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• W1966634071 abstract "Stearoyl-coenzyme A desaturase 1-deficient (SCD1−/−) mice have impaired MUFA synthesis. When maintained on a very low-fat (VLF) diet, SCD1−/− mice developed severe hypercholesterolemia, characterized by an increase in apolipoprotein B (apoB)-containing lipoproteins and the appearance of lipoprotein X. The rate of LDL clearance was decreased in VLF SCD1−/− mice relative to VLF SCD1+/+ mice, indicating that reduced apoB-containing lipoprotein clearance contributed to the hypercholesterolemia. Additionally, HDL-cholesterol was dramatically reduced in these mice. The presence of increased plasma bile acids, bilirubin, and aminotransferases in the VLF SCD1−/− mice is indicative of cholestasis. Supplementation of the VLF diet with MUFA- and PUFA-rich canola oil, but not saturated fat-rich hydrogenated coconut oil, prevented these plasma phenotypes. However, dietary oleate was not as effective as canola oil in reducing LDL-cholesterol, signifying a role for dietary PUFA deficiency in the development of this phenotype. These results indicate that the lack of SCD1 results in an increased requirement for dietary unsaturated fat to compensate for impaired MUFA synthesis and to prevent hypercholesterolemia and hepatic dysfunction. Therefore, endogenous MUFA synthesis is essential during dietary unsaturated fat insufficiency and influences the dietary requirement of PUFA. Stearoyl-coenzyme A desaturase 1-deficient (SCD1−/−) mice have impaired MUFA synthesis. When maintained on a very low-fat (VLF) diet, SCD1−/− mice developed severe hypercholesterolemia, characterized by an increase in apolipoprotein B (apoB)-containing lipoproteins and the appearance of lipoprotein X. The rate of LDL clearance was decreased in VLF SCD1−/− mice relative to VLF SCD1+/+ mice, indicating that reduced apoB-containing lipoprotein clearance contributed to the hypercholesterolemia. Additionally, HDL-cholesterol was dramatically reduced in these mice. The presence of increased plasma bile acids, bilirubin, and aminotransferases in the VLF SCD1−/− mice is indicative of cholestasis. Supplementation of the VLF diet with MUFA- and PUFA-rich canola oil, but not saturated fat-rich hydrogenated coconut oil, prevented these plasma phenotypes. However, dietary oleate was not as effective as canola oil in reducing LDL-cholesterol, signifying a role for dietary PUFA deficiency in the development of this phenotype. These results indicate that the lack of SCD1 results in an increased requirement for dietary unsaturated fat to compensate for impaired MUFA synthesis and to prevent hypercholesterolemia and hepatic dysfunction. Therefore, endogenous MUFA synthesis is essential during dietary unsaturated fat insufficiency and influences the dietary requirement of PUFA. Although dietary saturated fat is generally regarded as hypercholesterolemic, the roles of de novo synthesized saturated fatty acids and MUFAs in the regulation of plasma cholesterol levels have not been thoroughly investigated (1Dietschy J.M. Dietary fatty acids and the regulation of plasma low density lipoprotein cholesterol concentrations.J. Nutr. 1998; 128: 444-448Crossref Google Scholar, 2Hayes K.C. Khosla P. Dietary fatty acid thresholds and cholesterolemia.FASEB J. 1992; 6: 2600-2607Crossref PubMed Scopus (186) Google Scholar, 3Mensink R.P. Zock P.L. Kester A.D. Katan M.B. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials.Am. J. Clin. Nutr. 2003; 77: 1146-1155Crossref PubMed Scopus (2093) Google Scholar). Stearoyl-coenzyme A desaturase 1 (SCD1) is a central enzyme in lipid metabolism that catalyzes the desaturation of palmitoyl-CoA and stearoyl-CoA to palmitoleoyl-CoA and oleoyl-CoA, respectively (4Ntambi J.M. Miyazaki M. Recent insights into stearoyl-CoA desaturase-1.Curr. Opin. Lipidol. 2003; 14: 255-261Crossref PubMed Scopus (216) Google Scholar). The dietary requirement for MUFA, if any, is confounded by the capacity for endogenous MUFA synthesis. Furthermore, under certain metabolic conditions, both dietary and endogenously synthesized MUFAs have been hypothesized to influence the dietary requirement for certain PUFAs (5Cunnane S.C. The Canadian Society for Nutritional Sciences 1995 Young Scientist Award Lecture. Recent studies on the synthesis, beta-oxidation, and deficiency of linoleate and alpha-linolenate: are essential fatty acids more aptly named indispensable or conditionally dispensable fatty acids?.Can. J. Physiol. Pharmacol. 1996; 74: 629-639Crossref PubMed Google Scholar). SCD1-deficient (SCD1−/−) mice have impaired MUFA synthesis and are a useful animal model to study the influence of de novo synthesized MUFAs on lipoprotein metabolism and the requirement for dietary unsaturated fat. Four SCD isoforms (SCD1–SCD4), encoded by different genes, have been identified in the mouse (4Ntambi J.M. Miyazaki M. Recent insights into stearoyl-CoA desaturase-1.Curr. Opin. Lipidol. 2003; 14: 255-261Crossref PubMed Scopus (216) Google Scholar). However, SCD1 is the most abundant isoform expressed in lipogenic tissues, such as liver and adipose tissue (4Ntambi J.M. Miyazaki M. Recent insights into stearoyl-CoA desaturase-1.Curr. Opin. Lipidol. 2003; 14: 255-261Crossref PubMed Scopus (216) Google Scholar). SCD1 gene expression is regulated by both hormones (insulin, leptin) and by a variety of nutrients such as cholesterol, glucose, fructose, and PUFAs (4Ntambi J.M. Miyazaki M. Recent insights into stearoyl-CoA desaturase-1.Curr. Opin. Lipidol. 2003; 14: 255-261Crossref PubMed Scopus (216) Google Scholar, 6Foufelle F. Ferre P. New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c.Biochem. J. 2002; 366: 377-391Crossref PubMed Scopus (404) Google Scholar, 7Kaestner K.H. Ntambi J.M. Kelly Jr., T.J. Lane M.D. Differentiation-induced gene expression in 3T3-L1 preadipocytes. A second differentially expressed gene encoding stearoyl-CoA desaturase.J. Biol. Chem. 1989; 264: 14755-14761Abstract Full Text PDF PubMed Google Scholar, 8Kim H.J. Miyazaki M. Ntambi J.M. Dietary cholesterol opposes PUFA-mediated repression of the stearoyl-CoA desaturase-1 gene by SREBP-1 independent mechanism.J. Lipid Res. 2002; 43: 1750-1757Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 9Lin J. Choi Y.H. Hartzell D.L. Li C. Della-Fera M.A. Baile C.A. CNS melanocortin and leptin effects on stearoyl-CoA desaturase-1 and resistin expression.Biochem. Biophys. Res. Commun. 2003; 311: 324-328Crossref PubMed Scopus (40) Google Scholar, 10Miyazaki M. Dobrzyn A. Man W.C. Chu K. Sampath H. Kim H.J. Ntambi J.M. Stearoyl-CoA desaturase 1 gene expression is necessary for fructose-mediated induction of lipogenic gene expression by sterol regulatory element-binding protein-1c-dependent and -independent mechanisms.J. Biol. Chem. 2004; 279: 25164-25171Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 11Sessler A.M. Kaur N. Palta J.P. Ntambi J.M. Regulation of stearoyl-CoA desaturase 1 mRNA stability by polyunsaturated fatty acids in 3T3-L1 adipocytes.J. Biol. Chem. 1996; 271: 29854-29858Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). This transcriptional regulation involves several transcription factors, including carbohydrate response element binding protein, sterol-regulatory element binding protein-1c (SREBP-1c), and liver X receptor, highlighting the importance of SCD1 activity for the adaptation to different metabolic demands (12Iizuka K. Bruick R.K. Liang G. Horton J.D. Uyeda K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis.Proc. Natl. Acad. Sci. USA. 2004; 101: 7281-7286Crossref PubMed Scopus (576) Google Scholar, 13Liang G. Yang J. Horton J.D. Hammer R.E. Goldstein J.L. Brown M.S. Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c.J. Biol. Chem. 2002; 277: 9520-9528Abstract Full Text Full Text PDF PubMed Scopus (526) Google Scholar). SCD1 activity influences the fatty acid composition of cellular and circulating triglycerides, cholesteryl esters, phospholipids, and free fatty acids (14Attie A.D. Krauss R.M. Gray-Keller M.P. Brownlie A. Miyazaki M. Kastelein J.J. Lusis A.J. Stalenhoef A.F. Stoehr J.P. Hayden M.R. et al.Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia.J. Lipid Res. 2002; 43: 1899-1907Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 15Miyazaki M. Kim Y.C. Ntambi J.M. A lipogenic diet in mice with a disruption of the stearoyl-CoA desaturase 1 gene reveals a stringent requirement of endogenous monounsaturated fatty acids for triglyceride synthesis.J. Lipid Res. 2001; 42: 1018-1024Abstract Full Text Full Text PDF PubMed Google Scholar). SCD1 activity is also essential for the normal posttranslational processing of SREBP-1c and the upregulation of SREBP-1c target genes in response to a fat-free, high-carbohydrate diet (10Miyazaki M. Dobrzyn A. Man W.C. Chu K. Sampath H. Kim H.J. Ntambi J.M. Stearoyl-CoA desaturase 1 gene expression is necessary for fructose-mediated induction of lipogenic gene expression by sterol regulatory element-binding protein-1c-dependent and -independent mechanisms.J. Biol. Chem. 2004; 279: 25164-25171Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 15Miyazaki M. Kim Y.C. Ntambi J.M. A lipogenic diet in mice with a disruption of the stearoyl-CoA desaturase 1 gene reveals a stringent requirement of endogenous monounsaturated fatty acids for triglyceride synthesis.J. Lipid Res. 2001; 42: 1018-1024Abstract Full Text Full Text PDF PubMed Google Scholar). This indicates that dietary induction of SCD1 not only affects fatty acid composition but also augments the expression of other lipogenic genes. Previous studies using SCD1−/− mice have identified several interesting metabolic phenotypes, including resistance to diet-induced obesity, decreased lipogenesis, increased insulin sensitivity, fatty acid oxidation, and basal thermogenesis (4Ntambi J.M. Miyazaki M. Recent insights into stearoyl-CoA desaturase-1.Curr. Opin. Lipidol. 2003; 14: 255-261Crossref PubMed Scopus (216) Google Scholar). It is important to note that most of these phenotypes, with the exception of impaired lipogenesis, have been identified using chow or high-fat diets containing ample unsaturated fat. Short-term feeding of a semipurified low-fat, high-carbohydrate diet has been shown to increase hepatic SCD1 expression, MUFA production, and triglyceride synthesis in wild-type (SCD1+/+), but not SCD1−/−, mice (10Miyazaki M. Dobrzyn A. Man W.C. Chu K. Sampath H. Kim H.J. Ntambi J.M. Stearoyl-CoA desaturase 1 gene expression is necessary for fructose-mediated induction of lipogenic gene expression by sterol regulatory element-binding protein-1c-dependent and -independent mechanisms.J. Biol. Chem. 2004; 279: 25164-25171Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 15Miyazaki M. Kim Y.C. Ntambi J.M. A lipogenic diet in mice with a disruption of the stearoyl-CoA desaturase 1 gene reveals a stringent requirement of endogenous monounsaturated fatty acids for triglyceride synthesis.J. Lipid Res. 2001; 42: 1018-1024Abstract Full Text Full Text PDF PubMed Google Scholar). However, the chronic effect of this feeding regimen in SCD1−/− mice has not been adequately explored. We report here that SCD1−/− mice fed a very low-fat (VLF) diet for 10 days develop severe hypercholesterolemia and hepatic dysfunction. These phenotypes are prevented by a combination of dietary MUFAs and PUFAs, indicating that lack of SCD1 results in an increased requirement for dietary unsaturated fat to compensate for impaired MUFA synthesis. These results also highlight the intricate balance between dietary and de novo unsaturated fat and indicate that upregulation of SCD1 during dietary unsaturated fat insufficiency may be a protective mechanism against the pathologies described in this study. SV129 SCD1−/− mice were backcrossed to C57BL/6 mice for at least five generations. Genetic purity was ascertained by marker-assisted genotyping. Both breeder mice and offspring were fed a standard rodent chow diet (PMI 5008 Formulab; PMI Nutrition International, Richmond, IN) and housed in a controlled environment with 12 h light and dark cycles. Male SCD1−/− mice were crossed with female heterozygous (SCD1+/−) mice to produce SCD1+/− and SCD1−/− littermates. SCD1+/+ mice were produced by crossing male and female C57BL/6 SCD1+/+ mice. Protocols for animal experiments were approved by the Animal Care Research Committee of the University of Wisconsin-Madison. For the experiments described, male or female animals 7–12 weeks old were used. For diet studies, mice were maintained on chow until 10 weeks of age before dietary intervention. Diets TD03045 (VLF), TD03138 (VLF-coconut), and TD04422 (VLF-canola) were obtained from Harlan Teklad (Madison, WI). The VLF-oleate diet was prepared using TD99252 basal mix supplemented with corn oil and triolein (99% pure; Sigma). These semipurified diets all contain sucrose (50%, w/w) as the primary carbohydrate source and corn oil (1%, w/w) as the invariant basal fat source. VLF-coconut, VLF-canola, and VLF-oleate diets differ primarily in the fat source used to supplement the VLF diet. The starch content of the fat-supplemented VLF-coconut, VLF-canola, and VLF-oleate diets was reduced to compensate for the added fat. See Supplementary Table I for more explicit diet composition information. Fat composition and nutrient content are expressed as percentage of weight of diet and were provided by the manufacturer. Plasma from animals fasted for 4 h in the early light cycle was used for lipid analysis. Animals were euthanized by CO2 asphyxiation, and blood was collected into EDTA (4 mM final concentration). Fresh plasma (100 μl) was fractionated on a Superose 6HR 10/30 fast-protein liquid chromatography (FPLC) column (Amersham Biosciences), and 500 μl fractions were collected. FPLC fractions or whole plasma were assayed for total cholesterol and triglyceride using the Infinity Cholesterol reagent and Infinity Triglyceride reagent (Thermo Electron Corp.). Plasma concentrations of free cholesterol were determined using the Free Cholesterol C kit (Wako, Richmond, VA). Plasma cholesteryl ester levels were calculated as the difference between total and free cholesterol. Plasma phospholipid levels were determined by the method of Rouser, Fkeischer, and Yamamoto (16Rouser G. Fkeischer S. Yamamoto A. Two dimensional thin layer chromatographic separation of polar lipids and determination of phospholipids by phosphorus analysis of spots.Lipids. 1970; 5: 494-496Crossref PubMed Scopus (2879) Google Scholar). Total and direct bilirubin were measured using Infinity Total Bilirubin and Infinity Direct Bilirubin kits (Thermo Electron Corp.). Plasma bile acids were measured by a colorimetric enzyme cycling assay (Bioquant). Bile was collected by aspiration of the gallbladder or upon gallbladder cannulation and analyzed for cholesterol and phospholipids as described (17Elferink R.P. Ottenhoff R. van Marle J. Frijters C.M. Smith A.J. Groen A.K. Class III P-glycoproteins mediate the formation of lipoprotein X in the mouse.J. Clin. Invest. 1998; 102: 1749-1757Crossref PubMed Google Scholar). Briefly, biliary cholesterol was measured by an enzymatic assay, using the cholesterol oxidase reaction coupled to fluorimetric determination of hydrogen peroxide. Choline-containing biliary phospholipids were determined by a similar approach using the oxidation of choline to generate hydrogen peroxide. The choline was liberated by enzymatic treatment with phospholipase D and choline oxidase. Total bile salt concentrations were measured using the 3α-hydroxysteroid dehydrogenase method (18Turley S.D. Dietschy J.M. Re-evaluation of the 3 alpha-hydroxysteroid dehydrogenase assay for total bile acids in bile.J. Lipid Res. 1978; 19: 924-928Abstract Full Text PDF PubMed Google Scholar). Biliary bile acid and phospholipid fatty acid compositions were determined by capillary gas chromatography after their conversion into methyl ester-trimethylsilyl ether derivatives or methyl esters, respectively, exactly as described (19Kok T. Hulzebos C.V. Wolters H. Havinga R. Agellon L.B. Stellaard F. Shan B. Schwarz M. Kuipers F. Enterohepatic circulation of bile salts in farnesoid X receptor-deficient mice: efficient intestinal bile salt absorption in the absence of ileal bile acid-binding protein.J. Biol. Chem. 2003; 278: 41930-41937Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 20Werner A. Minich D.M. Havinga R. Bloks V. Van Goor H. Kuipers F. Verkade H.J. Fat malabsorption in essential fatty acid-deficient mice is not due to impaired bile formation.Am. J. Physiol. 2002; 283: G900-G908Crossref PubMed Scopus (24) Google Scholar). To determine bile flow, the gallbladder of the mice was cannulated under isoflurane anesthesia after distal ligation of the common bile duct. Bile was collected in 10 min fractions, and flow was determined gravimetrically. For hepatic lipid analysis, 100 mg of liver was homogenized, and an aliquot representing ∼5 mg of tissue was lipid-extracted (21Bligh E.G. Dyer W.J. A rapid method of total lipid extraction and purification.Can. J. Biochem. Physiol. 1959; 37: 911-917Crossref PubMed Scopus (42878) Google Scholar), dried under N2, and resuspended in 10 μl of CHCl3. After the addition of 90 μl of 10% Triton X-100 in isopropanol, the sample was vortexed for 10 s and assayed with Wako Triglyceride, Free Cholesterol C, or Cholesterol CII reagent according to the manufacturer's instructions, except that samples were vortexed to clarity before absorbance measurement. Hepatic cholesteryl ester levels were calculated as the difference between total and free cholesterol. Protein determination was by the method of Lowry et al. (22Lowry O.H. Rosebrough N.J. Farr A.L. Randall R.J. Protein measurement with the Folin phenol reagent.J. Biol. Chem. 1951; 193: 265-275Abstract Full Text PDF PubMed Google Scholar), and lipid data are expressed as μg lipid/mg protein. Plasma glucose and liver glycogen were measured as described previously (10Miyazaki M. Dobrzyn A. Man W.C. Chu K. Sampath H. Kim H.J. Ntambi J.M. Stearoyl-CoA desaturase 1 gene expression is necessary for fructose-mediated induction of lipogenic gene expression by sterol regulatory element-binding protein-1c-dependent and -independent mechanisms.J. Biol. Chem. 2004; 279: 25164-25171Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar). Fresh plasma or FPLC-fractionated plasma lipoproteins were precipitated using PMH-L-Liposorb (Calbiochem) and resolved by SDS-PAGE. Gels were stained with SYPRO Ruby (Molecular Probes), and proteins were imaged by Fluorimager quantitation (ImageQuant; Molecular Dynamics). For detection of lipoprotein X, fresh plasma was stained with Sudan black (0.02%, v/v) and subjected to agarose gel electrophoresis as described elsewhere (17Elferink R.P. Ottenhoff R. van Marle J. Frijters C.M. Smith A.J. Groen A.K. Class III P-glycoproteins mediate the formation of lipoprotein X in the mouse.J. Clin. Invest. 1998; 102: 1749-1757Crossref PubMed Google Scholar, 23Bloks V.W. Plosch T. van Goor H. Roelofsen H. Baller J. Havinga R. Verkade H.J. van Tol A. Jansen P.L. Kuipers F. Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice.J. Lipid Res. 2001; 42: 41-50Abstract Full Text Full Text PDF PubMed Google Scholar), except for the substitution of a Tris-Tricine buffer for barbital (24Monthony J.F. Wallace E.G. Allen D.M. A non-barbital buffer for immunoelectrophoresis and zone electrophoresis in agarose gels.Clin. Chem. 1978; 24: 1825-1827Crossref PubMed Scopus (47) Google Scholar). Hepatic triglyceride secretion rates were determined by measuring the temporal increase in plasma triglyceride after inhibition of lipoprotein lipase by intraperitoneal injection of poloxamer 407 (P-407; BASF Corp.), as described by Millar et al. (25Millar J.S. Cromley D.A. McCoy M.G. Rader D.J. Billheimer J.T. Determining hepatic triglyceride production in mice: comparison of poloxamer 407 with Triton WR-1339.J. Lipid Res. 2005; 46: 2023-2028Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar). Briefly, mice were fasted for 4 h and then administered P-407 at 2 g/kg. Blood was collected by retro-orbital puncture immediately before injection and at 30, 60, and 120 min after injection. The triglyceride and cholesterol secretion rates were calculated as the difference in plasma triglyceride and cholesterol over the 2 h time interval and are expressed as μmol/kg/h. LDL (d = 1.019–1.063 g/ml) was isolated from LDL receptor-deficient donors by density gradient ultracentrifugation, dialyzed to PBS, and labeled with [125I]NaI (Perkin-Elmer Life Sciences). [125I]NaI was added to IODO-Gen precoated tubes (Pierce Biotechnology), allowed to activate for 6 min, and then transferred to a new IODO-Gen tube containing LDL and allowed to react for 15 min according to the manufacturer's instructions. Unincorporated 125I was removed by dialysis to PBS, and the specific activity of 125I-LDL was determined by the amount of 125I precipitable by 10% TCA. A typical 125I-LDL preparation yielded >90% TCA-precipitable counts, and the major protein components of the isolated LDL were apolipoprotein B-100 (apoB-100), apoB-48, and apoE. After a 4 h fast, mice were delivered a tail vein injection of 125I-LDL and bled by retro-orbital puncture at the indicated time. TCA-precipitable counts remaining in the plasma were measured by liquid scintillation counting and normalized to the amount of radioactivity present at 2 min after injection. Plasma LCAT activity was determined using a proteoliposome substrate as described (26Gillett M.P.T. Owen J.S. Converse C.A. Skinner E.R. Cholesterol esterifying enzymes—lecithin:cholesterol acyltransferase (LCAT) and acylcoenzyme A:cholesterol acyltransferase (ACAT). In Lipoprotein Analysis: A Practical Approach. Oxford University Press, New York1992: 187-201Google Scholar) containing [4-14C]cholesterol (American Radiolabeled Chemicals), human apoA-I (Calbiochem), and egg phosphatidylcholine (Sigma). Proteoliposome substrate was incubated with 15 μl of test plasma at 37°C for 1 h and immediately lipid-extracted. The ratio of [14C]cholesteryl ester to [14C]free cholesterol was determined by TLC and subsequent quantitation using an Instant Imager (Packard Instrument Co.). Plasma LCAT cholesterol esterification rates are expressed as nmol/ml/h. Total RNA was extracted from liver using RNAzol reagent (Tel-Test) and purified with RNeasy mini columns (Qiagen) before being subjected to microarray studies using Affymetrix Mouse 430 2.0 microarray chips. A total of 20 arrays were used to study female SCD1+/+ and SCD1−/− mice on chow or the VLF diet (2 strains × 2 diets × 5 replicates = 20 arrays). The complete MIAME formatted data set is deposited as Gene Expression Omnibus accession GSE3889, which may be accessed at http://www.ncbi.nlm.nih.gov/geo. Expression measurements were background-adjusted, normalized, and summarized with RMA (27Irizarry R.A. Hobbs B. Collin F. Beazer-Barclay Y.D. Antonellis K.J. Scherf U. Speed T.P. Exploration, normalization, and summaries of high density oligonucleotide array probe level data.Biostatistics. 2003; 4: 249-264Crossref PubMed Scopus (8483) Google Scholar) implemented in R, a publicly available statistical analysis environment (28R Development Core TeamR: A Language and Environment for Statistical Computing. 2005; (R Foundation for Statistical Computing, Vienna, Austria)Google Scholar). Comparison for each of the clinical variables was done by one-way ANOVA, and two-way ANOVA was used for comparisons containing both genotype and diet variables. Variables with unequal variance were log-transformed before analysis. Significant interactions were analyzed with Bonferroni posttests, and Bonferroni corrected P values < 0.05 were considered significant. The expression levels of genes involved in lipoprotein, bile, and cholesterol metabolism were compared by two-way ANOVA and further by within-genotype and within-diet t-tests. The false-discovery rate was estimated by calculating q-values (29Storey J.D. Tibshirani R. Statistical significance for genomewide studies.Proc. Natl. Acad. Sci. USA. 2003; 100: 9440-9445Crossref PubMed Scopus (7105) Google Scholar) based on the P values from the t-tests. This calculation was done twice to yield two estimated false-discovery rates, once within genotype and a second time within diet. We first studied plasma lipid profiles in animals maintained on either a chow diet or a VLF diet for 10 days. Surprisingly, total plasma cholesterol levels in the VLF SCD1−/− mice increased by ∼250% relative to chow SCD1−/− mice (Table 1 ). In contrast, plasma cholesterol levels in VLF SCD1+/− mice were increased by only ∼20% relative to chow SCD1+/− mice (Table 1). No significant increase was elicited by the VLF diet in SCD1+/+ mice. In chow-fed animals, SCD1 deficiency decreased plasma cholesterol levels, primarily as a result of differences in the HDL fraction (Table 1, Fig. 1A ). The absence of this abnormal phenotype in VLF SCD1+/− mice indicates that SCD1+/− mice retained sufficient SCD activity to maintain normal cholesterol homeostasis. Therefore, the combination of complete SCD1 deficiency and VLF diet treatment is required to elicit hypercholesterolemia.TABLE 1Plasma cholesterol and triglyceride concentrationsAnimal and MeasurementMale, ChowMale, VLFFemale, ChowFemale, VLFTriglyceride (mg/dl)SCD1+/+80.0 ± 15.4 (12Iizuka K. Bruick R.K. Liang G. Horton J.D. Uyeda K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis.Proc. Natl. Acad. Sci. USA. 2004; 101: 7281-7286Crossref PubMed Scopus (576) Google Scholar)93.7 ± 24.5 (6Foufelle F. Ferre P. New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c.Biochem. J. 2002; 366: 377-391Crossref PubMed Scopus (404) Google Scholar)55.9 ± 12.2 (11Sessler A.M. Kaur N. Palta J.P. Ntambi J.M. Regulation of stearoyl-CoA desaturase 1 mRNA stability by polyunsaturated fatty acids in 3T3-L1 adipocytes.J. Biol. Chem. 1996; 271: 29854-29858Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar)94.7 ± 6.0aP < 0.05, diet effect (same genotype). (5Cunnane S.C. The Canadian Society for Nutritional Sciences 1995 Young Scientist Award Lecture. Recent studies on the synthesis, beta-oxidation, and deficiency of linoleate and alpha-linolenate: are essential fatty acids more aptly named indispensable or conditionally dispensable fatty acids?.Can. J. Physiol. Pharmacol. 1996; 74: 629-639Crossref PubMed Google Scholar)SCD1+/−85.7 ± 14.3 (11Sessler A.M. Kaur N. Palta J.P. Ntambi J.M. Regulation of stearoyl-CoA desaturase 1 mRNA stability by polyunsaturated fatty acids in 3T3-L1 adipocytes.J. Biol. Chem. 1996; 271: 29854-29858Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar)92.1 ± 15.8 (8Kim H.J. Miyazaki M. Ntambi J.M. Dietary cholesterol opposes PUFA-mediated repression of the stearoyl-CoA desaturase-1 gene by SREBP-1 independent mechanism.J. Lipid Res. 2002; 43: 1750-1757Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar)56.1 ± 7.6 (8Kim H.J. Miyazaki M. Ntambi J.M. Dietary cholesterol opposes PUFA-mediated repression of the stearoyl-CoA desaturase-1 gene by SREBP-1 independent mechanism.J. Lipid Res. 2002; 43: 1750-1757Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar)90.3 ± 21.5 (4Ntambi J.M. Miyazaki M. Recent insights into stearoyl-CoA desaturase-1.Curr. Opin. Lipidol. 2003; 14: 255-261Crossref PubMed Scopus (216) Google Scholar)SCD1−/−78.0 ± 23.3 (7Kaestner K.H. Ntambi J.M. Kelly Jr., T.J. Lane M.D. Differentiation-induced gene expression in 3T3-L1 preadipocytes. A second differentially expressed gene encoding stearoyl-CoA desaturase.J. Biol. Chem. 1989; 264: 14755-14761Abstract Full Text PDF PubMed Google Scholar)50.0 ± 15.3bP < 0.05, genotype effect (same diet) versus SCD1+/+.,cP < 0.05, genotype effect (same diet) versus SCD1+/−. (5Cunnane S.C. The Canadian Society for Nutritional Sciences 1995 Young Scientist Award Lecture. Recent studies on the synthesis, beta-oxidation, and deficiency of linoleate and alpha-linolenate: are essential fatty acids more aptly named indispensable or conditionally dispensable fatty acids?.Can. J. Physiol. Pharmacol. 1996; 74: 629-639Crossref PubMed Google Scholar)60.7 ± 12.5 (14Attie A.D. Krauss R.M. Gray-Keller M.P. Brownlie A. Miyazaki M. Kastelein J.J. Lusis A.J. Stalenhoef A.F. Stoehr J.P. Hayden M.R. et al.Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia.J. Lipid Res. 2002; 43: 1899-1907Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar)53.6 ± 15.9bP < 0.05, genotype effect (same diet) versus SCD1+/+.,cP < 0.05, genotype effect (same diet) versus SCD1+/−. (9Lin J. Choi Y.H. Hartzell D.L. Li C. Della-Fera M.A. Baile C.A. CNS melanocortin and leptin effects on stearoyl-CoA desaturase-1 and resistin expression.Biochem. Biophys. Res. Commun. 2003; 311: 324-328Crossref PubMed Scopus (40) Google Scholar)Cholesterol (mg/dl)SCD1+/+99.1 ± 13.3 (12Iizuka K. Bruick R.K. Liang G. Horton J.D. Uyeda K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis.Proc." @default.
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