We produced transgenic mice that express a dominant-positive truncated form of sterol regulatory element-binding protein-2 (SREBP-2) in liver and adipose tissue. The encoded protein lacks the membrane-binding and COOH-terminal regulatory domains, and it is therefore not susceptible to negative regulation by cholesterol. Livers from the transgenic mice showed increases in mRNAs encoding multiple enzymes of cholesterol biosynthesis, the LDL receptor, and fatty acid biosynthesis. The elevations in mRNA for 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase and HMG CoA reductase were especially marked (13-fold and 75-fold, respectively). As a result, the transgenic livers showed a 28-fold increase in the rate of cholesterol synthesis and a lesser fourfold increase in fatty acid synthesis, as measured by intraperitoneal injection of [3H]water. These results contrast with previously reported effects of dominant-positive SREBP-1a, which activated fatty acid synthesis more than cholesterol synthesis. In adipose tissue of the SREBP-2 transgenics, the mRNAs for cholesterol biosynthetic enzymes were elevated, but the mRNAs for fatty acid biosynthetic enzymes were not. We conclude that SREBP-2 is a relatively selective activator of cholesterol synthesis, as opposed to fatty acid synthesis, in liver and adipose tissue of mice.
J D Horton, I Shimomura, M S Brown, R E Hammer, J L Goldstein, H Shimano
Title and authors | Publication | Year |
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Lipids in Health and Disease
PJ Quinn, X Wang |
Lipids in Health and Disease | 2008 |
Lipids in Health and Disease
PJ Quinn, X Wang |
Lipids in Health and Disease | 2008 |
Lipids in Health and Disease
PJ Quinn, X Wang |
Lipids in Health and Disease | 2008 |
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Acute clozapine exposure in vivo induces lipid accumulation and marked sequential changes in the expression of SREBP, PPAR, and LXR target genes in rat liver
J Fernø, AO Vik-Mo, G Jassim, B Håvik, K Berge, S Skrede, OA Gudbrandsen, J Waage, N Lunder, S Mørk, RK Berge, HA Jørgensen, VM Steen |
Psychopharmacology | 2008 |
Hormonal Regulation of Testicular Steroid and Cholesterol Homeostasis
SM Eacker, N Agrawal, K Qian, HL Dichek, EY Gong, K Lee, RE Braun |
Molecular Endocrinology | 2008 |
Maternal undernutrition programmes atherosclerosis in the ApoE*3-Leiden mouse
Z Yates, EJ Tarling, SC Langley-Evans, AM Salter |
British Journal of Nutrition | 2008 |
Bioactive lipids in metabolic syndrome
K Nagao, T Yanagita |
Progress in Lipid Research | 2008 |
Expression of sterol regulatory element-binding transcription factor (SREBF) 2 and SREBF cleavage-activating protein (SCAP) in human atheroma and the association of their allelic variants with sudden cardiac death
YM Fan, PJ Karhunen, M Levula, E Ilveskoski, J Mikkelsson, OA Kajander, O Järvinen, N Oksala, J Thusberg, M Vihinen, JP Salenius, L Kytömäki, JT Soini, R Laaksonen, T Lehtimäki |
Thrombosis Journal | 2008 |
Dynamical modeling of the cholesterol regulatory pathway with Boolean networks
G Kervizic, L Corcos |
BMC Systems Biology | 2008 |
High-carbohydrate diets affect the size and composition of plasma lipoproteins in hamsters (Mesocricetus auratus)
L Wang, J Yu, RL Walzem |
Comparative medicine | 2008 |
The citrus flavonoids hesperetin and nobiletin differentially regulate low density lipoprotein receptor gene transcription in HepG2 liver cells
B Morin, LN Nichols, KM Zalasky, JW Davis, JA Manthey, LJ Holland |
The Journal of nutrition | 2008 |
Eicosapentaenoic acid lowers plasma and liver cholesterol levels in the presence of peroxisome proliferators-activated receptor alpha
E Sugiyama, Y Ishikawa, Y Li, T Kagai, M Nobayashi, N Tanaka, Y Kamijo, S Yokoyama, A Hara, T Aoyama |
Life Sciences | 2008 |
Association between the insulin-induced gene 2 (INSIG2) and weight gain in a German sample of antipsychotic-treated schizophrenic patients: perturbation of SREBP-controlled lipogenesis in drug-related metabolic adverse effects?
SL Hellard, FM Theisen, M Haberhausen, MB Raeder, J Fernø, S Gebhardt, A Hinney, H Remschmidt, JC Krieg, C Mehler-Wex, MM Nöthen, J Hebebrand, VM Steen |
Molecular Psychiatry | 2008 |
Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples
SL Hellard, TW Mühleisen, S Djurovic, J Fernø, Z Ouriaghi, M Mattheisen, C Vasilescu, MB Raeder, T Hansen, J Strohmaier, A Georgi, FF Brockschmidt, I Melle, I Nenadic, H Sauer, M Rietschel, MM Nöthen, T Werge, OA Andreassen, S Cichon, VM Steen |
Molecular Psychiatry | 2008 |
Peroxisome proliferator-activated receptor-δ induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice
X Qin, X Xie, Y Fan, J Tian, Y Guan, X Wang, Y Zhu, N Wang |
Hepatology | 2008 |
Statins as effectors of key activities involved in apoE-dependent VLDL metabolism: Review and hypothesis
AD Dergunov, S Visvikis-Siest, G Siest |
Vascular Pharmacology | 2008 |
Feedback Inhibition of Cholesterol Biosynthesis by Dietary Cholesterol in Experimental Chronic Renal Failure
M Chmielewski, E Sucajtys-Szulc, E Kossowska, J Swierczynski, B Rutkowski, W Boguslawski |
Journal of Renal Nutrition | 2008 |
Nuclear SREBP-1a causes loss of pancreatic beta-cells and impaired insulin secretion
Y Iwasaki, H Iwasaki, S Yatoh, M Ishikawa, T Kato, T Matsuzaka, Y Nakagawa, N Yahagi, K Kobayashi, A Takahashi, H Suzuki, N Yamada, H Shimano |
Biochemical and Biophysical Research Communications | 2008 |
Soy protein ameliorates metabolic abnormalities in liver and adipose tissue of rats fed a high fat diet
I Torre-Villalvazo, AR Tovar, VE Ramos-Barragán, MA Cerbón-Cervantes, N Torres |
The Journal of nutrition | 2008 |
Dietary pea protein stimulates bile acid excretion and lowers hepatic cholesterol concentration in rats
J Spielmann, GI Stangl, K Eder |
Journal of Animal Physiology and Animal Nutrition | 2008 |
TOXICOLOGY OF BILE SALTS IN ANIMALS
YH Yeh, DF Hwang, JF Deng, YT Lee |
Toxin Reviews | 2008 |
Deletion of Scap in Alveolar Type II Cells Influences Lung Lipid Homeostasis and Identifies a Compensatory Role for Pulmonary Lipofibroblasts
V Besnard, SE Wert, MT Stahlman, AD Postle, Y Xu, M Ikegami, JA Whitsett |
The Journal of biological chemistry | 2008 |
Peroxisome Deficiency Causes a Complex Phenotype because of Hepatic SREBP/Insig Dysregulation Associated with Endoplasmic Reticulum Stress
WJ Kovacs, KN Tape, JE Shackelford, TM Wikander, MJ Richards, SJ Fliesler, SK Krisans, PL Faust |
The Journal of biological chemistry | 2008 |
Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity
M Ishikawa, Y Iwasaki, S Yatoh, T Kato, S Kumadaki, N Inoue, T Yamamoto, T Matsuzaka, Y Nakagawa, N Yahagi, K Kobayashi, A Takahashi, N Yamada, H Shimano |
Journal of lipid research | 2008 |
Cholesterol feedback: from Schoenheimer's bottle to Scap's MELADL
MS Brown, JL Goldstein |
Journal of lipid research | 2008 |
The Effects of Soy Isoflavones on Obesity
A Ørgaard, L Jensen |
Experimental biology and medicine (Maywood, N.J.) | 2008 |
The blind men 'see' the elephant-the many faces of fatty liver disease
MG Sanal |
World journal of gastroenterology : WJG | 2008 |
Lipid Extract of Nostoc commune var. sphaeroides Kützing, a Blue-Green Alga, Inhibits the Activation of Sterol Regulatory Element Binding Proteins in HepG2 Cells
HE Rasmussen, KR Blobaum, YK Park, SJ Ehlers, F Lu, JY Lee |
The Journal of nutrition | 2008 |