Biomedical subjects

Judy K Shigenaga

Publications and source records attributed to Judy K Shigenaga.

12 recordsLinked to original sources

PubMed2007

Tumor necrosis factor and interleukin 1 decrease RXRalpha, PPARalpha, PPARgamma, LXRalpha, and the coactivators SRC-1, PGC-1alpha, and PGC-1beta in liver cells.

During the acute phase response, cytokines induce marked alterations in lipid metabolism including an increase in serum triglyceride levels and a decrease in hepatic fatty acid oxidation, in bile acid synthesis, and in high-density lipoprotein levels. Here we demonstrate that tumor necrosis factor (TNF) and interleukin 1 (IL-1), but not IL-6, decrease the expression of retinoid X receptor alpha (RXRalpha), peroxisome proliferator-activated receptor alpha (PPARalpha), PPARgamma, liver X receptor alpha (LXRalpha), and coactivators PPARgamma coactivator 1alpha (PGC-1alpha), PGC-1beta, and steroid receptor coactivator 1 (SRC-1) in Hep3B human hepatoma cells. In addition, treatment of mice with TNF and IL-1 also decreased RXRalpha, PPARalpha, PPARgamma, LXRalpha, and PGC-1alpha messenger RNA (mRNA) levels in the liver. These decreases were accompanied by reduced binding of nuclear extracts to RXR, PPAR, and LXR response elements and decreased luciferase activity driven by PPAR and LXR response elements. In addition, the mRNA levels of proteins regulated by PPARalpha (carnitine palmitoyltransferase 1alpha) and LXR (sterol regulatory element binding protein) were decreased in Hep3B cells treated with TNF or IL-1. Finally, using constructs of the LXRalpha promoter or the PGC-1alpha promoter linked to luciferase, we were able to demonstrate that a decrease in transcription contributes to the reduction in mRNA levels of nuclear hormone receptors and coactivators. Thus, our results suggest that decreased expression of nuclear hormone receptors RXRalpha, PPARalpha, PPARgamma, and LXRalpha, as well as coactivators PGC-1alpha, PGC-1beta, and SRC-1 may contribute to the cytokine-induced alterations in hepatic lipid metabolism during the acute phase response.

Acute-Phase Reaction↗

PubMed2006

Type II nuclear hormone receptors, coactivator, and target gene repression in adipose tissue in the acute-phase response.

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.

Acute-Phase Reaction↗

PubMed2006

Decreased nuclear hormone receptor expression in the livers of mice in late pregnancy.

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.

Animals↗

PubMed2005

Downregulation of liver X receptor-alpha in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines.

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.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2005

Suppression of estrogen-related receptor alpha and medium-chain acyl-coenzyme A dehydrogenase in the acute-phase response.

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.

Acute-Phase Reaction↗

PubMed2005

Adipocyte fatty acid-binding protein expression and lipid accumulation are increased during activation of murine macrophages by toll-like receptor agonists.

OBJECTIVE: Toll-like receptors (TLRs) recognize pathogens and mediate signaling pathways important for host defense. Recent studies implicate TLR polymorphisms in atherosclerosis risk in humans. Adipocyte fatty acid-binding protein (aP2) is present in macrophages and has an important role in atherosclerotic plaque development. We investigated aP2 expression in RAW 264.7 cells treated with lipopolysaccharide (LPS) and other TLR agonists and assessed lipid accumulation in these activated murine macrophages. METHODS AND RESULTS: Stimulation with LPS, a TLR4 ligand, resulted in a 56-fold increase in aP2 mRNA expression, and zymosan, a TLR2 ligand, induced an approximately 1500-fold increase. Polyinosine: polycytidylic acid (poly I:C), a TLR3 ligand, led to a 9-fold increase. Levels of aP2 protein were significantly increased in LPS or zymosan-treated macrophages compared with control or poly I:C-treated cells. In addition, the cholesteryl ester content of LPS or zymosan-treated macrophages was approximately 5-fold greater in the presence of low-density lipoprotein, and triglyceride content was approximately 2-fold greater in the absence of exogenous lipid than control or poly I:C-treated cells. CONCLUSIONS: Expression of macrophage aP2 is induced on TLR activation and parallels increases in cholesteryl ester and triglyceride levels. These results provide a molecular link between the known roles of TLR and aP2 in foam cell formation.

Animals↗

PubMed2005

Parotid secretory protein is an HDL-associated protein with anticandidal activity.

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.

Amino Acid Sequence↗

PubMed2004

Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.

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.

Animals↗

PubMed2004

Apolipoproteins A-IV and A-V are acute-phase proteins in mouse HDL.

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.

Acute-Phase Proteins↗

PubMed2003

Endotoxin down-regulates ABCG5 and ABCG8 in mouse liver and ABCA1 and ABCG1 in J774 murine macrophages: differential role of LXR.

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.

ATP Binding Cassette Transporter 1↗

PubMed2002

Sick euthyroid syndrome is associated with decreased TR expression and DNA binding in mouse liver.

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.

Animals↗

PubMed2002

Reduction in cytochrome P-450 enzyme expression is associated with repression of CAR (constitutive androstane receptor) and PXR (pregnane X receptor) in mouse liver during the acute phase response.

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.

Animals↗