Disease relevance of Pcho1

• Unlike the human apo CII (HuCII)- and apo CIII (HuCIII)-transgenic mouse models of hypertriglyceridemia, plasma cholesterol was disproportionately elevated (95 +/- 23 vs 73 +/- 23, P = 0.002, fasted and 90 +/- 24 vs 61 +/- 14, P < 0.0001, fed) [1].
• Coincidence of genetic loci for plasma cholesterol levels and obesity in a multifactorial mouse model [2].
• In the present report we describe a patient with multiple myeloma and long-standing paraproteinemia who developed xanthoma in the absence of an elevation in plasma cholesterol or triglyceride concentrations [3].
• This progression to advanced lesions is largely dependent on diabetes-induced dyslipidemia, because hyperlipidemic diabetic and nondiabetic mice with similar plasma cholesterol levels show a similar extent of atherosclerosis [4].
• The confounding variables of body weight, plasma cholesterol, and monocyte differential, which were all affected by op genotype, had no significant additional effect on lesion area once they were adjusted for the effects of op genotype and gender [5].

Psychiatry related information on Pcho1

• Whether or not changes in the plasma cholesterol concentration alter sterol metabolism in the CNS or whether such changes affect cognitive function in the brain or the incidence of dementia remain uncertain at this time [6].
• CONCLUSIONS: Our results show that the combination of loss of apoE function with high plasma cholesterol and especially brain injury results in dramatic BBB defects in the cortex and may explain in part the importance of apoE in Alzheimer's disease and in successful recovery from brain injury [7].

High impact information on Pcho1

• Hepatocyte nuclear factor-1alpha is an essential regulator of bile acid and plasma cholesterol metabolism [8].
• On a low fat, low cholesterol chow diet these animals have plasma cholesterol levels of 494 mg/dl compared with 60 mg/dl in control animals, and when challenged with a high fat Western-type diet, these animals have plasma cholesterol levels of 1821 mg/dl compared with 132 mg/dl in controls [9].
• Supplementation with vitamin E significantly reduced isoprostane generation, but had no effect on plasma cholesterol levels in apoE-/- mice [10].
• The TMX-treated mice had 11% +/- 5% less total plasma cholesterol, with most of the reduction in the high density lipoprotein fraction, whereas plasma triglycerides were significantly elevated, and circulating concentrations of 17 beta-estradiol and testosterone were unaffected [11].
• In healthy individuals, acute changes in cholesterol intake produce modest changes in plasma cholesterol levels [12].

Chemical compound and disease context of Pcho1

• Fractalkine-deficient B6.ApoE(-/-) mice were comparable with controls in body weight, plasma cholesterol, plasma high-density lipoprotein cholesterol and white blood cell counts [13].
• Dietary sphingolipids lower plasma cholesterol and triacylglycerol and prevent liver steatosis in APOE*3Leiden mice [14].
• Western-type diets induce insulin resistance and hyperinsulinemia in LDL receptor-deficient mice but do not increase aortic atherosclerosis compared with normoinsulinemic mice in which similar plasma cholesterol levels are achieved by a fructose-rich diet [15].
• 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors have been clinically used for lowering plasma cholesterol levels, and are known to induce various forms of skeletal muscle abnormalities including myopathy and rhabdomyolysis [16].
• In both treatments, while BM-573 did not affect body weight, systolic blood pressure, total plasma cholesterol or triglycerides levels, it partially reduced TxA(2) but did not affect prostacyclin biosynthesis [17].

Biological context of Pcho1

• Similar elevations of total plasma cholesterol occurred in both the apo E knockout and apo E knockout mice also expressing the human apo AI transgene [18].
• Thus, chronic ETA receptor blockade normalizes NO-mediated endothelial dysfunction and reduces atheroma formation independent of plasma cholesterol and blood pressure in a mouse model of human atherosclerosis [19].
• ACAT2 deficiency in the apoE-deficient background also led to a compensatory increase in the activity of lecithincholesterol acyltransferase, the major plasma cholesterol esterification enzyme, which increased high-density lipoprotein cholesterol esters [20].
• The increase in plasma cholesterol caused by apoE2 is due mostly to impaired clearance, whereas the increase in plasma triglycerides is caused mainly by apoE2-impaired lipolysis of triglyceride-rich lipoproteins [21].
• This is confirmed by the phenotype of ApoE-deficient mice that have high plasma cholesterol levels and spontaneously develop atherosclerotic lesions [22].

Anatomical context of Pcho1

• The mutant mice had five times normal plasma cholesterol, and developed foam cell-rich depositions in their proximal aortas by age 3 months [23].
• In contrast, the plasma cholesterol and phospholipid concentration in Mdr2(-)/- mice decreased upon bile duct ligation, and plasma fractionation revealed a complete absence of LpX [24].
• Three weeks after bone marrow transplantation, apoE was expressed from arterial macrophages and was detectable in plasma associated with lipoproteins at 0.5% to 1% of normal levels but did not affect plasma cholesterol levels [25].
• Genetic alterations of IL-1 receptor antagonist in mice affect plasma cholesterol level and foam cell lesion size [26].
• This higher expression of the 7alpha- and 12alpha-hydroxylase genes resulted in a 33% higher bile acid pool in their gallbladders, bile more enriched in cholic acid, and a 13% decrease in plasma cholesterol levels [27].

Associations of Pcho1 with chemical compounds

• Their plasma cholesterol and triglyceride levels are both twice to three times those in (normolipidemic) mice that are expressing human apoE3 (3/3) made in an identical manner [28].
• Our data indicate that a reduction in plasma cholesterol caused by probucol does not necessarily lead to an antiatherogenic effect [29].
• Reduced plasma cholesterol and increased fecal sterol loss in multidrug resistance gene 2 P-glycoprotein-deficient mice [30].
• In-vivo and cell-culture experiments have shown that lowering the plasma cholesterol concentration or intervening in the mevalonate pathway with 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitors decreases tumour growth [31].
• RESULTS: Abcg5 deficiency was associated with strongly elevated plasma levels of beta-sitosterol (37-fold) and campesterol (7.7-fold) as well as reduced plasma cholesterol concentrations (-40%) [32].

Regulatory relationships of Pcho1

• Because leptin administration to rodents promotes the biliary elimination of plasma cholesterol, this study was designed to elucidate a pathophysiological role for leptin during the development of obesity [33].
• Low levels of transgenic mouse apolipoprotein E (apoE) suppress atherosclerosis in apoE knockout (apoE-/-) mice without normalizing plasma cholesterol [34].
• In chow-fed mice, neither plasma cholesterol concentrations nor the concentrations and compositions of plasma phospholipids were influenced by PC-TP expression [35].
• The mouse CCR2 gene is regulated by two promoters that are responsive to plasma cholesterol and peroxisome proliferator-activated receptor gamma ligands [36].
• Ezetimibe is the first in class 2-azetidinone that decreases plasma cholesterol by blocking intestinal cholesterol absorption [37].

Other interactions of Pcho1

• In contrast, E2 treatment of ovariectomized alphaalphaee females caused minimal reduction in lesion size and no reduction in total plasma cholesterol compared with alphaalphaee mice without E2, demonstrating that ERalpha is a major mediator of the atheroprotective effect of E2 [38].
• On a normal chow diet, apoE(-/-) mice had higher mean plasma cholesterol levels than LDLR(-/-) mice (579 vs. 268 mg/dl) [39].
• Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9 [40].
• On a high-fat diet, the Mttp+/- mice exhibited a marked reduction in total plasma cholesterol levels, compared with those in Mttp+/+ mice [41].
• These results challenge the notion that dietary cholesterol regulation of Cyp7a1 is a major determinant of plasma cholesterol responsiveness [42].

Analytical, diagnostic and therapeutic context of Pcho1

• They showed no difference in plasma cholesterol levels and lipoprotein profile from controls when fed both normal and atherogenic diets [43].
• Bile duct ligation of Mdr2(+)/+ mice induced a dramatic increase in the plasma cholesterol and phospholipid concentration [24].
• Intravenous injection of recombinant virus acutely lowered plasma cholesterol levels and increased the rate of 125I-labeled LDL clearance from the circulation in normal mice [44].
• Mice homozygous for the disrupted gene have no plasma apolipoprotein A-I detectable by double immunodiffusion; their total plasma cholesterol and HDL-cholesterol levels after overnight fasting are reduced to about one-third and one-fifth of normal levels, and they are grossly deficient in alpha-migrating HDL particles [45].
• After an additional 14 weeks on a low-fat diet, plasma cholesterol levels decreased from 21.0 +/- 2.6 to 8.4 +/- 0.6 mmol/L, but lesions did not regress [46].

References