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1.
Am J Physiol Endocrinol Metab ; 295(6): E1502-9, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18940942

ABSTRACT

Infection and inflammation affect adipose triglyceride metabolism, resulting in increased plasma free fatty acid (FFA) and VLDL levels during the acute-phase response. Lipin-1, a multifunctional protein, plays a critical role in adipose differentiation, mitochondrial oxidation, and triglyceride synthesis. Here, we examined whether LPS [a Toll-like receptor (TLR)-4 activator], zymosan (a TLR-2 activator), and proinflammatory cytokines regulate lipin-1 in adipose tissue. LPS administration caused a marked decrease in the levels of lipin-1 mRNA and protein in adipose tissue. The decrease in lipin-1 mRNA levels occurred rapidly and lasted for at least 24 h. In contrast, lipin-2 and -3 mRNA levels did not change, suggesting specific repression of lipin-1. Zymosan similarly decreased lipin-1 mRNA without affecting lipin-2 or lipin-3 mRNA levels. To determine the pathways by which LPS repressed lipin-1, we examined the effect of proinflammatory cytokines on cultured adipocytes. In 3T3-L1 adipocytes, TNF-alpha, IL-1beta, and IFN-gamma, but not LPS or IL-6, caused a decrease in lipin-1 mRNA levels. Furthermore, TNF-alpha and IL-1beta administration also decreased mRNA levels of lipin-1 in adipose tissue in mice. Importantly, the LPS-induced decrease in lipin-1 mRNA levels was significantly but not totally blunted in TNF-alpha/IL-1 receptor-null mice compared with controls, suggesting key roles for TNF-alpha/IL-1beta and other cytokines in mediating LPS-induced repression of lipin-1. Together, our results demonstrate that expression of lipin-1, one of the essential triglyceride synthetic enzymes, was suppressed by LPS, zymosan, and proinflammatory cytokines in mouse adipose tissue and in cultured 3T3-L1 adipocytes, which could contribute to a decrease in the utilization of FFA to synthesize triglycerides in adipose tissue, thus promoting the release of FFA into the circulation.


Subject(s)
Adipocytes/drug effects , Adipose Tissue/drug effects , Cytokines/pharmacology , Lipopolysaccharides/pharmacology , Nuclear Proteins/genetics , 3T3-L1 Cells , Adipocytes/metabolism , Adipose Tissue/metabolism , Animals , Female , Gene Expression Regulation/drug effects , Inflammation Mediators/pharmacology , Mice , Mice, Inbred C57BL , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Nuclear Proteins/metabolism , PPAR alpha/genetics , PPAR alpha/metabolism , Phosphatidate Phosphatase , RNA, Messenger/metabolism , Zymosan/pharmacology
2.
Biochem Biophys Res Commun ; 374(2): 341-4, 2008 Sep 19.
Article in English | MEDLINE | ID: mdl-18638454

ABSTRACT

Inflammation induces marked changes in lipid and lipoprotein metabolism. Proprotein convertase subtilisin kexin 9 (PCSK9) plays an important role in regulating LDL receptor degradation. Here, we demonstrate that LPS decreases hepatic LDL receptor protein but at the same time hepatic LDL receptor mRNA levels are not decreased. We therefore explored the effect of LPS on PCSK9 expression. LPS results in a marked increase in hepatic PCSK9 mRNA levels (4h 2.5-fold increase; 38h 12.5-fold increase). The increase in PCSK9 is a sensitive response with 1microg LPS inducing a (1/2) maximal response. LPS also increased PCSK9 expression in the kidney. Finally, zymosan and turpentine, other treatments that induce inflammation, also stimulated hepatic expression of PCSK9. Thus, inflammation stimulates PCSK9 expression leading to increased LDL receptor degradation and decreasing LDL receptors thereby increasing serum LDL, which could have beneficial effects on host defense.


Subject(s)
Inflammation/enzymology , Receptors, LDL/metabolism , Serine Endopeptidases/biosynthesis , Animals , Female , Humans , Inflammation/chemically induced , Inflammation/immunology , Irritants/toxicity , Kidney/metabolism , Lipopolysaccharides/immunology , Lipopolysaccharides/toxicity , Liver/metabolism , Mice , Mice, Inbred C57BL , Proprotein Convertase 9 , Proprotein Convertases , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptors, LDL/blood , Serine Endopeptidases/genetics , Turpentine/toxicity , Zymosan/toxicity
3.
Biochim Biophys Acta ; 1771(9): 1177-85, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17590392

ABSTRACT

Phospholipid scramblase 1 (PLSCR1) is a member of PLSCR gene family that has been implicated in multiple cellular processes including movement of phospholipids, gene regulation, immuno-activation, and cell proliferation/apoptosis. In the present study, we identified PLSCR1 as a positive intracellular acute phase protein that is upregulated by LPS in liver, heart, and adipose tissue, but not skeletal muscle. LPS administration resulted in a marked increase in PLSCR1 mRNA and protein levels in the liver. This stimulation occurred rapidly (within 2 h), and was very sensitive to LPS (half-maximal response at 0.1 microg/mouse). Moreover, two other APR-inducers, zymosan and turpentine, also produced significant increases in PLSCR1 mRNA and protein levels, indicating that PLSCR1 was stimulated in a number of models of the APR. To determine signaling pathways by which LPS stimulated PLSCR1, we examined the effect of proinflammatory cytokines in vitro and in vivo. TNFalpha, IL-1beta, and IL-6 all stimulated PLSCR1 in cultured Hep B3 hepatocytes, whereas only TNFalpha stimulated PLSCR1 in cultured 3T3-L1 adipocytes, suggesting cell type-specific effects of cytokines. Furthermore, the LPS-stimulated increase in liver PLSCR1 mRNA was greatly attenuated by 80% in TNFalpha and IL-1beta receptor null mice as compared to wild-type controls. In contrast, PLSCR1 levels in adipose tissue were induced to a similar extent in TNFalpha and IL-1beta receptor null mice and controls. These results indicate that maximal stimulation of PLSCR1 by LPS in liver required TNFalpha and/or IL-1beta, whereas the stimulation of PLSCR1 in adipose tissue is not dependent on TNFalpha and/or IL-1beta. These data provide evidence that PLSCR1 is a positive intracellular acute phase protein with a tissue-specific mechanism for up-regulation.


Subject(s)
Acute-Phase Reaction , Enzyme Induction , Isoenzymes , Phospholipid Transfer Proteins , 3T3-L1 Cells , Adipose Tissue/enzymology , Animals , Female , Genes, Immediate-Early , Humans , Interleukin-1beta/metabolism , Isoenzymes/genetics , Isoenzymes/metabolism , Lipopolysaccharides/immunology , Liver/enzymology , Mice , Mice, Inbred C57BL , Mice, Knockout , Multigene Family , Muscle, Skeletal/enzymology , Myocardium/enzymology , Phospholipid Transfer Proteins/genetics , Phospholipid Transfer Proteins/metabolism , Solvents , Tumor Necrosis Factor-alpha/metabolism , Turpentine/metabolism , Zymosan/immunology
4.
J Lipid Res ; 47(11): 2575-80, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16894239

ABSTRACT

Oxidized cholesterol is present in significant quantities in the typical Western diet. When ingested, oxidized cholesterol is absorbed by the small intestine and incorporated into both chylomicrons and LDL, resulting in LDL that is more susceptible to further oxidation. Feeding studies in animal models and epidemiological studies in humans have suggested that oxidized cholesterol in the diet increases the development of atherosclerosis. In this study, we determined the effect of ezetimibe, a drug that inhibits small intestinal absorption of cholesterol, on the levels of oxidized cholesterol in the serum after a test meal containing oxidized cholesterol. We demonstrate that ezetimibe, 10 mg per day for 1 month, markedly reduced the levels (50% decrease) of oxidized cholesterol in the serum after feeding a test meal containing either alpha-epoxy cholesterol or 7-keto cholesterol, two of the predominant oxidized cholesterols found in the diet. Moreover, the decrease in oxidized cholesterol in the serum was attributable to a decrease in the incorporation of dietary oxidized cholesterol into both chylomicrons and LDL. Because there was no decrease in postprandial triglyceride levels, we conclude that this decrease in oxidized cholesterol levels in the serum is attributable to decreased absorption and not to enhanced clearance. Whether this decrease in oxidized cholesterol absorption prevents or delays the development of atherosclerosis remains to be determined.


Subject(s)
Anticholesteremic Agents/pharmacology , Azetidines/pharmacology , Cholesterol, Dietary/metabolism , Lipoproteins/chemistry , Absorption , Atherosclerosis/pathology , Cholesterol/metabolism , Chylomicrons , Ezetimibe , Female , Humans , Lipids/chemistry , Lipoproteins/blood , Male , Oxygen/chemistry , Postprandial Period , Time Factors
5.
J Lipid Res ; 47(10): 2179-90, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16847310

ABSTRACT

The acute-phase response (APR) leads to alterations in lipid metabolism and type II nuclear hormone receptors, which regulate lipid metabolism, are suppressed, in liver, heart, and kidney. Here, we examine the effect of the APR in adipose tissue. In mice, lipopolysaccharide produces a rapid, marked decrease in mRNA levels of nuclear hormone receptors [peroxisome proliferator-activated receptor gamma (PPARgamma), liver X receptor alpha (LXRalpha) and LXRbeta, thyroid receptor alpha (TRalpha) and TRbeta, and retinoid X receptor alpha (RXRalpha) and RXRbeta] and receptor coactivators [cAMP response element binding protein, steroid receptor coactivator 1 (SRC1) and SRC2, thyroid hormone receptor-associated protein, and peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC1alpha) and PGC1beta] along with decreased expression of target genes (adipocyte P2, phosphoenolpyruvate carboxykinase, glycerol-3-phosphate acyltransferase, ABCA1, apolipoprotein E, sterol-regulatory element binding protein-1c, glucose transport protein 4 (GLUT4), malic enzyme, and Spot14) involved in triglyceride (TG) and carbohydrate metabolism. We show that key TG synthetic enzymes, 1-acyl-sn-glycerol-3-phosphate acyltransferase-2, monoacylglycerol acyltransferase 1, and diacylglycerol acyltransferase 1, are PPARgamma-regulated genes and that they also decrease in the APR. In 3T3-L1 adipocytes, tumor necrosis factor-alpha (TNF-alpha) significantly decreases PPARgamma, LXRalpha and LXRbeta, RXRalpha and RXRbeta, SRC1 and SRC2, and PGC1alpha and PGC1beta mRNA levels, which are associated with a marked reduction in receptor-regulated genes. Moreover, TNF-alpha significantly reduces PPAR and LXR response element-driven transcription. Thus, the APR suppresses the expression of many nuclear hormone receptors and their coactivators in adipose tissue, which could be a mechanism to coordinately downregulate TG biosynthesis and thereby redirect lipids to other critical organs during the APR.


Subject(s)
Acute-Phase Reaction/metabolism , Adipose Tissue/metabolism , Gene Expression Regulation , Receptors, Cytoplasmic and Nuclear/metabolism , Acute-Phase Reaction/genetics , Acyltransferases/metabolism , Adipocytes , Animals , Cells, Cultured , DNA-Binding Proteins , Female , Lipopolysaccharides/metabolism , Liver X Receptors , Mice , Mice, Inbred C57BL , Orphan Nuclear Receptors , PPAR gamma , RNA, Messenger/analysis , Transcription, Genetic , Tumor Necrosis Factor-alpha/metabolism , Zymosan/metabolism
6.
Am J Physiol Endocrinol Metab ; 290(6): E1313-20, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16434558

ABSTRACT

During the third trimester of pregnancy, there is an increase in serum triglyceride and cholesterol levels. The mechanisms accounting for these changes in lipid metabolism during pregnancy are unknown. We hypothesized that, during pregnancy, the expression of nuclear hormone receptors involved in regulating lipid metabolism would decrease. In 19-day pregnant mice, serum triglyceride and non-HDL cholesterol levels were significantly increased, whereas total cholesterol was slightly decreased, because of a decrease in the HDL fraction. Peroxisome proliferator-activated receptor (PPAR)alpha, PPARbeta/delta, and PPARgamma, liver X receptor (LXR)alpha and LXRbeta, farnesoid X receptor (FXR), and retinoid X receptor (RXR)alpha, RXRbeta, and RXRgamma mRNA levels were significantly decreased in the livers of 19-day pregnant mice. Additionally, the expressions of thyroid receptor (TR)alpha, pregnane X receptor, sterol regulatory element-binding proteins (SREBP)-1a, SREBP-1c, SREBP-2, and liver receptor homolog 1 were also decreased, whereas the expression of TRbeta, constitutive androstane receptor, and hepatic nuclear factor 4 showed no significant change. mRNA levels of the PPAR target genes carnitine-palmitoyl transferase 1alpha and acyl-CoA oxidase, the LXR target genes SREBP1c, ATP-binding cassettes G5 and G8, the FXR target gene SHP, and the TR target genes malic enzyme and Spot14 were all significantly decreased. Finally, the expressions of PPARgamma coactivator (PGC)-1alpha and PGC-1beta, known activators of a number of nuclear hormone receptors, were also significantly decreased. The decreases in expression of RXRs, PPARs, LXRs, FXR, TRs, SREBPs, and PGC-1s could contribute to the alterations in lipid metabolism during late pregnancy.


Subject(s)
Gene Expression Regulation , Liver/metabolism , Pregnancy, Animal/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Animals , DNA-Binding Proteins/metabolism , Female , Hepatocyte Nuclear Factor 4/physiology , Lipids/blood , Liver X Receptors , Mice , Orphan Nuclear Receptors , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Peroxisome Proliferator-Activated Receptors/metabolism , Pregnancy , Receptors, Retinoic Acid/metabolism , Trans-Activators , Transcription Factors
7.
J Lipid Res ; 46(11): 2377-87, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16106051

ABSTRACT

The acute-phase response (APR) suppresses type II nuclear hormone receptors and alters the expression of their target genes involved in lipid metabolism in the liver and heart. Therefore, we examined the expression of liver X receptor/retinoid X receptor (LXR/RXR) and their target genes in kidney from mice treated with lipopolysaccharide (LPS) and in human proximal tubular HK-2 cells treated with interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). We found that LXRalpha and RXRalpha expression was suppressed by LPS in kidney and by IL-1beta or TNF-alpha in HK-2 cells. The decrease in LXRalpha/RXRalpha expression was associated with a decrease in the expression of several LXRalpha target genes [apolipoprotein E (apoE), ABCA1, ABCG1, and sterol-regulatory element binding protein-1c (SREBP-1c)] and a decrease in ligand-induced apoE expression. Moreover, IL-1beta and TNF-alpha significantly reduced liver X receptor response element (LXRE)-driven transcription as measured by LXRE-linked luciferase activity. However, overexpression of LXRalpha/RXRalpha only partially restored the cytokine-mediated reduction in LXRE-linked luciferase activity. Additionally, expression of the LXR coactivators peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC1alpha) and steroid receptor coactivator-2 (SRC-2) was decreased by IL-1beta or TNF-alpha. We conclude that the APR suppresses the expression of both nuclear receptors LXRalpha/RXRalpha and several LXRalpha coactivators in kidney, which could be a mechanism for coordinately regulating the expression of multiple LXR target genes that play important roles in lipid metabolism in kidney during the APR.


Subject(s)
Cytokines/metabolism , DNA-Binding Proteins/biosynthesis , Down-Regulation , Kidney Tubules/cytology , Kidney/metabolism , Lipopolysaccharides/metabolism , Receptors, Cytoplasmic and Nuclear/biosynthesis , ATP Binding Cassette Transporter, Subfamily G, Member 1 , ATP-Binding Cassette Transporters/metabolism , Animals , Apolipoproteins E/metabolism , Blotting, Northern , Cell Line , Cells, Cultured , DNA Primers/chemistry , DNA-Binding Proteins/metabolism , Dose-Response Relationship, Drug , Fatty Acids/metabolism , Female , Heat-Shock Proteins/metabolism , Histone Acetyltransferases , Humans , Inflammation , Interleukin-1/metabolism , Liver X Receptors , Luciferases/metabolism , Mice , Mice, Inbred C57BL , Models, Statistical , Nuclear Receptor Coactivator 1 , Orphan Nuclear Receptors , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , RNA/metabolism , RNA, Messenger/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Retinoid X Receptor alpha/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sterol Regulatory Element Binding Protein 1/metabolism , Time Factors , Transcription Factors/metabolism , Transcription, Genetic , Transfection , Tumor Necrosis Factor-alpha/metabolism
8.
J Lipid Res ; 46(10): 2282-8, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16061943

ABSTRACT

Fatty acid oxidation provides energy in tissues with high metabolic demands. During the acute-phase response (APR) induced by infection and inflammation, fatty acid oxidation is decreased associated with hypertriglyceridemia. Little is known about the mechanism by which the APR decreases fatty acid oxidation. Therefore, we investigated whether the APR affects the expression of medium-chain acyl-coenzyme A dehydrogenase (MCAD), its regulator the estrogen-related receptor alpha (ERRalpha), and a key coactivator of ERRalpha, the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). mRNA levels of PGC-1alpha, ERRalpha, and MCAD are markedly reduced in the liver, heart, and kidney of mice during the lipopolysaccharide (LPS)-induced APR. The decreases were rapid and occurred at very low doses of LPS. MCAD activity in liver was also reduced. Furthermore, binding of hepatic nuclear extracts to the ERRalpha response element found in the promoter region of MCAD was significantly decreased during the APR, suggesting the decreased transcription of the MCAD gene. The binding activity was identified as ERRalpha by supershift with antibody to ERRalpha. Similar decreases in mRNA levels of these genes occur during zymosan- and turpentine-induced inflammation, indicating that suppression of the PGC-1alpha, ERRalpha, and MCAD pathway is a general response during infection and inflammation. Our study provides a potential mechanism by which the APR decreases fatty acid oxidation.


Subject(s)
Acute-Phase Reaction/physiopathology , Acyl-CoA Dehydrogenase/biosynthesis , Receptors, Cytoplasmic and Nuclear/biosynthesis , Receptors, Estrogen/biosynthesis , Trans-Activators/biosynthesis , Animals , Down-Regulation , Fatty Acids/metabolism , Female , Heart/drug effects , Inflammation/chemically induced , Kidney/drug effects , Kidney/metabolism , Lipopolysaccharides , Liver/drug effects , Liver/metabolism , Mice , Mice, Inbred C57BL , Myocardium/metabolism , Oxidation-Reduction , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Transcription Factors , Turpentine/pharmacology , Zymosan/pharmacology , ERRalpha Estrogen-Related Receptor
9.
Am J Physiol Regul Integr Comp Physiol ; 288(5): R1306-15, 2005 May.
Article in English | MEDLINE | ID: mdl-15637169

ABSTRACT

High-density lipoprotein (HDL) is part of innate immunity, protecting against infection and inflammation. Using a proteomic approach, we identified an amino acid sequence in a hamster HDL protein that showed homology to rat and mouse parotid secretory protein (PSP), a salivary protein secreted from the parotid glands. We cloned the cDNA encoding a putative hamster homolog of rat and mouse PSP. Searches for conserved domains of the protein showed that the COOH terminus of hamster PSP contains a region homologous to the NH2 termini of a family of HDL-associated proteins, including LPS-binding protein, cholesteryl ester transfer protein, and phospholipid transfer protein. In mice, PSP was also associated with HDL but was not detected in very-low-density lipoprotein, low-density lipoprotein, or lipoprotein-deficient sera. In addition to salivary glands, we found that PSP mRNA was expressed in lung, testis, and ovary. The level of PSP in HDL was increased after endotoxin injection in hamsters, but not in mice. Recombinant PSP inhibits growth of Candida albicans in culture. In summary, our results showed that PSP is a novel anticandidal protein associated with HDL.


Subject(s)
Candida albicans/immunology , Lipoproteins, HDL/blood , Salivary Proteins and Peptides/blood , Salivary Proteins and Peptides/physiology , Amino Acid Sequence , Animals , Cricetinae , Endotoxins , Gene Expression , Immunity, Innate , Lipoproteins, HDL/chemistry , Lipoproteins, HDL/physiology , Mice , Molecular Sequence Data , Rats , Salivary Glands/metabolism , Salivary Proteins and Peptides/chemistry , Sequence Homology, Amino Acid , Species Specificity
10.
Atherosclerosis ; 176(1): 37-44, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15306172

ABSTRACT

BACKGROUND: Infection and inflammation are associated with atherosclerosis. During infection and inflammation, HDL decreases and there are changes in the levels of several HDL-associated proteins. To identify changes in the protein composition of HDL during infection and inflammation, a proteomic approach was utilized. METHODS AND RESULTS: Using two-dimensional gel electrophoresis and mass spectrometry, we found the expected increases in apolipoprotein (apo) SAA and apo E, as well as a decrease in apo A-I on HDL isolated from mice injected with endotoxin. We identified apo A-IV and apo A-V as positive acute-phase proteins in mouse HDL. We also found an increase in hepatic mRNA levels of apo A-IV and apo A-V after injection of endotoxin. Interleukin-6 increased apo A-IV and apo A-V mRNA levels in Hep3B cells. Additionally, we demonstrated that the protein levels of apo A-II in acute-phase HDL and the hepatic mRNA levels of apo A-II were decreased. CONCLUSIONS: Apo A-IV and A-V are positive acute-phase proteins that increase in the serum during inflammation while apo A-II is a negative acute-phase protein in mice. Similar to other positive and negative acute-phase proteins, changes in hepatic production account for the changes in serum levels. However, the changes in apo A-IV and apo A-V, two apolipoproteins whose activities are not fully understood, may serve functions other than regulating lipid metabolism during the acute-phase response (APR). Coupled with the other changes in HDL proteins that occur, these changes are likely to alter the functional properties of HDL perhaps increasing the risk of atherosclerosis.


Subject(s)
Acute-Phase Proteins/immunology , Apolipoproteins A/immunology , Arteriosclerosis/immunology , Cholesterol, HDL/immunology , Acute-Phase Proteins/genetics , Acute-Phase Proteins/metabolism , Animals , Apolipoprotein A-V , Apolipoproteins/blood , Apolipoproteins/genetics , Apolipoproteins/immunology , Apolipoproteins A/blood , Apolipoproteins A/genetics , Arteriosclerosis/blood , Arteriosclerosis/physiopathology , Carcinoma, Hepatocellular , Cell Line, Tumor , Cholesterol, HDL/blood , Humans , Interleukin-6/pharmacology , Lipopolysaccharides/pharmacology , Liver/physiology , Mice , Mice, Inbred C57BL , Proteomics , RNA, Messenger/metabolism
11.
J Invest Dermatol ; 123(2): 305-12, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15245430

ABSTRACT

Previous studies demonstrated that peroxisome-proliferator-activated receptor (PPAR)-alpha or PPAR-delta activation stimulates keratinocyte differentiation, is anti-inflammatory, and improves barrier homeostasis. Here we demonstrate that treatment of cultured human keratinocytes with ciglitazone, a PPAR-gamma activator, increases involucrin and transglutaminase 1 mRNA levels. Moreover, topical treatment of hairless mice with ciglitazone or troglitazone increases loricrin, involucrin, and filaggrin expression without altering epidermal morphology. These results indicate that PPAR-gamma activation stimulates keratinocyte differentiation. Additionally, PPAR-gamma activators accelerated barrier recovery following acute disruption by either tape stripping or acetone treatment, indicating an improvement in permeability barrier homeostasis. Treatment with PPAR-gamma activators also reduced the cutaneous inflammatory response that is induced by phorbol 12-myristate-13-acetate, a model of irritant contact dermatitis and oxazolone, a model of allergic contact dermatitis. To determine whether the effects of PPAR-gamma activators are mediated by PPAR-gamma, we next examined animals deficient in PPAR-gamma. Mice with a deficiency of PPAR-gamma specifically localized to the epidermis did not display any cutaneous abnormalites on inspection, but on light microscopy there was a modest increase in epidermal thickness associated with an increase in proliferating cell nuclear antigen (PCNA) staining. Key functions of the skin including permeability barrier homeostasis, stratum corneum surface pH, and water-holding capacity, and response to inflammatory stimuli were not altered in PPAR-gamma-deficient epidermis. Although PPAR-gamma activators stimulated loricrin and filaggrin expression in wild-type animals, however, in PPAR-gamma-deficient mice no effect was observed indicating that the stimulation of differentiation by PPAR-gamma activators is mediated by PPAR-gamma. In contrast, PPAR-gamma activators inhibited inflammation in both PPAR-gamma-deficient and wild-type mouse skin, indicating that the inhibition of cutaneous inflammation by these PPAR-gamma activators does not require PPAR-gamma in keratinocytes. These observations suggest that thiazolidindiones and perhaps other PPAR-gamma activators maybe useful in the treatment of cutaneous disorders.


Subject(s)
Keratinocytes/cytology , Keratinocytes/metabolism , Receptors, Cytoplasmic and Nuclear/agonists , Receptors, Cytoplasmic and Nuclear/metabolism , Transcription Factors/agonists , Transcription Factors/metabolism , Animals , Cell Differentiation/drug effects , Cell Differentiation/physiology , Dermatitis, Irritant/drug therapy , Dermatitis, Irritant/metabolism , Dermatitis, Irritant/pathology , Epidermis/pathology , Female , Filaggrin Proteins , Homeostasis/drug effects , Homeostasis/physiology , Hypoglycemic Agents/pharmacology , Keratinocytes/drug effects , Male , Mice , Mice, Hairless , Mice, Transgenic , Protein Precursors/genetics , RNA, Messenger/analysis , Receptors, Cytoplasmic and Nuclear/genetics , Thiazolidinediones/pharmacology , Transcription Factors/genetics , Transglutaminases/genetics
12.
J Lipid Res ; 45(7): 1169-96, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15102878

ABSTRACT

Infection and inflammation induce the acute-phase response (APR), leading to multiple alterations in lipid and lipoprotein metabolism. Plasma triglyceride levels increase from increased VLDL secretion as a result of adipose tissue lipolysis, increased de novo hepatic fatty acid synthesis, and suppression of fatty acid oxidation. With more severe infection, VLDL clearance decreases secondary to decreased lipoprotein lipase and apolipoprotein E in VLDL. In rodents, hypercholesterolemia occurs attributable to increased hepatic cholesterol synthesis and decreased LDL clearance, conversion of cholesterol to bile acids, and secretion of cholesterol into the bile. Marked alterations in proteins important in HDL metabolism lead to decreased reverse cholesterol transport and increased cholesterol delivery to immune cells. Oxidation of LDL and VLDL increases, whereas HDL becomes a proinflammatory molecule. Lipoproteins become enriched in ceramide, glucosylceramide, and sphingomyelin, enhancing uptake by macrophages. Thus, many of the changes in lipoproteins are proatherogenic. The molecular mechanisms underlying the decrease in many of the proteins during the APR involve coordinated decreases in several nuclear hormone receptors, including peroxisome proliferator-activated receptor, liver X receptor, farnesoid X receptor, and retinoid X receptor. APR-induced alterations initially protect the host from the harmful effects of bacteria, viruses, and parasites. However, if prolonged, these changes in the structure and function of lipoproteins will contribute to atherogenesis.


Subject(s)
Infections/metabolism , Inflammation/metabolism , Lipid Metabolism , Animals , Humans , Immunity, Innate , Infections/immunology , Inflammation/immunology , Lipids/immunology , Lipoproteins/immunology , Lipoproteins/metabolism , Receptors, Cytoplasmic and Nuclear/physiology
13.
J Invest Dermatol ; 122(4): 971-83, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15102088

ABSTRACT

Peroxisome proliferator-activated receptor (PPAR) are nuclear hormone receptors that are activated by endogenous lipid metabolites. Previous studies have demonstrated that PPAR-alpha activation stimulates keratinocyte differentiation in vitro and in vivo, is anti-inflammatory, and improves barrier homeostasis. Recent studies have shown that PPAR-beta/delta activation induces keratinocyte differentiation in vitro. This study demonstrated that topical treatment of mice with a selective PPAR-beta/delta agonist (GW1514) in vivo had pro-differentiating effects, was anti-inflammatory, improved barrier homeostasis, and stimulated differentiation in a disease model of epidermal hyperproliferation [corrected]. In contrast to PPAR-alpha activation, PPAR-beta/deltain vivo did not display anti-proliferative or pro-apoptotic effects. The pro-differentiating effects persisted in mice lacking PPAR-alpha, but were decreased in mice deficient in retinoid X receptor-alpha, the major heterodimerization partner of PPAR. Furthermore, in vitro PPAR-beta/delta activation, aside from stimulating differentiation-related genes, additionally induced adipose differentiation-related protein (ADRP) and fasting induced adipose factor (FIAF) mRNA in cultures keratinocytes, which was paralleled by increased oil red O staining indicative of lipid accumulation, the bulk of which were triglycerides (TG). Comparison of differentially expressed genes between PPAR-beta/delta and PPAR-alpha activation revealed distinct profiles. Together, these studies indicate that PPAR-beta/delta activation stimulates keratinocyte differentiation, is anti-inflammatory, improves barrier homeostasis, and stimulates TG accumulation in keratinocytes.


Subject(s)
Keratinocytes/cytology , Keratinocytes/metabolism , Lipid Metabolism , Receptors, Cytoplasmic and Nuclear/physiology , Transcription Factors/physiology , Administration, Topical , Animals , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cytokines/pharmacology , Dermatitis/prevention & control , Epidermal Cells , Epidermis/metabolism , Gene Expression Regulation , Humans , Keratinocytes/drug effects , Keratinocytes/radiation effects , Male , Mice , Mice, Hairless , Permeability , Receptors, Cytoplasmic and Nuclear/agonists , Thiazoles/administration & dosage , Thiazoles/pharmacology , Transcription Factors/agonists , Ultraviolet Rays
14.
J Lipid Res ; 44(9): 1728-36, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12777468

ABSTRACT

Several of the ATP binding cassette (ABC) transporters have recently been shown to play important roles in reverse cholesterol transport (RCT) and prevention of atherosclerosis. In the liver, ABCG5 and ABCG8 have been proposed to efflux sterols into the bile for excretion. ABCG5 and ABCG8 also limit absorption of dietary cholesterol and plant sterols in the intestine. In macrophages, ABCA1 and ABCG1 mediate cholesterol removal from these cells to HDL. Many of these ABC transporters are regulated by the liver X receptor (LXR). We have previously shown that endotoxin (lipopolysaccharide) down-regulates LXR in rodent liver. In the present study, we examined the in vivo and in vitro regulation of these ABC transporters by endotoxin. We found that endotoxin significantly decreased mRNA levels of ABCG5 and ABCG8 in the liver, but not in the small intestine. When endotoxin or cytokines (tumor necrosis factor and interleukin-1) were incubated with J774 murine macrophages, the mRNA levels of ABCA1 were decreased. This effect was rapid and sustained, and was associated with a reduction in ABCA1 protein levels. Endotoxin and cytokines also decreased ABCG1 mRNA levels in J774 cells. Although LXR is a positive regulator of ABCA1 and ABCG1, we did not observe a reduction in protein levels of LXR or in binding of nuclear proteins to an LXR response element in J774 cells. The decrease in ABCG5 and ABCG8 levels in the liver as well as a reduction in ABCA1 and ABCG1 in macrophages during the host response to infection and inflammation coupled with other previously described changes in the RCT pathway may aggravate atherosclerosis.


Subject(s)
ATP-Binding Cassette Transporters/metabolism , Endotoxins/pharmacology , Lipoproteins/metabolism , Liver/drug effects , Macrophages/drug effects , Receptors, Cytoplasmic and Nuclear/metabolism , ATP Binding Cassette Transporter 1 , ATP Binding Cassette Transporter, Subfamily G, Member 1 , ATP Binding Cassette Transporter, Subfamily G, Member 5 , ATP Binding Cassette Transporter, Subfamily G, Member 8 , ATP-Binding Cassette Transporters/genetics , Animals , Cyclic AMP/metabolism , Cyclic AMP/pharmacology , DNA-Binding Proteins , Down-Regulation/drug effects , Interleukin-1/pharmacology , Intestine, Small/drug effects , Intestine, Small/metabolism , Lipoproteins/genetics , Liver/metabolism , Liver X Receptors , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Orphan Nuclear Receptors , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Retinoic Acid/metabolism , Retinoid X Receptors , Transcription Factors/metabolism , Tumor Necrosis Factor-alpha/pharmacology
15.
Am J Physiol Endocrinol Metab ; 284(1): E228-36, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12388159

ABSTRACT

Infection is associated with low serum thyroid hormones and thyrotropin levels. Here we demonstrate that infection also reduces thyroid hormone receptor (TR) expression. In gel shift experiments, retinoid X receptor (RXR)/TR DNA binding was reduced in mouse liver by 60 and 77%, respectively, 4 and 16 h after lipopolysaccharide (LPS) administration. Surprisingly, LPS did not decrease either TR-alpha or TR-beta protein levels at 4 h, but by 16 h TR-alpha(1), TR-alpha(2), and TR-beta levels were reduced by 55, 87, and 41%, respectively. We previously reported that LPS rapidly decreases RXR protein levels in liver. Therefore, we added RXR-beta to hepatic nuclear extracts prepared 4 h after LPS treatment, which restored RXR/TR DNA binding to a level comparable to that of controls. A similar experiment conducted on extracts prepared 16 h after LPS administration did not restore RXR/TR DNA binding. We propose that decreased RXR expression is limiting for RXR/TR DNA binding at 4 h, whereas the reduction in both TR and RXR levels results in further decreased binding at 16 h.


Subject(s)
DNA/metabolism , Euthyroid Sick Syndromes/metabolism , Gene Expression , Liver/metabolism , Receptors, Thyroid Hormone/genetics , Receptors, Thyroid Hormone/metabolism , Animals , Dimerization , Escherichia coli , Female , Kinetics , Lipopolysaccharides/pharmacology , Malate Dehydrogenase/genetics , Mice , Mice, Inbred C57BL , Nuclear Proteins , Protein Isoforms/genetics , Proteins/genetics , RNA, Messenger/analysis , Receptors, Retinoic Acid/metabolism , Response Elements , Retinoid X Receptors , Thyroid Hormone Receptors alpha/genetics , Thyroid Hormone Receptors beta , Transcription Factors/metabolism
16.
Biochem Biophys Res Commun ; 293(1): 145-9, 2002 Apr 26.
Article in English | MEDLINE | ID: mdl-12054576

ABSTRACT

Expression of P-450 (Cyp) enzymes is reduced in liver during the acute phase response, contributing to the decrease in bile acid levels and drug metabolism during infection. Nuclear hormone receptors CAR and PXR are key transactivators of Cyp2b and Cyp3a genes, respectively. Injection of bacterial lipopolysaccharide (LPS) induced the expected reduction in Cyp2b10 and Cyp3a mRNA levels in mouse liver. These decreases were associated with a marked reduction in CAR and PXR mRNA levels within 4 h following treatment. LPS-induced CAR and PXR repression were dose-dependent and sustained for at least 16 h. LPS treatment also reversed the up-regulation of Cyp3a in mice pre-treated with PXR ligand RU486. In addition, we observed a concomitant decrease in RXR (retinoid X receptor) mRNA levels, the obligatory partner of both CAR and PXR for high affinity binding to DNA. These findings represent one possible molecular mechanism underlying sepsis-induced repression of Cyp enzymes.


Subject(s)
Aryl Hydrocarbon Hydroxylases , Cytochrome P-450 Enzyme System/genetics , Gene Expression Regulation, Enzymologic , Liver/enzymology , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Steroid/genetics , Transcription Factors/genetics , Animals , Constitutive Androstane Receptor , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/drug effects , Escherichia coli , Female , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred C57BL , Models, Animal , Oxidoreductases, N-Demethylating/genetics , Pregnane X Receptor , Repressor Proteins/genetics , Trans-Activators/metabolism
17.
J Invest Dermatol ; 118(1): 25-34, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11851872

ABSTRACT

Liver X receptor-alpha and -beta are members of the nuclear hormone receptor superfamily that heterodimerize with retinoid X receptor and are activated by oxysterols. In recent studies we found that treatment of cultured human keratinocytes with oxysterolstimulated differentiation, as demonstrated by increased expression of involucrin and transglutaminase, and inhibited proliferation. The aims of this study were to determine: (i) whether oxysterols applied topically to the skin of mice induce differentiation in normal epidermis; (ii) whether this effect is mediated via liver X receptor-alpha and/or liver X receptor-beta; and (iii) whether oxysterols normalize epidermal morphology in an animal model of epidermal hyperplasia. Topical treatment of normal hairless mice with 22(R)-hydroxycholesterol or 24(S),25-epoxycholesterol resulted in a decrease in epidermal thickness and a decrease in keratinocyte proliferation assayed by proliferating cell nuclear antigen staining. Moreover, oxysterol treatment increased the levels of involucrin, loricrin, and profilaggrin protein and mRNA in the epidermis, indicating that oxysterols stimulate epidermal differentiation. Additionally, topical oxysterol pretreatment improved permeability barrier homeostasis. Whereas liver X receptor-alpha-/- mice revealed no alterations in epidermal differentiation, the epidermis was thinner in liver X receptor-beta-/- mice than in wild-type mice, with a reduced number of proliferating cell nuclear antigen positive cells and a modest reduction in the expression of differentiation markers. Topical oxysterol treatment induced differentiation in liver X receptor-alpha-/- mice whereas in liver X receptor-beta-/- mice there was no increase in the expression of differentiation markers. Whereas both liver X receptor-alpha and liver X receptor-beta are expressed in cultured human keratinocytes and in fetal rat skin, only liver X receptor-beta was observed on northern blotting in adult mouse epidermis. Finally, treatment of hyperproliferative epidermis with oxysterols restored epidermal homeostasis. These studies demonstrate that epidermal differentiation is regulated by liver X receptor-beta and that oxysterols, acting via liver X receptor-beta, can induce differentiation and inhibit proliferation in vivo. The ability of oxysterols to reverse epidermal hyperplasia suggests that these agents could be beneficial for the treatment of skin disorders associated with hyperproliferation and/or altered differentiation.


Subject(s)
Cholesterol/pharmacology , Epidermal Cells , Epidermis/drug effects , Hydroxycholesterols/pharmacology , Liver/metabolism , Receptors, Retinoic Acid/physiology , Transcription Factors/physiology , Animals , Cell Differentiation/drug effects , Cholesterol/analogs & derivatives , Epidermis/metabolism , Epidermis/pathology , Homeostasis/drug effects , Hyperplasia , Keratinocytes/cytology , Mice , Mice, Hairless , Permeability/drug effects , Protein Isoforms/physiology , Receptors, Retinoic Acid/deficiency , Retinoid X Receptors , Transcription Factors/deficiency
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