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1.
Biochim Biophys Acta Mol Basis Dis ; 1867(11): 166215, 2021 11 01.
Article in English | MEDLINE | ID: mdl-34265370

ABSTRACT

Ezetimibe and pemafibrate are lipid-lowering drugs and promote reverse cholesterol transport. However, it is unknown whether cholesterol is mainly excreted by hepatobiliary excretion or by non-biliary transintestinal cholesterol efflux (TICE). We evaluated the effects of ezetimibe and pemafibrate on hepatic and intestinal cholesterol transporter regulation in Sham-operated rats, and examined the effects of these drugs on TICE in bile duct-ligated rats. Seven-week-old male Sprague-Dawley rats were treated as follows for two weeks: 1) Sham, Sham operation; 2) BDL, bile duct ligation; 3) E-Sham, Sham + ezetimibe; 4) E-BDL, BDL + ezetimibe; 5) P-Sham, Sham + pemafibrate; and 6) P-BDL, BDL + pemafibrate. Blood, liver, jejunum, and feces were collected 72 h post-surgery. Hepatic cholesterol levels were decreased in P-Sham and E-Sham, and were lower in E-BDL and P-BDL than in BDL. Fecal cholesterol levels increased in E-Sham and P-Sham compared with Sham, and were higher in E-BDL and P-BDL than in BDL. In liver, Abcg5 mRNA showed induction in E-Sham, Abcg5 and Abca1 mRNA were induced in P-Sham, Abcg5 mRNA was reduced in E-BDL, and Abca1 mRNA was increased in P-BDL. In jejunum, Abcg5 mRNA was induced in E-Sham. Abcg8 mRNA was induced in E-Sham and P-Sham. NPC1L1 mRNA showed reduced expression in P-Sham and P-BDL. SR-B1 mRNA was reduced in P-Sham, and the expression decreased in P-BDL. LDL receptor mRNA was induced in BDL and P-BDL. Ezetimibe and pemafibrate may promote TICE by increasing Abcg5/g8, while pemafibrate may inhibit intestinal cholesterol absorption by decreasing SR-B1 and NPC1L1.


Subject(s)
Benzoxazoles/pharmacology , Butyrates/pharmacology , Cholesterol/metabolism , Ezetimibe/pharmacology , Hepatobiliary Elimination/drug effects , Hypolipidemic Agents/pharmacology , ATP Binding Cassette Transporter, Subfamily G, Member 5/agonists , ATP Binding Cassette Transporter, Subfamily G, Member 5/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 8/agonists , ATP Binding Cassette Transporter, Subfamily G, Member 8/metabolism , Animals , Benzoxazoles/therapeutic use , Butyrates/therapeutic use , Ezetimibe/therapeutic use , Humans , Hypercholesterolemia/drug therapy , Hypolipidemic Agents/therapeutic use , Intestinal Absorption/drug effects , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Lipoproteins/agonists , Lipoproteins/metabolism , Liver/drug effects , Liver/metabolism , Male , Membrane Transport Proteins/metabolism , Rats , Scavenger Receptors, Class B/antagonists & inhibitors , Scavenger Receptors, Class B/metabolism
2.
J Lipid Res ; 55(12): 2576-86, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25278499

ABSTRACT

Statins are effective cholesterol-lowering drugs to treat CVDs. Bile acids (BAs), the end products of cholesterol metabolism in the liver, are important nutrient and energy regulators. The present study aims to investigate how statins affect BA homeostasis in the enterohepatic circulation. Male C57BL/6 mice were treated with atorvastatin (100 mg/kg/day po) for 1 week, followed by BA profiling by ultra-performance LC-MS/MS. Atorvastatin decreased BA pool size, mainly due to less BA in the intestine. Surprisingly, atorvastatin did not alter total BAs in the serum or liver. Atorvastatin increased the ratio of 12α-OH/non12α-OH BAs. Atorvastatin increased the mRNAs of the BA-synthetic enzymes cholesterol 7α-hydroxylase (Cyp7a1) (over 10-fold) and cytochrome P450 27a1, the BA uptake transporters Na⁺/taurocholate cotransporting polypeptide and organic anion transporting polypeptide 1b2, and the efflux transporter multidrug resistance-associated protein 2 in the liver. Noticeably, atorvastatin suppressed the expression of BA nuclear receptor farnesoid X receptor (FXR) target genes, namely small heterodimer partner (liver) and fibroblast growth factor 15 (ileum). Furthermore, atorvastatin increased the mRNAs of the organic cation uptake transporter 1 and cholesterol efflux transporters Abcg5 and Abcg8 in the liver. The increased expression of BA-synthetic enzymes and BA transporters appear to be a compensatory response to maintain BA homeostasis after atorvastatin treatment. The Cyp7a1 induction by atorvastatin appears to be due to suppressed FXR signaling in both the liver and intestine.


Subject(s)
Cholesterol 7-alpha-Hydroxylase/metabolism , Cytochrome P-450 Enzyme Inducers/pharmacology , Heptanoic Acids/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Intestinal Mucosa/drug effects , Liver/drug effects , Pyrroles/pharmacology , RNA-Binding Proteins/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 5 , ATP Binding Cassette Transporter, Subfamily G, Member 8 , ATP-Binding Cassette Transporters/agonists , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Animals , Atorvastatin , Bile Acids and Salts/blood , Bile Acids and Salts/metabolism , Cholestanetriol 26-Monooxygenase/chemistry , Cholestanetriol 26-Monooxygenase/genetics , Cholestanetriol 26-Monooxygenase/metabolism , Cholesterol 7-alpha-Hydroxylase/chemistry , Cholesterol 7-alpha-Hydroxylase/genetics , Enterohepatic Circulation/drug effects , Humans , Ileum/drug effects , Ileum/enzymology , Ileum/metabolism , Intestinal Mucosa/enzymology , Intestinal Mucosa/metabolism , Lipoproteins/agonists , Lipoproteins/genetics , Lipoproteins/metabolism , Liver/enzymology , Liver/metabolism , Liver-Specific Organic Anion Transporter 1 , Male , Mice, Inbred C57BL , Organic Anion Transporters, Sodium-Dependent/agonists , Organic Anion Transporters, Sodium-Dependent/chemistry , Organic Anion Transporters, Sodium-Dependent/genetics , Organic Anion Transporters, Sodium-Independent/agonists , Organic Anion Transporters, Sodium-Independent/genetics , Organic Anion Transporters, Sodium-Independent/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Signal Transduction/drug effects , Symporters/agonists , Symporters/chemistry , Symporters/genetics
3.
PLoS One ; 8(2): e55307, 2013.
Article in English | MEDLINE | ID: mdl-23393567

ABSTRACT

Asthma is a chronic inflammatory disease of the airways characterized by variable airway obstruction and airway hyperresponsiveness (AHR). The T regulatory (Treg) cell subset is critically important for the regulation of immune responses. Adoptive transfer of Treg cells has been shown to be sufficient for the suppression of airway inflammation in experimental allergic asthma. Intervention strategies aimed at expanding the Treg cell population locally in the airways of sensitized individuals are therefore of high interest as a potential therapeutic treatment for allergic airway disease. Here, we aim to test whether long-term suppression of asthma manifestations can be achieved by locally expanding the Treg cell subset via intranasal administration of a TLR-2 agonist. To model therapeutic intervention aimed at expanding the endogenous Treg population in a sensitized host, we challenged OVA-sensitized mice by OVA inhalation with concomitant intranasal instillation of the TLR-2 agonist Pam3Cys, followed by an additional series of OVA challenges. Pam3Cys treatment induced an acute but transient aggravation of asthma manifestations, followed by a reduction or loss of AHR to methacholine, depending on the time between Pam3Cys treatment and OVA challenges. In addition, Pam3Cys-treatment induced significant reductions of eosinophils and increased numbers of Treg cells in the lung infiltrates. Our data show that, despite having adverse acute effects, TLR2 agonist treatment as a therapeutic intervention induces an expansion of the Treg cell population in the lungs and results in long-term protection against manifestation of allergic asthma upon subsequent allergen provocation. Our data indicate that local expansion of Tregs in allergic airway disease is an interesting therapeutic approach that warrants further investigation.


Subject(s)
Asthma/immunology , Asthma/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Toll-Like Receptor 2/metabolism , Animals , Asthma/drug therapy , Bronchoalveolar Lavage Fluid , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Immunoglobulin E/metabolism , Lipoproteins/agonists , Lipoproteins/pharmacology , Male , Methacholine Chloride , Mice , Mice, Inbred BALB C , Toll-Like Receptor 2/genetics
4.
J Immunol ; 186(2): 1119-30, 2011 Jan 15.
Article in English | MEDLINE | ID: mdl-21169547

ABSTRACT

TLR2 activation induces cellular and organ inflammation and affects lung function. Because deranged endothelial function and coagulation pathways contribute to sepsis-induced organ failure, we studied the effects of bacterial lipoprotein TLR2 agonists, including peptidoglycan-associated lipoprotein, Pam3Cys, and murein lipoprotein, on endothelial function and coagulation pathways in vitro and in vivo. TLR2 agonist treatment induced diverse human endothelial cells to produce IL-6 and IL-8 and to express E-selectin on their surface, including HUVEC, human lung microvascular endothelial cells, and human coronary artery endothelial cells. Treatment of HUVEC with TLR2 agonists caused increased monolayer permeability and had multiple coagulation effects, including increased production of plasminogen activator inhibitor-1 (PAI-1) and tissue factor, as well as decreased production of tissue plasminogen activator and tissue factor pathway inhibitor. TLR2 agonist treatment also increased HUVEC expression of TLR2 itself. Peptidoglycan-associated lipoprotein induced IL-6 production by endothelial cells from wild-type mice but not from TLR2 knockout mice, indicating TLR2 specificity. Mice were challenged with TLR2 agonists, and lungs and plasmas were assessed for markers of leukocyte trafficking and coagulopathy. Wild-type mice, but not TLR2 mice, that were challenged i.v. with TLR2 agonists had increased lung levels of myeloperoxidase and mRNAs for E-selectin, P-selectin, and MCP-1, and they had increased plasma PAI-1 and E-selectin levels. Intratracheally administered TLR2 agonist caused increased lung fibrin levels. These studies show that TLR2 activation by bacterial lipoproteins broadly affects endothelial function and coagulation pathways, suggesting that TLR2 activation contributes in multiple ways to endothelial activation, coagulopathy, and vascular leakage in sepsis.


Subject(s)
Anticoagulants/physiology , Blood Coagulation/immunology , Endothelium, Vascular/physiology , Escherichia coli Proteins/physiology , Lipoproteins/physiology , Peptidoglycan/pharmacology , Signal Transduction/immunology , Toll-Like Receptor 2/agonists , Animals , Anticoagulants/agonists , Anticoagulants/pharmacology , Capillary Permeability/immunology , Cell Line , Endothelium, Vascular/cytology , Endothelium, Vascular/immunology , Escherichia coli Proteins/agonists , Humans , Immunophenotyping , Lipoproteins/agonists , Mice , Mice, Inbred C57BL , Mice, Knockout , Toll-Like Receptor 2/deficiency , Toll-Like Receptor 2/physiology , Up-Regulation/immunology
5.
Life Sci ; 76(22): 2535-46, 2005 Apr 15.
Article in English | MEDLINE | ID: mdl-15769478

ABSTRACT

Several CYP enzymes are expressed in the lung of mammals but studies on their regulation have been rather neglected. In this study, the CAR and PXR expression and the inducibility of CYP 2B and CYP 3A isoforms in the lung rats and rabbits were investigated. Rats were treated with phenobarbital, clotrimazole or a mixture of dexametasone plus pregnenolone 16alpha-carbonitrile, whereas rabbits were treated with phenobarbital or rifampicin. A low constitutive expression of CAR mRNA was demonstrated by RT-PCR analysis in the lung of rat but not in rabbit. Phenobarbital treatment did not change the CAR expression profiles and did not induce in either rats and rabbits the pulmonary CYP 2B isoforms, as judged by western blot analysis and the marker pentoxyresorufin O-dealkylase and 7-ethoxy-4-trifluoroethylcoumarin O-deethylase activities. On the contrary, these marker activities were strongly induced by phenobarbital in the liver of both species. A low constitutive level of PXR mRNA was also detected by RT-PCR in the lung of rabbit but not in rat. However, also in this case, their expressions were not altered by the administration of strong CYP 3A inducers such as clotrimazole or a mixture of dexametasone plus pregnenolone 16alpha-carbonitrile for the rat and rifampicin or phenobarbital for the rabbit. For the first time, it was demonstrated by RT-PCR that rat lung expresses CYP 3A2, 3A9, 3A18 and 3A23 whereas the rabbit lung expresses the CYP 3A6, the only CYP 3A isoform identified in the rabbit so far. However, notwithstanding the differences observed in the constitutive presence of PXR and CYP 3A transcripts in both species, the above mentioned treatments did not affect in their lungs, unlike their livers, neither the anti-rat 3A immunoreactive proteins nor the CYP 3A marker 7-benzyloxyquinoline O-debenzylase and the 6beta-testosterone hydroxylase activities. The results obtained indicate that the role of CAR and PXR in the lung of rat and rabbit is different from that observed in the liver or other extrahepatic tissues where the induction of the CYP 2B and CYP 3A isoforms is regulated by these receptors.


Subject(s)
Air Pollutants , Aryl Hydrocarbon Hydroxylases/biosynthesis , Calcium-Binding Proteins/biosynthesis , Eye Proteins/biosynthesis , Lipoproteins/biosynthesis , Lung/enzymology , Oxidoreductases, N-Demethylating/biosynthesis , Pharmaceutical Preparations/administration & dosage , Receptors, Cytoplasmic and Nuclear/biosynthesis , Receptors, Steroid/biosynthesis , Air Pollutants/metabolism , Animals , Biomarkers , Calcium-Binding Proteins/agonists , Calcium-Binding Proteins/genetics , Clotrimazole/pharmacology , Cytochrome P-450 CYP3A , Dexamethasone/pharmacology , Enzyme Induction/drug effects , Enzyme Induction/genetics , Eye Proteins/agonists , Eye Proteins/genetics , Isoenzymes/biosynthesis , Lipoproteins/agonists , Lipoproteins/genetics , Male , Organ Specificity , Phenobarbital/pharmacology , Pregnane X Receptor , Rabbits , Rats , Rats, Sprague-Dawley , Receptors, Cytoplasmic and Nuclear/agonists , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Steroid/agonists , Receptors, Steroid/genetics , Recoverin , Rifampin/pharmacology , Species Specificity
6.
Microbes Infect ; 4(11): 1133-40, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12361913

ABSTRACT

Cutaneous immunobiology and spirochetal molecular biology have allowed investigators to propose a conceptual framework for the development of both the innate and adaptive immune response to Treponema pallidum infection. While some clinical manifestations can be attributed to humoral responses, most can be attributed to a combination of local innate and adaptive cellular immunity.


Subject(s)
Syphilis/immunology , Treponema pallidum/pathogenicity , Antibody Formation , Blister/etiology , Blister/immunology , Genome , Humans , Immunity, Cellular , Lipoproteins/agonists , Lipoproteins/metabolism , Polymorphism, Genetic , Sequence Analysis, DNA , Syphilis/pathology , Treponema pallidum/immunology , Treponema pallidum/ultrastructure
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