Disease relevance of Chol1

• Plasma cholesterol levels fell sharply, and microscopic analyses of gallbladder bile revealed cholesterol crystals as well as cholesterol gallstones [1].
• In situations of peripheral fat and cholesterol accumulation, such as obesity, these pathways may be overloaded, contributing to increased cholesterol deposition [2].
• Consistent with mobilization of stored cholesterol, cholesterol concentrations in adipose tissue remained unchanged during weight loss [1].
• We have previously shown that exposure of C57BL/6J mice to intermittent hypoxia (IH) leads to 1) hypertriglyceridemia due to upregulation of pathways of lipid biosynthesis, including sterol regulatory element binding protein (SREBP)-1 and stearoyl CoA desaturase (SCD)-1; and 2) hypercholesterolemia due to impaired cholesterol uptake [3].
• Chol1/NZO was not associated with elevated body weight, serum insulin, or hyperglycemia [4].

Psychiatry related information on Chol1

• Smith-Lemli-Opitz/RSH syndrome (SLOS), a relatively common birth-defect mental-retardation syndrome, is caused by mutations in DHCR7, whose product catalyzes an obligate step in cholesterol biosynthesis, the conversion of 7-dehydrocholesterol to cholesterol [5].
• Recent experimental and clinical retrospective studies support the view that reduction of brain cholesterol protects against Alzheimer's disease (AD) [6].
• In the search for an animal model of genetic determinants of cholesterol cholelithiasis, we found strain, gender and individual differences in mice [7].
• The aim of this study was to investigate the effect of moderate alcohol consumption on cholesterol efflux, using J774 mouse macrophages and Fu5AH cells, and on other parameters in the RCT pathway [8].
• Dietary modification of high density lipoprotein phospholipid and influence on cellular cholesterol efflux [9].

High impact information on Chol1

• Charting the fate of the "good cholesterol": identification and characterization of the high-density lipoprotein receptor SR-BI [10].
• Finally, because of the organizing potential of cholesterol in membranes, disturbances in cellular cholesterol transport have implications for a wide variety of human diseases, of which selected examples are given [11].
• Metabolites elevated in individuals with the metabolic syndrome and diabetes destabilize ABCA1 protein and decrease cholesterol export from macrophages [12].
• One of these factors is ATP-binding cassette transporter A1 (ABCA1), a cell membrane protein that mediates the transport of cholesterol, phospholipids, and other metabolites from cells to lipid-depleted HDL apolipoproteins [12].
• The high-affinity receptor state requires both Mg(2+) and cholesterol, which probably function as allosteric modulators [13].

Chemical compound and disease context of Chol1

• The high fat diet significantly increased serum cholesterol levels, but the fat content of the diet did not alter the absolute effect of Chol1/NZO.Conclusions: Chol1/NZO is a major susceptibility locus on the distal mouse chromosome 5, which produces gender-independent hypercholesterolemia in NZO mice [4].
• In contrast, CNTFAx15 treatment of db/db mice caused significantly greater weight loss and marked improvements in diabetic parameters (e.g., levels of glucose, insulin, triglyceride, cholesterol, and nonesterified free fatty acids) than could be accounted for by reduced caloric intake alone [14].
• These findings may provide an explanation for the observation that in conditions characterized by hyperglycemia, hyperleptinemia, and hyperinsulinemia, triglyceride lipolysis in adipocytes is increased while hydrolysis of cholesterol esters in macrophages is decreased, contributing to foam cell formation [15].
• In contrast, mice fed this diet with added cholesterol or with sucrose substituted by corn starch led to marked delays (8-10 weeks) in the elevations of insulin and leptin, although body weight gains were nearly identical among test diet groups [16].
• The mutants are characterized by retarded growth, infertility, mild anemia, elevated serum cholesterol, very low to undetectable serum thyroxine, and elevated serum thyroid-stimulating hormone [17].

Biological context of Chol1

• These data suggest that leptin regulates biliary lipid metabolism to promote efficient elimination of excess cholesterol stored in adipose tissue [1].
• Leptin administration also resulted in decreased expression of genes involved in fatty acid and cholesterol synthesis, glycolysis, gluconeogenesis, and urea synthesis, and increased expression of genes mediating fatty acid oxidation, ATP synthesis, and oxidant defenses [18].
• The impact of IH on serum TG levels in WT mice was significantly greater than that in Hif1a(+/-) mice (95 +/- 9 vs. 66 +/- 6 mg/dl, P < 0.05), whereas cholesterol and glucose levels were affected independently of genotype [3].
• Hypoandrogenemia in men and hyperandrogenemia in women are associated with visceral obesity; insulin resistance; low high-density lipoprotein (HDL) cholesterol (HDL-C); and elevated triglycerides, low-density lipoprotein cholesterol, and plasminogen activator type 1 [19].
• Human obesity is associated with abnormal hepatic cholesterol homeostasis and resistance to leptin action [20].

Anatomical context of Chol1

• Instead, cholesterol supersaturation of gallbladder bile was due to marked decreases in bile salt hydrophobicity and not to hypersecretion of biliary cholesterol per se, such as occurs in humans during weight loss [1].
• The chromosome 7 locus affecting body fat, total cholesterol and hepatic lipase activity was isolated in congenic strains whose donor strain regions overlap with the chromosome 7 BSB locus [21].
• In an effort to understand how this occurs, we have investigated whether these factors cause disregulation of cholesterol ester metabolism in J774.2 macrophages [15].
• Cholesterol-sensing receptors, liver X receptor alpha and beta, have novel and distinct roles in osteoclast differentiation and activation [22].
• Moreover, OEA decreases neutral lipid content in hepatocytes, as assessed by Oil red O staining, as well as serum cholesterol and triglyceride levels [23].

Associations of Chol1 with chemical compounds

• Thus, the mRNA levels of genes involved in fatty acid and cholesterol synthesis are rapidly (<1 h) repressed by leptin administration, in association with an acute decrease in plasma insulin levels and decreased sterol regulator element-binding protein-1 expression [18].
• In addition, taurocholenic acid greatly increased incorporation of labeled glucose into hepatic cholesterol in obese or non-obese mice fed either diet [24].
• Effect of delta22-5beta-taurocholenic acid on hepatic cholesterol and fatty acid in gold thioglucose obese mice fed low- or high-fat diets [24].
• Cholesterol levels were significantly elevated in both male and female homozygous carriers of the Chol1/NZO allele [4].
• T exerts proatherogenic effects on macrophage function by facilitating the uptake of modified lipoproteins and an antiatherogenic effect by stimulating efflux of cellular cholesterol to HDL [19].

Physical interactions of Chol1

• Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL [25].
• The plant sterol diosgenin has been shown to stimulate biliary cholesterol secretion in mice without affecting the expression of the adenosine triphosphate-binding cassette transporter heterodimer Abcg5/g8 [26].
• In the present study we hypothesized that cholesteryl ester is transported from caveolae through the cytosol to an internal membrane by a caveolin chaperone complex similar to the one we originally described for the transport of newly synthesized cholesterol [27].
• Thus, we suggest that SgIII directly binds to cholesterol components of the SGM and targets CgA to SGs in pituitary and pancreatic endocrine cells [28].
• ACAT inhibitor pactimibe sulfate (CS-505) reduces and stabilizes atherosclerotic lesions by cholesterol-lowering and direct effects in apolipoprotein E-deficient mice [29].

Enzymatic interactions of Chol1

• Acyl-CoA:cholesterol acyltransferase (ACAT) catalyzes esterification of cellular cholesterol [30].
• PPARgamma regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1 [31].
• The expression of maleyl albumin-stimulated TNF-alpha mRNA expression could be reproduced by lipid extracts of oxidized LDL provided to macrophages at the same cholesterol concentration as from the intact lipoprotein particle [32].
• Mevalonate is the direct product of the rate-limiting step in cholesterol synthesis which is catalyzed by 3-hydroxy-3-methylglutaryl coenzyme A reductase [33].

Co-localisations of Chol1

• Caspase3 whole mount immunostaining revealed that cholesterol biosynthesis colocalizes with apoptotic regions that are targets of the morphogenic signal Sonic hedgehog [34].

Regulatory relationships of Chol1

• The NH2-terminal domain of sterol-regulatory element binding protein-1a (SREBP-1a) activates transcription of genes encoding enzymes of cholesterol and fatty acid biosynthesis in cultured cells [35].
• Pcsk9 expression is down-regulated by dietary cholesterol, and mutations in Pcsk9 have been associated with a form of autosomal dominant hypercholesterolemia [36].
• These results establish a structural model for understanding how SHP interacts with LRH-1 to regulate cholesterol homeostasis and provide new insights into how nuclear receptor/coregulator selectivity is achieved [37].
• These results have implications for cholesterol metabolism in human macrophages and its potential to be regulated by synthetic LXR and/or PPAR gamma ligands [38].
• Analysis of the kinetics of cholesterol secretion suggested that diosgenin probably activates a step before Abcg5/g8 [26].

Other interactions of Chol1

• Surprisingly, leptin reduced biliary cholesterol secretion rates without affecting secretion rates of bile salts or phospholipids [1].
• We conclude that 1) the effect of IH on serum TG levels is mediated through HIF-1, 2) HIF-1 may impact on posttranscriptional regulation of SREBP-1, and 3) the effect of IH on serum cholesterol levels was not altered by partial HIF-1alpha deficiency [3].
• In contrast, expression of genes associated with cholesterol metabolism (sterol-regulatory element-binding protein-2, 3-hydroxy-3-methylglutaryl-CoA reductase, acyl-CoA:cholesterol acyltransferase-1) and thermogenesis (uncoupling protein-2) was upregulated in both WAT and BAT of HSL-/- mice [39].
• We conclude that NPY, interacting with the Y2 receptor, participates in cholesterol and glucose homeostasis of obese mice [40].
• Plasma HDL-C and glucose levels and body weight in B6-db/db mice and their normal littermates were measured at intervals between 2 and 12 weeks of age to determine when the changes in cholesterol occurred in relationship to hyperglycemia and obesity [41].

Analytical, diagnostic and therapeutic context of Chol1

• Activation markers, scavenger receptors (SR) and cholesterol accumulation were analyzed using flow cytometry and Taqman analysis [42].
• In a dose-dependent manner, leptin promoted cholesterol crystallization and gallstone formation, which did not occur in saline-treated mice [43].
• In summary, the impairment (P < 0.05) in remnant metabolism as assessed by the breath test in obese mice was corrected by food restriction, associated with improvements in plasma glucose, triglyceride and cholesterol levels [44].
• In wild-type mice, the ratio of campesterol to cholesterol in serum was also significantly lower after treatment with leptin (28.0 +/- 3.3 microg/mg vs. 22.6 +/- 5.0 microg/mg, P < 0.05) [45].
• Cholesterol absorption was measured by the constant isotope feeding method and indirectly by the ratio of campesterol to cholesterol in serum [45].

References