Clinical interventions that accelerate conversion of cholesterol to bile acids reduce circulating low density lipoprotein (LDL) cholesterol concentrations. The initial and rate-limiting step in the bile acid biosynthetic pathway is catalyzed by hepatic cholesterol 7 alpha-hydroxylase. To examine the effects of transient primary overexpression of this enzyme on sterol metabolism and lipoprotein transport, we constructed a recombinant adenovirus in which a cDNA encoding rat 7 alpha-hydroxylase is expressed from the human cytomegalovirus immediate-early promoter (AdCMV7 alpha). Syrian hamsters administered AdCMV7 alpha intravenously accumulated transgene-specific mRNA in the liver and demonstrated a dose-dependent increase in hepatic microsomal 7 alpha-hydroxylase activity. The increased conversion of cholesterol to bile acids resulted in a compensatory increase in hepatic cholesterol synthesis. In addition, overexpression of 7 alpha-hydroxylase reduced the rate of LDL cholesterol entry into the plasma space and, in animals maintained on a Western-type diet, restored hepatic LDL receptor expression. As a consequence, plasma LDL concentrations fell by approximately 60% in animals maintained on control diet and by approximately 75% in animals consuming a Western-type diet. Plasma high density lipoprotein cholesterol levels were reduced to a lesser degree. These results demonstrate that transient upregulation of bile acid synthesis by direct transfer of a 7 alpha-hydroxylase gene favorably alters circulating lipoprotein profiles and suggest one potential molecular target for genetic strategies aimed at reducing cardiovascular risk.
D K Spady, J A Cuthbert, M N Willard, R S Meidell
Title and authors | Publication | Year |
---|---|---|
Ferulic acid attenuates high-fat diet-induced hypercholesterolemia by activating classic bile acid synthesis pathway
Luo Z, Li M, Yang J, Li J, Zhang Y, Liu F, El-Omar E, Han L, Bian J, Gong L, Wang M |
Frontiers in Nutrition | 2022 |
IIAEK Targets Intestinal Alkaline Phosphatase (IAP) to Improve Cholesterol Metabolism with a Specific Activation of IAP and Downregulation of ABCA1
A Takeuchi, K Hisamatsu, N Okumura, Y Sugimitsu, E Yanase, Y Ueno, S Nagaoka |
Nutrients | 2020 |
Low-molecular-weight peptides with potential cardiovascular regulatory functions from Atlantic salmon skin
WY Liu, T Miyakawa, J Lu, RZ Gu, YH Hsieh, Y Miyauchi, K Katsuno, MY Cai, M Tanokura |
INT J FOOD ENG | 2020 |
Genetic variants in CYP7A1 and risk of myocardial infarction and symptomatic gallstone disease
F Qayyum, BK Lauridsen, R Frikke-Schmidt, KF Kofoed, BG Nordestgaard, A Tybjærg-Hansen |
European Heart Journal | 2018 |
Effects of oral selenium and magnesium co-supplementation on lipid metabolism, antioxidative status, histopathological lesions, and related gene expression in rats fed a high-fat diet
Q Zhang, ZY Qian, PH Zhou, X Zhou, DL Zhang, N He, J Zhang, YH Liu, Q Gu |
Lipids in Health and Disease | 2018 |
Prenatal Exposure to a Maternal High Fat Diet Increases Hepatic Cholesterol Accumulation in Intrauterine Growth Restricted Rats in Part Through MicroRNA-122 Inhibition of Cyp7a1
EK Zinkhan, B Yu, A Schlegel |
Frontiers in physiology | 2018 |
Nutrition and Food Science Studies of Cholesterol Metabolism Regulation: (JSNFS Award for Excellence in Research (2015))
S Nagaoka |
Nippon Eiyo Shokuryo Gakkaishi | 2018 |
Structure-function properties of hypolipidemic peptides
S Nagaoka |
Journal of Food Biochemistry | 2018 |
Uteroplacental Insufficiency Impairs Cholesterol Elimination in Adult Female Growth-Restricted Rat Offspring Fed a High-Fat Diet
EK Zinkhan, B Yu, R McKnight |
Reproductive sciences (Thousand Oaks, Calif.) | 2018 |
New Development of the Study on Lifestyle-Related Disease Preventive and Improvement Action of Peptides Derived from Food Proteins
S NAGAOKA |
KAGAKU TO SEIBUTSU | 2016 |
Identification of a Novel Hypocholesterolemic Protein, Major Royal Jelly Protein 1, Derived from Royal Jelly
Y Kashima, S Kanematsu, S Asai, M Kusada, S Watanabe, T Kawashima, T Nakamura, M Shimada, T Goto, S Nagaoka, A Moschetta |
PloS one | 2014 |
Cholesterol-lowering effect of Lactobacillus plantarum NCU116 in a hyperlipidaemic rat model
C Li, SP Nie, Q Ding, KX Zhu, ZJ Wang, T Xiong, J Gong, MY Xie |
Journal of Functional Foods | 2014 |
Combination of intrauterine growth restriction and a high-fat diet impairs cholesterol elimination in rats
EK Zinkhan, JR Chin, JM Zalla, B Yu, B Numpang, X Yu, C Jiang, CW Callaway, RA McKnight, L Joss-Moore, RH Lane |
Pediatric Research | 2014 |
Knockout of mouse Cyp3a gene enhances synthesis of cholesterol and bile acid in the liver
M Hashimoto, K Kobayashi, M Watanabe, Y Kazuki, S Takehara, A Inaba, S Nitta, N Senda, M Oshimura, K Chiba |
Journal of lipid research | 2013 |
Lipoproteins and Cardiovascular Disease
LA Freeman |
2013 | |
Lipoproteins and Cardiovascular Disease
LA Freeman |
2013 | |
Lipoproteins and Cardiovascular Disease
LA Freeman |
2013 | |
Effects of NS Lactobacillus strains on lipid metabolism of rats fed a high-cholesterol diet
X Hu, T Wang, W Li, F Jin, L Wang |
Lipids in Health and Disease | 2013 |
Knockout of mouse Cyp3a gene enhances synthesis of cholesterol and bile acid in the liver[S]
M Hashimoto, K Kobayashi, M Watanabe, Y Kazuki, S Takehara, A Inaba, S Nitta, N Senda, M Oshimura, K Chiba |
Journal of lipid research | 2013 |
Knockout of mouse Cyp3a gene enhances synthesis of cholesterol and bile acid in the liver
M Hashimoto, K Kobayashi, M Watanabe, Y Kazuki, S Takehara, A Inaba, S Nitta, N Senda, M Oshimura, K Chiba |
Journal of lipid research | 2013 |
Thyroid Hormone Receptor Agonists Reduce Serum Cholesterol Independent of the LDL Receptor
JZ Lin, AJ Martagón, WA Hsueh, JD Baxter, JÅ Gustafsson, P Webb, KJ Phillips |
Endocrinology | 2012 |
An Egg-Enriched Diet Attenuates Plasma Lipids and Mediates Cholesterol Metabolism of High-Cholesterol Fed Rats
F Yang, M Ma, J Xu, X Yu, N Qiu |
Lipids | 2012 |
Food Proteins and Peptides: Chemistry, Functionality, Interactions, and Commercialization
S Nagaoka |
Food Proteins and Peptides: Chemistry, Functionality, Interactions, and Commercialization | 2012 |
The Ileal Lipid Binding Protein Is Required for Efficient Absorption and Transport of Bile Acids in the Distal Portion of the Murine Small Intestine
D Praslickova, EC Torchia, MG Sugiyama, EJ Magrane, BL Zwicker, L Kolodzieyski, LB Agellon, A Moschetta |
PloS one | 2012 |
Genetics and molecular biology
J Pétremand, C Widmann |
Current Opinion in Lipidology | 2011 |
Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR −/− and apoE −/− mice
HB Hartman, SJ Gardell, CJ Petucci, S Wang, JA Krueger, MJ Evans |
Journal of lipid research | 2009 |
Activated polyamine catabolism leads to low cholesterol levels by enhancing bile acid synthesis
E Pirinen, H Gylling, P Itkonen, N Yaluri, S Heikkinen, M Pietilä, T Kuulasmaa, M Tusa, M Cerrada-Gimenez, J Pihlajamäki, L Alhonen, J Jänne, TA Miettinen, M Laakso |
Amino Acids | 2009 |
Farnesoid X receptor as a therapeutic target for dyslipidemia
MJ Evans, SJ Gardell |
Clinical Lipidology | 2009 |
Association between CYP7A1 and the risk of proximal colon cancer in Japanese
H Ito, K Matsuo, S Hosono, M Watanabe, T Kawase, T Suzuki, T Hirai, Y Yatabe, H Tanaka, K Tajima |
International journal of molecular epidemiology and genetics | 2009 |
CYP A-204C polymorphism is associated with subclinical atherosclerosis in postmenopausal women
IV Lambrinoudaki, GI Kaparos, SA Vlachou, KS Stamatelopoulos, GA Georgiopoulos, TN Sergentanis, CP Panoulis, GE Christodoulakos, AP Alexandrou, EE Kouskouni, MG Creatsa, CM Papamichael |
Menopause | 2008 |
CYP7A1 promoter polymorphism −203A>C affects bile salt synthesis rate in patients after ileal resection
M Leníček, V Komárek, M Zimolová, J Kovář, M Jirsa, M Lukáš, L Vítek |
Journal of lipid research | 2008 |
The pharmacological exploitation of cholesterol 7alpha-hydroxylase, the key enzyme in bile acid synthesis: from binding resins to chromatin remodelling to reduce plasma cholesterol
F Gilardi, N Mitro, C Godio, E Scotti, D Caruso, M Crestani, ED Fabiani |
Pharmacology & Therapeutics | 2007 |
Effects of Dipeptides Having a C-Terminal Lysine on the Cholesterol 7α-Hydroxylase mRNA Level in HepG2 Cells
K MORIKAWA, K ISHIKAWA, Y KANAMARU, G HORI, S NAGAOKA |
Bioscience, Biotechnology, and Biochemistry | 2007 |
A novel regulatory pathway for cholesterol degradation via lactostatin
K Morikawa, I Kondo, Y Kanamaru, S Nagaoka |
Biochemical and Biophysical Research Communications | 2007 |
Dietary Fats and Risk of Chronic Disease
V Ziboh, K Vang, B Morrissey, J Weineger, S Naguwa, ME Gershwin, M Watnik |
Dietary Fats and Risk of Chronic Disease | 2006 |
Cellular toxicity of oxycholesterols
T Wielkoszyński, K Gawron, J Strzelczyk, P Bodzek, M Zalewska-Ziob, G Trapp, M Srebniak, A Wiczkowski |
BioEssays | 2006 |
Genetic polymorphism of cholesterol 7alpha-hydroxylase (CYP7A1) and colorectal adenomas: Self Defense Forces Health Study
S Tabata, G Yin, S Ogawa, K Yamaguchi, M Mineshita, S Kono |
Cancer Science | 2006 |
Principles of Molecular Medicine
MS Runge, C Patterson |
2006 | |
Genetic polymorphism of cholesterol 7α‐hydroxylase (CYP7A1) and colorectal adenomas: Self Defense Forces Health Study
Tabata S, Yin G, Ogawa S, Yamaguchi K, Mineshita M, Kono S |
Cancer Science | 2006 |
Common polymorphisms in the CYP7A1 gene do not contribute to variation in rates of bile acid synthesis and plasma LDL cholesterol concentration
A Abrahamsson, S Krapivner, U Gustafsson, O Muhrbeck, G Eggertsen, I Johansson, I Persson, B Angelin, M Ingelman-Sundberg, I Björkhem, C Einarsson, FM Hooft |
Atherosclerosis | 2005 |
Chinese soft-shelled turtle egg powder lowers serum cholesterol, increases faecal neutral steroids and bile acid excretion, and up-regulates liver cytochrome P450 mRNA level in rats
Y Huanling, L Yong, W Junbo, Z Liping, Y Weixing |
British Journal of Nutrition | 2005 |
Principles of Molecular Cardiology
MS Runge, C Patterson |
2005 | |
Increased plasma HDL cholesterol levels and biliary cholesterol excretion in hamster by LCAT overexpression
AH Zhang, S Gao, J Fan, W Huang, TQ Zhao, G Liu |
FEBS Letters | 2004 |
Primary hypercholesterolemia: genetic causes and treatment of five monogenic disorders
CR Pullinger, JP Kane, MJ Malloy |
Expert Review of Cardiovascular Therapy | 2003 |
Genetic background of cholesterol gallstone disease
A Kosters, M Jirsa, AK Groen |
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | 2003 |
Human Cholesterol 7alpha-Hydroxylase (CYP7A1) Deficiency has a Hypercholesterolemic Phenotype
Clive R. Pullinger, Celeste Eng, Gerald Salen, Sarah Shefer, Ashok K. Batta, Sandra K. Erickson, Andrea Verhagen, Christopher R. Rivera, Sean J. Mulvihill, Mary J. Malloy, John P. Kane |
Journal of Clinical Investigation | 2002 |
Identification of Gene-selective Modulators of the Bile Acid Receptor FXR
I Dussault, R Beard, M Lin, K Hollister, J Chen, JH Xiao, R Chandraratna, BM Forman |
The Journal of biological chemistry | 2002 |
Corn Fiber Oil Lowers Plasma Cholesterol by Altering Hepatic Cholesterol Metabolism and Up-Regulating LDL Receptors in Guinea Pigs
T Ramjiganesh, S Roy, HC Freake, JC McIntyre, ML Fernandez |
The Journal of nutrition | 2002 |
Taurine 4
LD Corte, RJ Huxtable, G Sgaragli, KF Tipton |
2002 | |
Growth hormone reduces plasma cholesterol in LDL receptor-deficient mice
M Rudling, B Angelin |
The FASEB Journal | 2001 |
Expression of Sterol 12α-Hydroxylase Alters Bile Acid Pool Composition in Primary Rat Hepatocytes and In Vivo
WM Pandak, P Bohdan, C Franklund, DH Mallonee, G Eggertsen, I Björkhem, G Gil, ZR Vlahcevic, PB Hylemon |
Gastroenterology | 2001 |
Increased Production of Apolipoprotein B-containing Lipoproteins in the Absence of Hyperlipidemia in Transgenic Mice Expressing Cholesterol 7α-Hydroxylase
JH Miyake, XD Doung, W Strauss, GL Moore, LW Castellani, LK Curtiss, JM Taylor, RA Davis |
The Journal of biological chemistry | 2001 |
Orphan Nuclear Receptors as eLiXiRs and FiXeRs of Sterol Metabolism
TT Lu, JJ Repa, DJ Mangelsdorf |
The Journal of biological chemistry | 2001 |
In Vivo and in Vitro Regulation of Sterol 27-Hydroxylase in the Liver during the Acute Phase Response: POTENTIAL ROLE OF HEPATOCYTE NUCLEAR FACTOR-1
RA Memon, AH Moser, JK Shigenaga, C Grunfeld, KR Feingold |
The Journal of biological chemistry | 2001 |
Effects of CYP7A1 overexpression on cholesterol and bile acid homeostasis
WM Pandak, C Schwarz, PB Hylemon, D Mallonee, K Valerie, DM Heuman, RA Fisher, K Redford, ZR Vlahcevic |
AJP Gastrointestinal and Liver Physiology | 2001 |
Overexpression of CYP27 in hepatic and extrahepatic cells: role in the regulation of cholesterol homeostasis
E Hall, P Hylemon, Z Vlahcevic, D Mallonee, K Valerie, N Avadhani, W Pandak |
AJP Gastrointestinal and Liver Physiology | 2001 |
Regulation of sterol 12α-hydroxylase and cholic acid biosynthesis in the rat
ZR Vlahcevic, G Eggertsen, I Björkhem, PB Hylemon, K Redford, WM Pandak |
Gastroenterology | 2000 |
THEROLE OFORPHANNUCLEARRECEPTORS IN THEREGULATION OFCHOLESTEROLHOMEOSTASIS
JJ Repa, DJ Mangelsdorf |
Annual Review of Cell and Developmental Biology | 2000 |
The effect of peroxisome-proliferator-activated receptor-alpha on the activity of the cholesterol 7 alpha-hydroxylase gene
DD Patel, BL Knight, AK Soutar, GF Gibbons, DP Wade |
Biochemical Journal | 2000 |
Oxysterols: Modulators of Cholesterol Metabolism and Other Processes
GJ Schroepfer |
Physiological reviews | 2000 |
Elevated Cholesterol Metabolism and Bile Acid Synthesis in Mice Lacking Membrane Tyrosine Kinase Receptor FGFR4
C Yu, F Wang, M Kan, C Jin, RB Jones, M Weinstein, CX Deng, WL McKeehan |
The Journal of biological chemistry | 2000 |
Role of Acyl-Coenzyme A:Cholesterol Acyltransferase-1 in the Control of Hepatic Very Low Density Lipoprotein Secretion and Low Density Lipoprotein Receptor Expression in the Mouse and Hamster
DK Spady, MN Willard, RS Meidell |
The Journal of biological chemistry | 2000 |
Bile acids and lipoprotein metabolism
B Angelin, M Eriksson, M Rudling |
Current Opinion in Lipidology | 1999 |
Contribution of cholesterol 7α-hydroxylase to the regulation of lipoprotein metabolism
JC Cohen |
Current Opinion in Lipidology | 1999 |
CPF: an orphan nuclear receptor that regulates liver-specific expression of the human cholesterol 7alpha-hydroxylase gene
M Nitta, S Ku, C Brown, AY Okamoto, B Shan |
Proceedings of the National Academy of Sciences | 1999 |
REGULATION OF BILE ACID BIOSYNTHESIS
ZR Vlahcevic, WM Pandak, RT Stravitz |
Gastroenterology Clinics of North America | 1999 |
CPF: An orphan nuclear receptor that regulates liver-specific expression of the human cholesterol 7 -hydroxylase gene
M Nitta, S Ku, C Brown, AY Okamoto, B Shan |
Proceedings of the National Academy of Sciences | 1999 |
Dietary Taurine Enhances Cholesterol Degradation and Reduces Serum and Liver Cholesterol Concentrations in Rats Fed a High-Cholesterol Diet
H Yokogoshi, H Mochizuki, K Nanami, Y Hida, F Miyachi, H Oda |
The Journal of nutrition | 1999 |
Cholesterol and Lipoprotein Metabolism in Aging: Reversal of Hypercholesterolemia by Growth Hormone Treatment in Old Rats
P Parini, B Angelin, M Rudling |
Arteriosclerosis, thrombosis, and vascular biology | 1999 |
Improvement in cholesterol metabolism in mice given chronic treatment of taurine and fed a high-fat diet
S Murakami, Y Kondo-Ohta, K Tomisawa |
Life Sciences | 1998 |
Sex steroids increase cholesterol 7α-hydroxylase mRNA in nonhuman primates
PL Colvin, JD Wagner, MR Adams, MG Sorci-Thomas |
Metabolism | 1998 |
Gender-related differences in bile acid and sterol metabolism in outbred CD-1 mice fed low- and high-cholesterol diets
SD Turley, M Schwarz, DK Spady, JM Dietschy |
Hepatology | 1998 |
Markedly Reduced Bile Acid Synthesis but Maintained Levels of Cholesterol and Vitamin D Metabolites in Mice with Disrupted Sterol 27-Hydroxylase Gene
H Rosen, A Reshef, N Maeda, A Lippoldt, S Shpizen, L Triger, G Eggertsen, I Björkhem, E Leitersdorf |
The Journal of biological chemistry | 1998 |
Overexpression of Cholesterol 7α-Hydroxylase (CYP7A) in Mice Lacking the Low Density Lipoprotein (LDL) Receptor Gene: LDL TRANSPORT AND PLASMA LDL CONCENTRATIONS ARE REDUCED
DK Spady, JA Cuthbert, MN Willard, RS Meidell |
The Journal of biological chemistry | 1998 |
Pharmacological expression in rat hepatocytes of a gene transferred by an adenovirus vector enabled by a chimeric promoter containing multiple cyclic adenosine monophosphate response elements
M Suzuki, RN Singh, RG Crystal |
Hepatology | 1998 |
Effect of dietary cholesterol on low density lipoprotein-receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and low density lipoprotein receptor-related protein mRNA expression in healthy humans
P Boucher, M de Lorgeril, P Salen, P Crozier, J Delaye, JJ Vallon, A Geyssant, R Dante |
Lipids | 1998 |
Complex genetic control of HDL levels in mice in response to an atherogenic diet. Coordinate regulation of HDL levels and bile acid metabolism
D Machleder, B Ivandic, C Welch, L Castellani, K Reue, AJ Lusis |
Journal of Clinical Investigation | 1997 |
Kinetic parameters for high density lipoprotein apoprotein AI and cholesteryl ester transport in the hamster
LA Woollett, DK Spady |
Journal of Clinical Investigation | 1997 |
Gene therapy for atherosclerosis
DJ Rader |
International Journal of Clinical & Laboratory Research | 1997 |
Partial transfection of liver with a synthetic cholesterol 7α-hydroxylase transgene is sufficient to stimulate the reduction of cholesterol in the plasma of hypercholesterolemic mice
LB Agellon |
Biochemistry and Cell Biology | 1997 |
Expression of human cholesterol 7alpha-hydroxylase in atherosclerosis-susceptible mice via adenovirus infection
GL Moore, CA Drevon, D Machleder, JD Trawick, A McClelland, S Roy, R Lyons, R Jambou, RA Davis |
Biochemical Journal | 1997 |
Antithrombotic gene therapy
RD Gerard |
Fibrinolysis and Proteolysis | 1997 |
Adenovirus gene therapy for hypercholesterolemia, thrombosis and restenosis
RD Gerard, D Collen |
Cardiovascular Research | 1997 |
Gene Transfer in the Cardiovascular System
KL March |
1997 | |
Cholesterol: Its Functions and Metabolism in Biology and Medicine
R Bittman |
1997 | |
Adenovirus-Mediated Transfer of Tissue-Type Plasminogen Activator Augments Thrombolysis in Tissue-Type Plasminogen Activator–Deficient and Plasminogen Activator Inhibitor-1–Overexpressing Mice
P Carmeliet, JM Stassen, IV Vlaenderen, RS Meidell, D Collen, RD Gerard |
Blood | 1997 |
Adenovirus-mediated transfer of a gene encoding acyloxyacyl hydrolase (AOAH) into mice increases tissue and plasma AOAH activity
MG Coulthard, J Swindle, RS Munford, RD Gerard, RS Meidell |
Infection and immunity | 1996 |
Disruption of cholesterol 7alpha-hydroxylase gene in mice. II. Bile acid deficiency is overcome by induction of oxysterol 7alpha-hydroxylase
M Schwarz, E G Lund, K D Setchell, H J Kayden, J E Zerwekh, I Björkhem, J Herz, D W Russell |
The Journal of biological chemistry | 1996 |
Disruption of Cholesterol 7α-Hydroxylase Gene in Mice
Margrit Schwarz, Erik G. Lund, Kenneth D. R. Setchell, Herbert J. Kayden, Joseph E. Zerwekh, Ingemar Björkhem, Joachim Herz, David W. Russell |
The Journal of biological chemistry | 1996 |
Feedback Regulation of Hepatic 7α-Hydroxylase Expression by Bile Salts in the Hamster
DK Spady, JA Cuthbert, MN Willard, RS Meidell |
The Journal of biological chemistry | 1996 |
Disruption of Cholesterol 7α-Hydroxylase Gene in Mice: II. BILE ACID DEFICIENCY IS OVERCOME BY INDUCTION OF OXYSTEROL 7α-HYDROXYLASE
M Schwarz, EG Lund, KD Setchell, HJ Kayden, JE Zerwekh, I Björkhem, J Herz, DW Russell |
The Journal of biological chemistry | 1996 |
Endotoxin, TNF, and IL-1 decrease cholesterol 7 alpha-hydroxylase mRNA levels and activity
KR Feingold, DK Spady, AS Pollock, AH Moser, C Grunfeld |
Journal of lipid research | 1996 |
Section Review: Cardiovascular & Renal: Genetic therapies for vascular diseases and lipid disorders
P Denèfle, N Duverger, D Branellec |
Expert Opinion on Investigational Drugs | 1995 |
Advances in Pharmacology
B Drenger, Y Ginosar, Y Gozal |
Advances in Pharmacology | 1994 |
Genetic Engineering
P Little |
Genetic Engineering | 1981 |