Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The epsilon4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). The mechanism underlying this increased risk is not completely clear, yet mounting evidence supports the idea that the ability of apoE to interact with the amyloid-beta (Abeta) peptide and influence its conformation and clearance plays a major role. Evidence to support this concept comes from in vitro and in vivo studies of apoE/Abeta interactions and the effects of these interactions on Abeta conformation and cellular clearance. Recent studies on the effect of murine and human apoE in APP transgenic mice provide direct evidence that apoE is critically involved in the in vivo converstion of Abeta into forms which contain high 5-sheet content and associated cellular toxicity (neuritic plaques and CAA). These studies also suggest a role for human apoE in Abeta clearance in vivo.
J Mol Neurosci 2001 Oct
PMID:Role of apoe/Abeta interactions in the pathogenesis of Alzheimer's disease and cerebral amyloid angiopathy. 1181 88

We generated aromatase gene knockout mice (ArKO mice) by targeting disruption of Cyp19, which encodes an enzyme responsible for conversion of androgens to estrogens. We found that ArKO males developed hepatic steatosis spontaneously with aging, indicating that the function of Cyp19 is required to maintain constitutive lipid metabolism in male mice. Plasma lipoprotein analysis using a gel permeation chromatography revealed that high density lipoprotein (HDL)-cholesterol levels were slightly higher in ArKO males than in wild-type males, whereas no other obvious alternations in the profiles were detected. Nevertheless, analysis of lipoprotein compositions by SDS-polyacrylamide gel electrophoresis demonstrated apparent reduction in the amounts of apolipoprotein E, functioning in receptor-mediated clearance of lipoproteins in the liver, in the IDL/LDL fraction of ArKO males as compared with that of wild-type males. Biochemical analysis on the ArKO livers revealed suppression of mRNA expression and activity of enzymes involved in fatty acid beta-oxidation. The impairment was reversed to the wild-type levels by treatment with 17beta-estradiol or bezafibrate, the latter is a synthetic peroxisome proliferator. These findings indicated a pivotal role of estrogen in supporting constitutive hepatic expression of genes involved in fatty acid beta-oxidation and in maintaining lipid homeostasis.
J Steroid Biochem Mol Biol 2001 Dec
PMID:Alternations in hepatic expression of fatty-acid metabolizing enzymes in ArKO mice and their reversal by the treatment with 17beta-estradiol or a peroxisome proliferator. 1185 Feb 2

The liver X receptors (LXRs), members of the nuclear receptor superfamily, play an important role in controlling lipid homeostasis by activating several genes involved in reverse cholesterol transport. These include members of the ATP binding cassette (ABC) superfamily of transporter proteins ABCA1 and ABCG1, surface constituents of plasma lipoproteins like apolipoprotein E, and cholesterol ester transport protein. They also play an important role in fatty acid metabolism by activating the sterol regulatory element-binding protein 1c gene. Here, we identify human LXRalpha (hLXRalpha) as an autoinducible gene. Induction in response to LXR ligands is observed in multiple human cell types including macrophages and occurs within 2--4 h. Analysis of the hLXRalpha promoter revealed three LXR response elements (LXREs); one exhibits strong affinity for both LXRalpha:RXR and LXRbeta:RXR (a type I LXRE), and deletion and mutational studies indicate it plays a critical role in LXR-mediated induction. The other two LXREs are identical to each other, exist within highly conserved Alu repeats, and exhibit selective binding to LXRalpha:RXR (type II LXREs). In transfections, the type I LXRE acts as a strong mediator of both LXRalpha and LXRbeta activity, whereas the type II LXRE acts as a weaker and selective mediator of LXRalpha activity. Our data suggest a model in which LXR ligands trigger an autoregulatory loop leading to selective induction of hLXRalpha gene expression. This would lead to increased hLXRalpha levels and transcription of its downstream target genes such as ABCA1, providing a simple yet exquisite mechanism for cells to respond to LXR ligands and cholesterol loading.
Mol Endocrinol 2002 Mar
PMID:Induction of human liver X receptor alpha gene expression via an autoregulatory loop mechanism. 1187 9

Disruption of the peroxisome proliferator-activated receptor gamma (PPAR gamma) gene causes embryonic lethality due to placental dysfunction. To circumvent this, a PPAR gamma conditional gene knockout mouse was produced by using the Cre-loxP system. The targeted allele, containing loxP sites flanking exon 2 of the PPAR gamma gene, was crossed into a transgenic mouse line expressing Cre recombinase under the control of the alpha/beta interferon-inducible (MX) promoter. Induction of the MX promoter by pIpC resulted in nearly complete deletion of the targeted exon, a corresponding loss of full-length PPAR gamma mRNA transcript and protein, and marked reductions in basal and troglitazone-stimulated expression of the genes encoding lipoprotein lipase, CD36, LXR alpha, and ABCG1 in thioglycolate-elicited peritoneal macrophages. Reductions in the basal levels of apolipoprotein E (apoE) mRNA in macrophages and apoE protein in total plasma and high-density lipoprotein (HDL) were also observed in pIpC-treated PPAR gamma-MXCre(+) mice. Basal cholesterol efflux from cholesterol-loaded macrophages to HDL was significantly reduced after disruption of the PPAR gamma gene. Troglitazone selectively inhibited ABCA1 expression (while rosiglitazone, ciglitazone, and pioglitazone had little effect) and cholesterol efflux in both PPAR gamma-deficient and control macrophages, indicating that this drug can exert paradoxical effects on cholesterol homeostasis that are independent of PPAR gamma. Together, these data indicate that PPAR gamma plays a critical role in the regulation of cholesterol homeostasis by controlling the expression of a network of genes that mediate cholesterol efflux from cells and its transport in plasma.
Mol Cell Biol 2002 Apr
PMID:Conditional disruption of the peroxisome proliferator-activated receptor gamma gene in mice results in lowered expression of ABCA1, ABCG1, and apoE in macrophages and reduced cholesterol efflux. 1190 55

Increased production of reactive oxygen and nitrogen species has recently been implicated in the pathogenesis of endothelial dysfunction associated with atherosclerosis, hypertension and aging. Oxidant induced cell injury triggers the activation of nuclear enzyme poly(ADP-ribose) polymerase (PARP), which in turn contributes to cardiac and vascular dysfunction in various pathophysiological conditions including diabetes, reperfusion injury and circulatory shock. Here we investigated the role of PARP activation in the pathogenesis of cardiac and endothelial dysfunction associated with atherosclerosis, hypertension and aging. Retired breeder spontaneously hypertensive rats (SHR, 40 weeks old) and apolipoprotein E knockout mice (apoE-Ko, 10 weeks old) were treated for 20 weeks with vehicle or the potent PARP inhibitor PJ34. In the vehicle-treated SHR rats and apoE-Ko mice (kept on atherogenic diet) there was a significant loss of endothelial function, as measured by the relaxant responsiveness of vascular rings to acetylcholine. SHR rats also developed severe hypertension and cardiac hypertrophy. Treatment with the PARP inhibitor did not influence high blood pressure and cardiac hypertrophy in SHR rats, but it improved Ach-induced, NO-mediated vascular relaxation. In addition to the beneficial effects of chronic treatment with PARP inhibitor, 1-h in vitro incubation of aortic rings from SHR rats with PJ34 (3 micromol/l) was also able to improve the endothelial dysfunction. In contrast, in apoE-Ko mice PJ34 treatment did not affect the parameters studied. Thus, PARP activation contributes to the pathogenesis of endothelial dysfunction associated with hypertension and aging, but not in the current experimental model of atherosclerosis.
Int J Mol Med 2002 Jun
PMID:Activation of poly(ADP-ribose) polymerase contributes to the endothelial dysfunction associated with hypertension and aging. 1201 85

We studied the association between common haplotypes in six relevant lipid metabolism genes with plasma lipid levels. We selected single-nucleotide polymorphisms (SNPs) in the cholesterol ester transfer protein (CETP), lipoprotein lipase (LPL), hepatic triglyceride lipase (HL), low-density lipoprotein cholesterol receptor (LDLR), apolipoprotein E (ApoE) and lecithin-cholesterol acyltransferase (LCAT) genes, and studied 732 individuals from 184 German families. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) were similar to those reported in other European and American populations. Haplotypes derived from SNP combinations resulted in more significance and of a higher degree than did single SNPs in the genotype-phenotype association analysis. Reduction of the polygenic variance attributable to haplotypes was estimated using variance components analysis. Under the biometrical genetic model, allelic association of haplotypes was highly significant for HDL, LDL and the LDL/HDL ratio. The residual kinship correlation was reduced accordingly. The ApoE gene had a strong effect on trait variation; however, the other genes also contributed substantially. An epistatic interaction could not be demonstrated in this sample. The data are consistent with the notion that common genetic variants influence common traits.
Hum Mol Genet 2002 Jun 01
PMID:Common haplotypes in five genes influence genetic variance of LDL and HDL cholesterol in the general population. 1202 90

Alzheimer's disease (AD) is a complex neurodegenerative disorder with multiple etiologies. The presence of the E4 isoform of apolipoprotein E (apoE) has been shown to increase the risk and to decrease the age of onset for AD and is the major susceptibility factor known for the disease. ApoE4 has been shown to intensify all the biochemical disturbances characteristic of AD, including beta amyloid (Abeta) deposition, tangle formation, neuronal cell death, oxidative stress, synaptic plasticity and dysfunctions of lipid homeostasis and cholinergic signalling. In contrast, other apoE isoforms are protective. Here we review and discuss these major hypotheses of the apoE4-AD association.
J Cell Mol Med
PMID:Apolipoprotein E: a major piece in the Alzheimer's disease puzzle. 1206 84

We examined whether administration of very low-density lipoproteins (VLDL) to pregnant rats increases surfactant phosphatidylcholine (PtdCho) content in fetal pre-type II alveolar epithelial cells. VLDL-triglycerides are hydrolyzed to fatty acids by lipoprotein lipase (LPL), an enzyme activated by heparin. Fatty acids released by LPL can incorporate into the PtdCho molecule or activate the key biosynthetic enzyme cytidylyltransferase (CCT). Dams were given BSA, heparin, VLDL, or VLDL with heparin intravenously. Radiolabeled VLDL given to the pregnant rat crossed the placenta and was distributed systemically in the fetus and incorporated into disaturated PtdCho (DSPtdCho) in pre-type II cells. Maternal administration of VLDL with heparin increased DSPtdCho content in cells by 45% compared with control (P < 0.05). VLDL produced a dose-dependent, saturable, and selective increase in CCT activity. VLDL did not significantly alter immunoreactive CCT content but increased palmitic, stearic, and oleic acids in pre-type II cells. Furthermore, hypertriglyceridemic apolipoprotein E knockout mice contained significantly greater levels of DSPtdCho content in alveolar lavage and CCT activity compared with either LDL receptor knockout mice or wild-type controls that have normal serum triglycerides. Thus the nutritional or genetic modulation of serum VLDL-triglycerides provides specific fatty acids that stimulate PtdCho synthesis and CCT activity thereby increasing surfactant content.
Am J Physiol Lung Cell Mol Physiol 2002 Aug
PMID:Maternal loading with very low-density lipoproteins stimulates fetal surfactant synthesis. 1211 92

The low density lipoprotein receptor-related protein (LRP) is a multifunctional receptor which is present on senile plaques in Alzheimer's disease (AD). It is suggested to play an important role in the balance between amyloid beta (Abeta) synthesis and clearance mechanisms. One of its ligands, apolipoprotein E (apoE), is also present on senile plaques and has been implicated as a risk factor for AD, potentially affecting the deposition, fibrillogenesis and clearance of Abeta. Using immunohistochemistry we show that LRP was present only on cored, apoE-containing senile plaques, in both PDAPP transgenic mice and human AD brains. We detected strong LRP staining in neurons and in reactive astrocytes, and immunostaining of membrane-bound LRP showed colocalization with fine astrocytic processes surrounding senile plaques. LRP was not present in plaques in young transgenic mice or in plaques of APOE-knockout mice. As LRP ligands associated with Abeta deposits in AD brain may play an important role in inducing levels of LRP in both neurons and astrocytes, our findings support the idea that apoE might be involved in upregulation of LRP (present in fine astrocytic processes) and act as a local scaffolding protein for LRP and Abeta. The upregulation of LRP would allow increased clearance of LRP ligands as well as clearance of Abeta/ApoE complexes.
Brain Res Mol Brain Res 2002 Jul 15
PMID:LRP and senile plaques in Alzheimer's disease: colocalization with apolipoprotein E and with activated astrocytes. 1211 49

The accurate clinical diagnosis of Alzheimer's disease can only be made with a high degree of certainty in specialized centres. The identification of predictive or diagnostic genetic factors may improve accuracy of disease prediction or diagnosis. One major genetic risk factor, the epsilon4 allele of the apolipoprotein E gene, is universally recognised. We have recently shown that the A allele of the apolipoprotein E, -491A/T promoter polymorphism is also an important risk factor for Alzheimer's disease in an Australian population. We designed the present study to investigate the association between apolipoprotein E genotype, -491A/T polymorphism, plasma apoE levels and the subjective experience of memory decline among 98 subjects and 49 age, gender and education-matched normal controls. An increased frequency of the epsilon4 allele of apolipoprotein E was significantly associated with the 'memory complainers' group (OR = 2.35, P = 0.02) as was the A allele of the -491A/T polymorphism (OR = 2, P = 0.02). Among all subjects, only seven individuals were homozygous for both of these alleles, and six of these seven individuals belonged to the 'memory complainers' group. This sub-group also had relatively elevated plasma apolipoprotein E levels (P < 0.01) and tended to score lower on the Mini-Mental State Examination (MMSE) and Cambridge Cognition Test. These data suggest that the epsilon4 allele of apolipoprotein E and the -491A allele are over-represented among individuals who complain of memory difficulties. Follow-up studies should clarify whether these genotypes and phenotypes are useful in the prediction and/or diagnosis of Alzheimer's disease.
Mol Psychiatry 2002
PMID:APOE-epsilon4 and APOE -491A polymorphisms in individuals with subjective memory loss. 1219 21


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