CYP27A1
Sterol 26-hydroxylase, mitochondrial precursor (EC 1.14.15.15) (5-beta-cholestane-3-alpha,7-alpha,12-alpha-triol 26-hydroxylase) (Cytochrome P-450C27/25) (Cytochrome P450 27) (Sterol 27-hydroxylase) (Vitamin D(3) 25-hydroxylase) [CYP27]
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Sterol 27-hydroxylase (CYP27A1) plays an important role in cholesterol homeostasis by degrading cholesterol to bile acids. Betaine can alleviate high-fat diet-induced hepatic cholesterol accumulation and maternal betaine treatment programs the hepatic expression of CYP27A1 in offspring. Excessive corticosterone (CORT) exposure causes hepatic cholesterol deposition in chickens, yet it remains unknown whether prenatal betaine modulates CORT-induced cholesterol accumulation in chicken liver later in life and whether it involves epigenetic gene regulation of CYP27A1. In this study, fertilized eggs were injected with saline or betaine at 2.5mg/egg before incubation, and the hatchlings were raised under the same condition till 56days of age followed by 7days of subcutaneous CORT injection. Plasma concentrations of total cholesterol (Tch), HDL- and LDL-cholesterol were significantly increased (P<0.05), after CORT challenge, in both control and betaine groups. However, prenatal betaine exposure prevented CORT-induced increase (P<0.05) in hepatic Tch content. Hepatic expression of cholesterol biosynthesis genes and ACAT1 protein that esterifies cholesterol for storage, were activated in both control and betaine groups upon CORT challenge. However, betaine-treated chickens were protected from CORT-induced repression (P<0.05) in LXR and CYP27A1 expression in the liver. CORT-induced down-regulation of LXR and CYP27A1 coincided with significantly increased (P<0.05) CpG methylation on their promoters, which was significantly ameliorated in betaine-treated chickens. These results suggest that in ovo betaine injection alleviates CORT-induced hepatic cholesterol deposition most probably through epigenetic regulation of CYP27A1 and LXR genes in juvenile chickens.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Anti-Inflammatory Agents
- Betaine
- Blotting, Western
- Chickens
- Cholestanetriol 26-Monooxygenase
- Cholesterol
- Corticosterone
- DNA Methylation
- Epigenesis, Genetic
- Female
- Gastrointestinal Agents
- Gene Expression Regulation, Enzymologic
- Immunoprecipitation
- Lipid Metabolism
- Liver
- Pregnancy
- Prenatal Exposure Delayed Effects
- Promoter Regions, Genetic
- RNA, Messenger
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
Keywords
- Betaine
- CYP27A1
- Cholesterol
- Corticosterone
- DNA methylation
n-3 PUFA such as EPA and DHA as well as oestrogen have been reported to decrease blood levels of cholesterol, but their underlying mechanism is unclear. The purpose of this study was to determine the effects of the combination of n-3 PUFA supplementation and oestrogen injection on hepatic cholesterol metabolism. Rats were fed a modified AIN-93G diet with 0, 1 or 2 % n-3 PUFA (EPA DHA) relative to the total energy intake for 12 weeks. Rats were surgically ovariectomised at week 8, and, after 1-week recovery, rats were injected with 17β-oestradiol-3-benzoate (E2) or maize oil for the last 3 weeks. Supplementation with n-3 PUFA and E2 injection significantly increased the ratio of the hepatic expression of phosphorylated AMP activated protein kinase (p-AMPK):AMP activated protein kinase (AMPK) and decreased sterol regulatory element-binding protein-2, 3-hydroxy-3-methylglutaryl coenzyme A reductase and proprotein convertase subtilisin/kexin type 9. Supplementation with n-3 PUFA increased hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), sterol 12α-hydroxylase (CYP8B1) and sterol 27-hydroxylase (CYP27A1); however, E2 injection decreased CYP7A1 and CYP8B1 but not CYP27A1. Additionally, E2 injection increased hepatic expression of oestrogen receptor-α and β. In conclusion, n-3 PUFA supplementation and E2 injection had synergic hypocholesterolaemic effects by down-regulating hepatic cholesterol synthesis (n-3 PUFA and oestrogen) and up-regulating bile acid synthesis (n-3 PUFA) in ovariectomised rats.
MeSH Terms
- Aging
- Animals
- Anticholesteremic Agents
- Cholestanetriol 26-Monooxygenase
- Cholesterol 7-alpha-Hydroxylase
- Combined Modality Therapy
- Diet, Fat-Restricted
- Dietary Supplements
- Estradiol
- Estrogens
- Fatty Acids, Omega-3
- Female
- Hydroxymethylglutaryl CoA Reductases
- Hypercholesterolemia
- Liver
- Ovariectomy
- Proprotein Convertase 9
- Random Allocation
- Rats, Wistar
- Serine Endopeptidases
- Steroid 12-alpha-Hydroxylase
- Sterol Regulatory Element Binding Protein 2
Keywords
- n-3 PUFA
- AMPK AMP activated protein kinase
- CYP27A1 sterol 27-hydroxylase
- CYP7A1 cholesterol 7α-hydroxylase
- CYP8B1 sterol 12α-hydroxylase
- Cholesterol metabolism
- E2 17β-oestradiol-3-benzoate
- ER-α oestrogen receptor-α
- ER-β oestrogen receptor-β
- HMG-CoA reductase 3-hydroxy-3-methylglutaryl coenzyme A reductase
- Oestrogen
- Ovariectomised rats
- Proprotein convertase subtilisin/kexin type 9
- SREBP-2 sterol regulatory element-binding protein-2
- TC total cholesterol
- p-AMPK phosphorylated AMP activated protein kinase
The Chernobyl accident released many radionuclides in the environment. Some are still contaminating the ground and thus the people through dietary intake. The long-term sanitary consequences of this disaster are still unclear and several biological systems remain to be investigated. Cholesterol metabolism is of particular interest, with regard to the link established between atherosclerosis and exposure to high-dose ionizing radiations. This study assesses the effect of cesium-137 on cholesterol metabolism in rats, after a chronic exposure since fetal life. To achieve this, rat dams were contaminated with cesium-137-supplemented water from two weeks before mating until the weaning of the pups. Thereafter, the weaned rats were given direct access to the contaminated drinking water until the age of 9 months. After the sacrifice, cholesterol metabolism was investigated in the liver at gene expression and protein level. The cholesterolemia was preserved, as well as the cholesterol concentration in the liver. At molecular level, the gene expressions of ACAT 2 (a cholesterol storage enzyme), of Apolipoprotein A-I and of RXR (a nuclear receptor involved in cholesterol metabolism) were significantly decreased. In addition, the enzymatic activity of CYP27A1, which catabolizes cholesterol, was increased. The results indicate that the rats seem to adapt to the cesium-137 contamination and display modifications of hepatic cholesterol metabolism only at molecular level and within physiological range.
MeSH Terms
- Administration, Oral
- Aging
- Animals
- Cesium Radioisotopes
- Cholesterol
- Female
- Liver
- Male
- Pregnancy
- Pregnancy, Animal
- Prenatal Exposure Delayed Effects
- Radiation Dosage
- Rats
- Rats, Sprague-Dawley
The developmental variation of cytochrome P450 (CYP)7A1, CYP7B1, CYP27A1, and 3beta-hydroxy-Delta(5)-C(27)-steroid dehydrogenase, key enzymes in bile acid biosynthesis, were investigated in pigs of different ages. As part of these studies, peptide sequences from a purified pig liver oxysterol 7alpha-hydroxylase were analyzed. The sequences showed a high degree of identity with those of murine and human CYP7B1. Enzymatic activities and mRNA levels of CYP27A1 and 3beta-hydroxy-Delta(5)-C(27)-steroid dehydrogenase were similar in livers of newborn and 6-month-old pigs. Enzymatic activity mediated by CYP7A1 increased several-fold between infancy and adolescence. Hepatic CYP7A1 and CYP7B1 mRNA levels increased several-fold with age. Hepatic microsomal 7alpha-hydroxylation of 27-hydroxycholesterol and dehydroepiandrosterone, substrates typical for CYP7B1, increased about 5-fold between infancy and adolescence whereas the activities in kidney microsomes decreased at least 10-fold. In conclusion, the results indicate that the expression of CYP27A1 and 3beta-hydroxy-Delta(5)-C(27)-steroid dehydrogenase are similar in livers of newborn and 6-month-old pigs whereas the levels of CYP7A1 increase. The finding that the levels of CYP7B1 increase with age in the liver but decrease in the kidney suggest a tissue-specific developmental regulation of CYP7B1. The age-dependent variation in the liver and kidney suggests that hormonal factors are involved in the regulation of CYP7B1.
MeSH Terms
- Aging
- Amino Acid Sequence
- Animals
- Animals, Newborn
- Base Sequence
- Bile Acids and Salts
- Cytochrome P-450 Enzyme System
- Cytochrome P450 Family 7
- Gene Expression Regulation, Developmental
- Gene Expression Regulation, Enzymologic
- Humans
- Kinetics
- Male
- Mice
- Mitochondria, Liver
- Molecular Sequence Data
- Orchiectomy
- Organ Specificity
- Peptide Fragments
- Polymerase Chain Reaction
- Progesterone Reductase
- RNA, Messenger
- Sequence Alignment
- Sequence Homology, Amino Acid
- Steroid Hydroxylases
- Swine
- Transcription, Genetic