| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Discordant regulation of proteins of cholesterol metabolism during the acute phase response Feingold, K. R., A. S. Pollock, et al. (1995), J Lipid Res 36(7): 1474-82. Abstract: Recent studies have shown that the administration of endotoxin (LPS) and cytokines to Syrian hamsters increases serum cholesterol levels, hepatic cholesterol synthesis, and the activity, protein levels, and mRNA levels of hepatic HMG-CoA reductase. Despite the greater than 10-fold increase in HMG-CoA reductase mRNA levels, LPS had only minimal effects on hepatic LDL receptor mRNA levels. In the present study, we demonstrate that LPS increases the transcription rate in the liver of HMG-CoA reductase mRNA approximately 4- to 5-fold without affecting LDL receptor mRNA transcription. Most stimuli that regulate HMG-CoA reductase and LDL receptor mRNA levels also regulate, in parallel, HMG-CoA synthase and farnesyl pyrophosphate (FPP) synthetase. However, in chow-fed animals, LPS and cytokines (TNF, IL-1, TNF + IL-1) increased hepatic HMG-CoA reductase mRNA levels without increasing LDL receptor, HMG-CoA synthase, or FPP synthetase mRNA levels. The feeding of cholesterol or bile resin binders regulates the mRNA levels of HMG-CoA reductase, LDL receptor, HMG-CoA synthase, and FPP synthetase. In both cholesterol- and colestipol-fed animals, LPS increased HMG-CoA reductase mRNA levels while either decreasing or causing minimal increases in the mRNA levels of the other proteins.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Discovery of 1-(4-fluorophenyl)-(3R)-3-(4-fluorophenyl)-(3S)-hydroxypropyl-(4S)-(4 -hydroxyphenyl)-2-azetidinone (SCH 58235): a designed, potent, orally active inhibitor of cholesterol absorption Rosenblum, S. B., T. Huynh, et al. (1998), J Med Chem 41(6): 973-80. Abstract: (3R)-(3-Phenylpropyl)-1,(4S)-bis(4-methoxyphenyl)-2-azetidinone (2, SCH 48461), a novel inhibitor of intestinal cholesterol absorption, has recently been described by Burnett et al. and has been demonstrated to lower total plasma cholesterol in man. The potential sites of metabolism of 2 were considered, and the most probable metabolites were prepared. The oral cholesterol-lowering efficacy of the putative metabolites was evaluated in a 7-day cholesterol-fed hamster model for the reduction of serum total cholesterol and liver cholesteryl esters versus control. On the basis of our analysis of the putative metabolite structure-activity relationship (SAR), SCH 58235 (1, 1-(4-fluorophenyl)-(3R)-3-(4-fluorophenyl)-(3S)-hydroxypropyl-(4S)- (4-hydroxyphenyl)-2-azetidinone) was designed to exploit activity enhancing oxidation and to block sites of potential detrimental metabolic oxidation. Additionally, a series of congeners of 2 were prepared incorporating strategically placed hydroxyl groups and fluorine atoms to further probe the SAR of 2-azetidinone cholesterol absorption inhibitors. Through the SAR analysis of a series of putative metabolites of 2, compound 1 was targeted and found to exhibit remarkable efficacy with an ED50 of 0.04 mg/kg/day for the reduction of liver cholesteryl esters in a 7-day cholesterol-fed hamster model. |
| Discovery of short, 3'-cholesterol-modified DNA duplexes with unique antitumor cell activity Zhou, J. H., B. S. Pai, et al. (1994), Cancer Res 54(22): 5783-7. Abstract: A new class of modified oligodeoxynucleotides with unique, selective cytotoxic properties has been discovered. Self-complementary, 3'-cholesterol-modified oligodeoxynucleotides caused morphology changes and death in certain cancer cell lines, whereas other cell lines were unaffected. Susceptible cells were killed in a dose-dependent manner at submicromolar concentrations. Optimum potency was exhibited by phosphodiester duplexes approximately 10 base pairs in length, and base composition was important only in the context of duplex stability. Phosphorothioate analogues were less potent. Although the molecular mechanism of action of these unique compounds is not yet known, they offer potential applications in cancer therapy and in studies of cell death. In addition, the path toward elucidation of the structure-based biological activity of these oligonucleotides should be especially instructive for researchers studying sequence-specific effects. |
| Discovery of the hepatic canalicular and intestinal cholesterol transporters. New targets for treatment of hypercholesterolemia Zanlungo, S. and F. Nervi (2003), Eur Rev Med Pharmacol Sci 7(2): 33-9. Abstract: Arteriosclerosis and cholesterol cholelithiasis are characterized by abnormal regulation of cholesterol trafficking and solubilization, and subsequent development of the arteriosclerotic plaque in the artery walls and gallstone formation in the gallbladder, respectively. Cholesterol metabolism is controlled by many complex polygenetic - environmental interactions that contribute to the regulation of serum lipoprotein cholesterol levels and biliary cholesterol and bile acids secretion, which constitute the only pathway for sterol elimination from the organism. Much of our understanding of cholesterol metabolism has arisen from studies of the pathways controlling cholesterol synthesis and the uptake and degradation of LDL and HDL lipoproteins. Recently, two new members of the ABC transporter family (ABCG5 and ABCG8 heterodimers) have been discovered in the apical pole of the enterocyte and in the canalicular membrane of hepatocytes. Experiments in genetically engineered mice have demonstrated that ABCG5/G8 represent the physiological canalicular transporter of biliary cholesterol and the intestinal secretory mechanism of absorbed dietary plant sterols. Interestingly, mutation of ABCG5 and or ABCG8 genes in man causes sitosterolemia, a rare genetic disease characterized by massive absorption of plant sterols and premature arteriosclerosis. The potential pharmacological manipulation of biliary cholesterol secretion represents another important therapeutic target to treat hypercholesterolemia, if this manipulation is simultaneously accompanied by measures aimed to avoid gallbladder cholesterol crystallization. The best theoretical drug should decrease serum lipoprotein cholesterol levels, increase biliary cholesterol secretion and fecal elimination and favoring at the same time gallbladder emptying to prevent gallstone formation. |
| Disodium ascorbyl phytostanyl phosphate reduces plasma cholesterol concentrations and atherosclerotic lesion formation in apolipoprotein E-deficient mice Lukic, T., K. M. Wasan, et al. (2003), Metabolism 52(4): 425-31. Abstract: Disodium ascorbyl phytostanyl phosphate (FM-VP4) consists of ascorbic acid covalently bound to phytostanols by a phosphodiester linkage and is derived as the disodium salt. The purpose of this study was to evaluate the lipid-lowering and antiatherosclerotic properties of FM-VP4 following administration to apolipoprotein E (ApoE)-deficient mice. Four-week-old male C57BL/6J mice with a homozygous deletion of the ApoE gene (apolipoprotein E knock-out) were administered 0 (control), 0.1%, 0.5%, 1.0%, and 2.0% (wt/vol) FM-VP4 in their drinking water or 2.0% FM-VP4 (wt/wt) in their diet for 12 consecutive weeks. All animals received a standard mouse chow diet consisting of 9.0% (wt/wt) fat and 0.2% (wt/wt) cholesterol. Plasma cholesterol and triglyceride levels were determined at baseline and at 4-week intervals (4, 8, and 12 weeks) throughout the term of the study. At the end of the study, mice were killed using CO(2) gas, and blood was taken from the heart. The heart and aorta were removed and sections of the aortic roots were stained with oil red O (ORO) and Movat's stain. The lesions found in this area were measured using a computer-assisted image analysis. Consumption of FM-VP4 by either food or drinking water routes was associated with an approximately 75% reduction in total plasma cholesterol levels and a 75% decrease in aortic atherosclerotic lesion area in ApoE-deficient mice over 12 weeks compared to controls. A trend in decreasing plasma triglyceride levels was also observed. Taken together these data suggest that FM-VP4 has both lipid-lowering and antiatherosclerotic properties following 12-week administration to ApoE-deficient mice. |
| Disorder of pericardial fluid cholesterol metabolism in cholesterol pericarditis Noiri, E. and T. Itoh (1991), Jpn J Med 30(4): 393. |
| Disorders of bile acid metabolism in cholesterol gallstone disease Berr, F., E. Pratschke, et al. (1992), J Clin Invest 90(3): 859-68. Abstract: The aim of the study was to evaluate the metabolism of individual bile acids in patients with cholesterol gallstone disease. Therefore, we determined pool size and turnover of deoxycholic (DCA), cholic (CA), and chenodeoxycholic acid (CDCA) in 23 female gallstone patients classified according to their gallbladder function and in 15 healthy female controls. Gallstone patients had normal hepatic bile acid synthesis, but, depending on gallbladder function, differed with respect to turnover and size of the bile acid pools: Patients with well-emptying gallbladder (group A, n = 9) had enhanced turnover and reduced pools of CA (-46%; P less than 0.01 vs. controls) and CDCA (-24%; P less than 0.05), but normal input and size of the DCA pool. With reduced gallbladder emptying (less than 50% of volume; group B, n = 6), turnover and pools of CA, CDCA, and DCA were similar as in controls. Patients with loss of gallbladder reservoir (group C, n = 8) had increased input (+100%; P less than 0.01) and pool size of DCA (+45%; P = 0.07) caused by rapid conversion of CA to DCA, while the pools of CA (-71%; P less than 0.001 vs. controls) and CDCA (-36%; P less than 0.05) were reduced by enhanced turnover. Thus, in patients with cholesterol gallstones, the pools of primary bile acids are diminished, unless gallbladder emptying is reduced. Furthermore, in a subgroup of gallstone patients, who had completely lost gallbladder function, the CA pool is largely replaced by DCA owing to rapid transfer of CA to the DCA pool. This probably contributes to supersaturation of bile with cholesterol. |
| Disorders of cholesterol biosynthesis Clayton, P. T. (1998), Arch Dis Child 78(2): 185-9. |
| Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes Herman, G. E. (2003), Hum Mol Genet 12 Spec No 1: R75-88. Abstract: Since 1998, five disorders involving enzyme defects in post-squalene cholesterol biosynthesis have been identified-desmosterolosis, X-linked dominant chondrodysplasia punctata, CHILD syndrome, lathosterolosis, and hydrops-ectopic calcification-moth-eaten skeletal dysplasia. They join the most common cholesterol biosynthetic disorder, Smith-Lemli-Opitz syndrome, whose underlying defect was identified in 1993. All are associated with major developmental malformations that are unusual for metabolic disorders. The existence of mouse models for five of these disorders is beginning to enable more detailed developmental and in vitro studies examining the mechanisms involved in disease pathogenesis. In this review, an overview of the cholesterol biosynthetic pathway will be presented. Clinical features of the human disorders and mouse models of post-squalene cholesterol biosynthesis will then be discussed. |
| Disorders of lipid metabolism--diagnosis and therapy in general practice. 2. Hypercholesteremia--diagnostic-therapeutic procedure in relation to total cholesterol concentration Richter, W. O. (1996), Fortschr Med 114(12): 147-8. |
| Disorders of post-squalene cholesterol biosynthesis leading to human dysmorphogenesis Andersson, H. C. (2002), Cell Mol Biol (Noisy-le-grand) 48(2): 173-7. Abstract: Insights in molecular developmental biology in animals and humans are facilitating the understanding of pathophysiologic mechanisms in dysmorphogenesis or abnormalities in normal embryologic structural development. A milestone was recognition of the role of shh in morphogenesis of craniofacial structures, especially the development of holoprosencephaly. The dependence of hedgehog morphogens on cholesterol modification for normal hedgehog signaling function has particular relevance to disorders of cholesterol synthesis which manifest dysmorphogenesis. Four human disorders of morphogenesis (Smith-Lemli-Opitz syndrome, desmosterolosis, X-linked chondrodysplasia punctata, CHILD syndrome) have recently been shown to be caused by sterol abnormalities resulting from cholesterol biosynthesis enzyme deficiencies. This review summarizes the clinical, biochemical and molecular data in these disorders with an emphasis on understanding the pathophysiology of dysmorphogenesis. |
| Disparate effects of a triglyceride lowering diet and of bezafibrate on the HDL system: a study in patients with hypertriglyceridaemia and low HDL-cholesterol levels Arnon, R., E. Sehayek, et al. (1993), Eur J Clin Invest 23(8): 492-8. Abstract: The response of plasma triglyceride and of the high density lipoprotein (HDL) system to a triglyceride lowering diet and to a bezafibrate was compared in a group of 24 human subjects with mild to moderate hypertriglyceridaemia and low HDL-cholesterol levels. Post-heparin plasma lipoprotein (LPL) and hepatic (HL) lipase activities were determined before the initiation of the study and at the end of the diet (12 weeks) and bezafibrate (12 weeks) periods. HDL structure and composition were determined on a zonal centrifugation system at the end of the diet and bezafibrate periods. Diet caused a 9-20% reduction of plasma triglycerides but there was no change in LPL, HL or HDL levels. The individual responses between plasma triglycerides and HDL cholesterol levels however were highly correlated (r = 0.60 to 0.78). Combined diet plus bezafibrate therapy caused a further 38% decrease of plasma triglycerides with a 28% increase of HDL-cholesterol and a 47% increase of LPL activity. HDL3 density decreased and the contribution of cholesteryl ester to the HDL mass was increased while the contribution of proteins and triglycerides decreased. In the majority of the subjects (61%) HDL cholesterol levels increased by 20% or more and in these subjects the change of HDL was highly correlated with the change of the LPL/HL ratio (r = 0.74) but not with the change of the plasma triglyceride levels. In the remaining subjects (39%), HDL cholesterol levels remained unchanged or increased by less than 20%. The change of HDL cholesterol levels in these subjects was unrelated to the decrease of plasma triglycerides or the change of post-heparin lipase activities.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Disparate effects of interleukin-3 on serum lipoprotein(a), and low- and high-density lipoprotein cholesterol levels Hansen, P. R. and D. Hovgaard (1995), Am J Cardiol 75(4): 296-7. |
| Disparate effects of oxidation on plasma acyltransferase activities: inhibition of cholesterol esterification but stimulation of transesterification of oxidized phospholipids Subbaiah, P. V. and M. Liu (1996), Biochim Biophys Acta 1301(1-2): 115-26. Abstract: Oxidation of lipoproteins results in the formation of several polar phospholipids with pro-inflammatory and pro-atherogenic properties. To examine the possible role of lecithin/cholesterol acyltransferase (LCAT) in the metabolism of these oxidized phospholipids, we oxidized whole plasma with either Cu(2+) or a free-radical generator, and determined the various activities of LCAT. Oxidation caused a reduction in plasma phosphatidylcholine (PC), an increase in a short-chain polar PC (SCP-PC), and an inhibition of the transfer of long-chain acyl groups to cholesterol (LCAT activity) or to lyso PC (lysolecithin acyltransferase (LAT) I activity). However, the transfer of short-chain acyl groups from SCP-PC to lyso PCLAT II activity) was stimulated several fold, in direct correlation with the degree of oxidation. LAT II activity was not stimulated by oxidation in LCAT-deficient plasma, showing that it is carried out by LCAT. Oxidized normal plasma exhibited low LCAT activity even in the presence of exogenous proteoliposome substrate, indicating that the depletion of substrate PC was not responsible for the loss of activity. Oxidation of isolated LDL or HDL abolished their ability to support LCAT and LAT I activities of exogenous enzyme, but promoted the LAT II activity. Purified LCAT lost its LCAT and LAT I functions, but not its LAT II function, when oxidized in vitro. These results show that while oxidation of plasma causes a loss of LCAT's ability to transfer long-chain acyl groups, its ability to transfer short-chain acyl groups, from SCP-PC is retained, and even stimulated, suggesting that LCAT may have a physiological role in the metabolism of oxidized PC in plasma. |
| Disparities in the diagnosis and pharmacologic treatment of high serum cholesterol by race and ethnicity: data from the Third National Health and Nutrition Examination Survey Nelson, K., K. Norris, et al. (2002), Arch Intern Med 162(8): 929-35. Abstract: BACKGROUND: Serum cholesterol is one of the most important modifiable risk factors for coronary artery disease. There are conflicting data on racial and ethnic variation in the treatment of high cholesterol. METHODS: We analyzed data from the Third National Health and Nutrition Examination Survey, a nationally representative cross-sectional survey conducted between 1988 and 1994. Participants included 7679 white, 4467 African American, and 4113 Mexican American adults older than 25 years who completed the household adult questionnaire. The adjusted odds of serum cholesterol screening and of taking a prescription medication to lower serum cholesterol among African Americans and Mexican Americans were compared with those of whites, controlling for differences in age, sex, income, educational level, insurance status, comorbid illness, and having a regular source of health care. RESULTS: African Americans and Mexican Americans were significantly less likely than whites to report ever having had their blood cholesterol checked (odds ratio, 0.7 for both; P<.001). Among individuals with high cholesterol who were told to take a medication, African Americans (P<.001) and Mexican Americans (P =.05) were less likely than whites to be taking a cholesterol-lowering agent (odds ratios, 0.3 and 0.5, respectively). Individuals who reported being told they had high cholesterol had significantly higher serum cholesterol measurements (from the laboratory examination) than those who reported being told their cholesterol was not high (234 vs 198 mg/dL 6.05 vs 5.12 mmol/L; P<.001). CONCLUSIONS: African Americans and Mexican Americans were less likely to report serum cholesterol screening than whites. Even when identified as having high cholesterol that required medication, African Americans and Mexican Americans were less likely than whites to be taking cholesterol-lowering agents. |
| Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells Burke, R., D. Nellen, et al. (1999), Cell 99(7): 803-15. Abstract: Members of the Hedgehog (Hh) family of secreted signaling proteins function as potent short-range organizers in animal development. Their range of action is limited by a C-terminal cholesterol tether and the upregulation of Patched (Ptc) receptor levels. Here we identify a novel segment-polarity gene in Drosophila, dispatched (disp), and demonstrate that its product is required in sending cells for normal Hh function. In the absence of Disp, cholesterol-modified but not cholesterol-free Hh is retained in these cells, indicating that Disp functions to release cholesterol-anchored Hh. Despite their opposite roles, Disp and Ptc share structural homology in the form of a sterol-sensing domain, suggesting that release and sequestration of cholesterol-modified Hh may be based on related molecular pathways. |
| Disposition of intracellular cholesterol in human fibroblasts Lange, Y. (1991), J Lipid Res 32(2): 329-39. Abstract: We have examined the intracellular distribution of unesterified cholesterol in cultured human fibroblasts. Intact cells were treated with cholesterol oxidase to selectively transform cell surface cholesterol to cholestenone. Isopycnic centrifugation of homogenates showed that the cholestenone had a peak buoyant density of 1.13 g/cm3. The approximately 10% of total cholesterol which remained unoxidized was distributed in two peaks of roughly equal size: a sharp peak at approximately 1.09 g/cm3 and a broad peak centered at 1.18 g/cm3. When intact cells were incubated with exogenous 3Hcholesterol, the radiolabel entered the nonoxidizable pool in a temperature-dependent fashion with a half time of 3 h at 37 degrees C. This label initially was associated with the dense but not the buoyant peak of nonoxidized cholesterol. After 40 h, the buoyant peak also became labeled; both peaks then had a specific activity slightly less than the surface cholestenone. The buoyant density of the unoxidized cholesterol did not coincide with markers for the Golgi apparatus, endoplasmic reticulum, or lysosomes. However, two ingested markers of pinocytosis, calcein and horseradish peroxidase, comigrated with the dense peak of unoxidized cholesterol. That the size of the unoxidized cholesterol pool was greater in cells deprived of serum lipoproteins than in fed cells suggested that none of the intracellular cholesterol need be ascribed to ingested sterols. The mass of unoxidizable cholesterol was not diminished when cholesterol biosynthesis was inhibited by lovastatin in lipoprotein-deprived cells. Furthermore, the newly synthesized radiolabeled cholesterol resistant to cholesterol oxidase did not migrate with intracellular cholesterol mass on sucrose density gradients. The newly synthesized cholesterol amounted to about 10% of the total unoxidized sterol. These data indicate that most of the intracellular cholesterol was not newly synthesized. We conclude that a) approximately 90% of fibroblast cholesterol is associated with the cell surface; b) the bulk of intracellular cholesterol, approximately 10% of total, is derived from internalized (endocytic) plasma membrane; and c) the most recently synthesized cholesterol, approximately 1% of the total, is in a discrete organelle. |
| Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion Yu, L., R. E. Hammer, et al. (2002), Proc Natl Acad Sci U S A 99(25): 16237-42. Abstract: Cholesterol and other sterols exit the body primarily by secretion into bile. In patients with sitosterolemia, mutations in either of two ATP-binding cassette (ABC) half-transporters, ABCG5 or ABCG8, lead to reduced secretion of sterols into bile, implicating these transporters in this process. To elucidate the roles of ABCG5 and ABCG8 in the trafficking of sterols, we disrupted Abcg5 and Abcg8 in mice (G5G8(-/-)). The G5G8(-/-) mice had a 2- to 3-fold increase in the fractional absorption of dietary plant sterols, which was associated with an approximately 30-fold increase in plasma sitosterol. Biliary cholesterol concentrations were extremely low in the G5G8(-/-) mice when compared with wild-type animals (mean = 0.4 vs. 5.5 micromol ml) and increased only modestly with cholesterol feeding. Plasma and liver cholesterol levels were reduced by 50% in the chow-fed G5G8(-/-) mice and increased 2.4- and 18-fold, respectively, after cholesterol feeding. These data indicate that ABCG5 and ABCG8 are required for efficient secretion of cholesterol into bile and that disruption of these genes increases dramatically the responsiveness of plasma and hepatic cholesterol levels to changes in dietary cholesterol content. |
| Disruption of actin microfilament organization by cholesterol oxides in 73/73 endothelial cells Palladini, G., G. Finardi, et al. (1996), Exp Cell Res 223(1): 72-82. Abstract: Various cholesterol oxides generated during the oxidation of low-density lipoproteins have been reported to exert cytotoxic effects on cultured endothelial cells and to decrease their barrier function. The cytoskeleton, and in particular the actin microfilament meshwork, is one of the preferential targets in oxidative stress-and thiol-depleting agent-induced cell injury. The alterations occurring in the microfilament network were investigated using the endothelial cell line 73/73 treated with increasing concentrations (0.5-10 micrograms/ml) of cholestane-3 beta, 5 alpha, 6 beta-triol, CH, 5-cholesten-3beta-ol-7one, KC, and 25-OH-cholesterol, COH, for up to 6 h. The distribution of microfilaments was visualized using immunofluorescence and laser scanner confocal microscopy. All cholesterol oxides caused a progressive disruption of actin microfilaments that was characterized by the disappearance of the stress fibers within the cell body and, in selected cells, by a complete marginalization and clustering of the filaments to one edge of the cell. In addition, COH promoted F-actin fragmentation, as revealed by the presence of scattered fragments of F-actin in various cell regions. The redistribution of actin microfilaments was associated with a similar redistribution of alpha-actinin, an actin-binding protein involved in bundle formation and in the anchorage of actin filaments to the adhesion plaques. Concomitantly, cholesterol oxides promoted a loss of vinculin, another actin-binding protein, from the focal adhesion plaques located under the cell body and their marginalization and thinning. These alterations preceded cell detachment and cell death by apoptosis as revealed by the subsequent leakage of cytosolic enzymes and nuclear fragmentation. These results suggest that cytoskeletal (microfilament) alterations caused by cholesterol oxides may be one of the cytopathological events involved in the detachment of endothelial cells from the inner vascular surface promoted by cholesterol oxides. |
| Disruption of cholesterol 7alpha-hydroxylase gene in mice. II. Bile acid deficiency is overcome by induction of oxysterol 7alpha-hydroxylase Schwarz, M., E. G. Lund, et al. (1996), J Biol Chem 271(30): 18024-31. Abstract: Past experiments and current paradigms of cholesterol homeostasis suggest that cholesterol 7alpha-hydroxylase plays a crucial role in sterol metabolism by controlling the conversion of cholesterol into bile acids. Consistent with this conclusion, we show in the accompanying paper that mice deficient in cholesterol 7alpha-hydroxylase (Cyp7-/- mice) exhibit a complex phenotype consisting of abnormal lipid excretion, skin pathologies, and behavioral irregularities (Ishibashi, S., Schwarz, M., Frykman, P. K., Herz, J., and Russell, D. W.(1996) J. Biol. Chem. 261, 18017-18023). Aspects of lipid metabolism in the Cyp7-/- mice are characterized here to deduce the physiological basis of this phenotype. Serum lipid, cholesterol, and lipoprotein contents are indistinguishable between wild-type and Cyp7-/- mice. Vitamin D3 and E levels are low to undetectable in knockout animals. Stool fat content is significantly elevated in newborn Cyp7-/- mice and gradually declines to wild-type levels at 28 days of age. Several species of 7alpha-hydroxylated bile acids are detected in the bile and stool of adult Cyp7-/- animals. A hepatic oxysterol 7alpha-hydroxylase enzyme activity that may account for the 7alpha-hydroxylated bile acids is induced between days 21 and 30 in both wild-type and deficient mice. An anomalous oily coat in the Cyp7-/- animals is due to the presence of excess monoglyceride esters in the fur. These data show that 7alpha-hydroxylase and the pathway of bile acid synthesis initiated by this enzyme are essential for proper absorption of dietary lipids and fat-soluble vitamins in newborn mice, but not for the maintenance of serum cholesterol and lipid levels. In older animals, an alternate pathway of bile acid synthesis involving an inducible oxysterol 7alpha-hydroxylase plays a crucial role in lipid and bile acid metabolism. |