimal.

Species: rabbit
Mutation name: WHHL
type: naturally occurring
fertility: subfertile
Comment: The Watanabe heritable hyperlipidemic (WHHL) rabbit has a genetic deficiency of LDL receptors and is a superb experimental model (Hornick et al., 1983) . Robins ED et al showed, that the WHHL rabbit has a defective low density lipoprotein receptor and is a model for familial hypercholesterolemia. WHHL rabbits are less fecund than NZW rabbits, the strain into which the defect has been inbred. WHHL rabbit oocytes remained encased in cumulus and had a lowered fertilization rate (9/50 vs. 83/87, P < 0.05). WHHL rabbits had lower baseline estradiol levels (7.1 +/- 0.72 vs. 10.2 +/- 0.94, P < 0.05) and had higher baseline follicle stimulating hormone (P < 0.05) and luteinizing hormone (P < 0.05) levels. The hypothalamic-pituitary-ovarian axis in WHHL rabbits is abnormal. The reduced availability of intracellular cholesterol for progesterone synthesis by inhibition of de novo cholesterol biosynthesis leads to a significant reduction in plasma progesterone concentrations in the WHHL. These findings have implications for women with familial hypercholesterolemia, particularly regarding treatment with inhibitors of de novo cholesterol synthesis.

Species: rabbit
Mutation name: Watanabe heritable hyperlipidemic rabbit
type: naturally occurring
fertility: subfertile
Comment: The Watanabe heritable hyperlipidemic (WHHL) rabbit has a genetic deficiency of LDL receptors and is a superb experimental model (Hornick et al., 1983) . Robins ED et al showed, that the WHHL rabbit has a defective low density lipoprotein receptor and is a model for familial hypercholesterolemia. WHHL rabbits are less fecund than NZW rabbits, the strain into which the defect has been inbred. WHHL rabbit oocytes remained encased in cumulus and had a lowered fertilization rate (9/50 vs. 83/87, P < 0.05). WHHL rabbits had lower baseline estradiol levels (7.1 +/- 0.72 vs. 10.2 +/- 0.94, P < 0.05) and had higher baseline follicle stimulating hormone (P < 0.05) and luteinizing hormone (P < 0.05) levels. The hypothalamic-pituitary-ovarian axis in WHHL rabbits is abnormal. The reduced availability of intracellular cholesterol for progesterone synthesis by inhibition of de novo cholesterol biosynthesis leads to a significant reduction in plasma progesterone concentrations in the WHHL. These findings have implications for women with familial hypercholesterolemia, particularly regarding treatment with inhibitors of de novo cholesterol synthesis.

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created: Feb. 15, 2000, midnight by: Hsueh   email:
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last update: July 27, 2006, 3:23 p.m. by: Alex    email:



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