Disease relevance of CPD-295

• Sc5d (-/-) pups were stillborn, had elevated lathosterol and decreased cholesterol levels, had craniofacial defects including cleft palate and micrognathia, and limb patterning defects [1].
• Tamoxifen and toremifene lower serum cholesterol by inhibition of delta 8-cholesterol conversion to lathosterol in women with breast cancer [2].
• In normocholesterolemic patients with primary biliary cirrhosis, lathosterol was significantly lower than in normocholesterolemic controls (P < 0.05) whereas no difference was found between hypercholesterolemic patients and hypercholesterolemic controls [3].
• Mean change in percent stenosis was positively associated with a percent change in lathosterol (r = 0.26, P < 0.005) and negatively associated with a percent change in beta-sitosterol (r = -0.21, P < 0.01) [4].
• The relationship of Lp(a) concentrations with other lipoprotein and apolipoprotein risk factors for coronary heart disease and with lathosterol, an indicator of whole-body cholesterol synthesis, was studied dependent on sex and generation [5].

Psychiatry related information on CPD-295

• Here we measured cholesterol, lathosterol, 24S- and 27-hydroxycholesterol, and plant sterols in four different brain areas of deceased Alzheimer's disease (AD) patients and controls [6].
• Taken together, these results confirm and expand the hypothesis that individual differences in plasma levels of noncholesterol sterols are moderately (lathosterol) to highly (plant sterols) heritable [7].

High impact information on CPD-295

• Thus, lathosterol 5-dehydrogenase is equally active which indicates that homozygotes liver microsomes are viable [8].
• Significant positive correlations were also obtained between length of resected ileum and serum levels of 7 alpha-hydroxycholesterol (a marker for bile acid biosynthesis) and lathosterol (a marker for cholesterol synthesis) [9].
• Many of the malformations found in Sc5d (-/-) mice are consistent with impaired hedgehog signaling, and appear to be a result of decreased cholesterol rather than increased lathosterol [1].
• Microsomes were preloaded in vitro with liposomes composed of lathosterol and phosphatidylcholine in the presence of a high-speed supernatant (S105) protein prior to enzyme assay [10].
• When whole retinas were incubated with 3H2O, radioactivity was incorporated into compounds which chromatographed on reversed-phase and silica high performance liquid chromatography at the elution positions of squalene, cholesterol, lathosterol, and methyl sterols [11].

Chemical compound and disease context of CPD-295

• METHODS AND RESULTS: From a total number of 137 male subjects with hypercholesterolemia, eight subjects with the lowest and eight subjects with the highest ratios of lathosterol to campesterol in serum were included in the study [12].
• Plasma plant sterol concentrations (an index of cholesterol absorption efficiency) and plasma lathosterol concentration (an index of cholesterol synthesis rate) were measured in 52 patients with non-insulin dependent diabetes mellitus (NIDDM) and 36 non-diabetic controls [13].
• In cholesteatoma, cholesterol is synthesized through desmosterol and delta 7-cholestenol (lathosterol), possibly in the matrix [14].

Biological context of CPD-295

• To evaluate cholesterol synthesis, serum levels of lathosterol were measured, and campesterol and sitosterol were considered to reflect intestinal absorption and biliary elimination of sterols [3].
• In normal pregnancy, increased serum cholesterol was associated with up to 2-fold increases in squalene, desmosterol, and lathosterol proportions, and the values remained elevated, especially for desmosterol, during the lactation period [15].
• In summary, on the island of Kosrae, a strong founder effect of a mutant ABCG8 allele results in a large number of carriers with increased plasma plant sterol levels and decreased lathosterol levels [16].
• Lathosterol median-change values were significantly greater in haplotype *1b than in haplotype *5 individuals (p=0.041, non-adjusted), which was congruent with the extent of mean changes in lathosterol-to-cholesterol ratios, although the latter did not reach statistical significance [17].
• Despite a significant decrease in absolute plasma concentrations of oxysterols, total cholesterol, and its endogenous synthesis rate, indicated by a decreased ratio of lathosterol to cholesterol, the plasma 24(S)-hydroxycholesterol to cholesterol ratio, a surrogate marker of brain cholesterol homeostasis, remained unchanged [18].

Anatomical context of CPD-295

• Tryptic digestion of previously lathosterol-loaded microsomes inactivated the delta 5-dehydrogenase [19].
• Here we show that primary murine embryonic astrocytes secrete endogenously synthesized cholesterol but also the cholesterol precursors desmosterol and lathosterol [20].
• A change in hepatic VLDL apoB secretion was significantly correlated with a change in visceral adipose tissue area (r = 0.59; P = 0.043), but not plasma concentrations of insulin, free fatty acids, or lathosterol [21].
• Concentrations of ezetimibe and its glucuronide in serum, urine, and feces, as well as cholesterol, lathosterol, and the plant sterols campesterol and sitosterol in serum, were quantified by use of liquid chromatography and gas chromatography with mass spectrometric detection [22].
• In human subjects, infusing [1-(13)C]acetate into the duodenum for 12 h demonstrated that approximately 50% of the plasma lathosterol pool was derived from de novo synthesis during this interval [23].

Associations of CPD-295 with other chemical compounds

• The introduction of the double bond in lathosterol at C-5[6] to form 7-dehydrocholesterol that is catalyzed by lathosterol-5-dehydrogenase was equally rapid in controls and homozygotes liver microsomes (120 +/- 8 vs 100 +/- 7 pmol/mg protein per min, P = NS) [8].
• The dehydrogenation of 5 alpha-cholest-7-en-3 beta-ol (lathosterol) to cholest-5,7-dien-3 beta-ol (7-dehydrocholesterol) was studied in rat liver microsomes with [3H]lathosterol as substrate [19].
• SCP-mediated lathosterol transfer was shown more directly by sucrose density gradient centrifugation to separate trypsinized and normal microsomes [19].
• Moreover, sterol supplementation significantly (P < 0.05) increased lathosterol, campesterol, and beta-sitosterol concentrations after treatment [24].
• Serum levels of lathosterol, campesterol, 7 alpha-hydroxycholesterol, and 27-hydroxycholesterol were measured by gas chromatography-mass spectrometry [25].

Gene context of CPD-295

• During multiple regression analysis including age, homeostasis model assessment score, plasma concentrations of sitosterol, and lathosterol, ABCG8 and apoE genotypes were independent determinants of VLDL-apoB PR and LDL-apoB FCR, respectively (P<0.05) [26].
• The CETP/apoBSP allelic combination was the most significant predictor of apoB secretion, and this was independent of visceral fat, plasma lathosterol and insulin levels, and dietary fat [27].
• However, at alpha-tocopherol concentrations higher than 50 microM, the LDL receptor binding activity, protein and mRNA, the HMG-CoA reductase mRNA and the cell lathosterol and cholesterol concentrations all returned to control levels [28].
• Sterol carrier protein (SCP) (Ritter, M. C., and Dempsey, M.E. (1973) Proc. Natl. Acad. Sci. U.S.A. 70, 265-269) promotes the microsomal dehydrogenation of 5-cholest-7-en-3 beta-ol (lathosterol) to 7-dehydrocholesterol [29].
• The measured serum parameters included the levels of TC, VLDL-C, LDL-C, HDL-C, TG, lathosterol, apoA-I, B, C-III, and E, as well as LCAT activity [30].

Analytical, diagnostic and therapeutic context of CPD-295

• The power of serum lathosterol concentration as an indicator of whole-body cholesterol synthesis was investigated in 47 human volunteers consuming two diets differing in fatty acid composition [31].
• The thermotropic properties of binary mixtures of D-erythro-n-palmitoyl-dihydrosphingomyelin (16:0-DHSM), D-erythro-n-palmitoyl-sphingomyelin (16:0-SM), cholesterol, lathosterol, and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) were studied by differential scanning calorimetry [32].
• Plant sterol concentrations correlated positively with cholesterol levels and inversely with body mass index and triglyceride and lathosterol concentrations [33].
• Lathosterol was quantitated by gas liquid chromatography and apo AI and B by immunoprecipitation [34].
• Plasma lathosterol levels were significantly elevated in patients with bile acid malabsorption (742 +/- 84 micrograms/ml compared with 400 +/- 59 micrograms/ml in control subjects) and correlated closely with faecal bile acid levels (r = 0.779, P < 0.001), with 75SeHCAT T1/2 (r = -0.524, P < 0.05) and with Schilling test (r = -0.591, P < 0.05) [35].

References