Search PubMed⌕ Search

Biomedical subjects

Carl Grunfeld

Publications and source records attributed to Carl Grunfeld.

At least 19 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

Single-dose lopinavir-ritonavir acutely inhibits insulin-mediated glucose disposal in healthy volunteers.

Previously, we found that 4 weeks of treatment with lopinavir-ritonavir did not decrease insulin sensitivity but did increase adiponectin levels. In the present study, a single dose of lopinavir-ritonavir decreases insulin sensitivity but does not alter adiponectin levels. Insulin resistance from protease inhibitors may decrease with prolonged use; an increase in adiponectin levels may mediate this effect.

Adiponectin↗
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

Cloning and characterization of a cDNA encoding human cardiolipin synthase (hCLS1).

Cardiolipin (CL) is a phospholipid localized to the mitochondria, and its biosynthesis is essential for mitochondrial structure and function. We report here the identification and characterization of a cDNA encoding the first mammalian cardiolipin synthase (CLS1) in humans and mice. This cDNA exhibits sequence homology with members of a CLS gene family that share similar domain structure and chemical properties. Expression of the human CLS (hCLS1) cDNA in reticulocyte lysates or insect cells led to a marked increase in CLS activity. The enzyme is specific for CL synthesis, because no significant increase in phosphatidylglycerol phosphate synthase activity was observed. In addition, CL pool size was increased in hCLS1-overexpressing cells compared with controls. Furthermore, the hCLS1 gene was highly expressed in tissues such as heart, skeletal muscle, and liver, which have been shown to have high CLS activities. These results demonstrate that hCLS1 encodes an enzyme that synthesizes CL.

Amino Acid Sequence↗
PubMed2006

The study of fat redistribution and metabolic change in HIV infection (FRAM): methods, design, and sample characteristics.

The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM), initiated in 2000, investigates the prevalence and correlates of changes in fat distribution, insulin resistance, and dyslipidemia among human immunodeficiency virus (HIV)-infected men and women compared with a population-based group of control men and women. Between June 2000 and September 2002, 1,480 participants (1,183 HIV-infected persons and 297 controls) were enrolled in FRAM. Measurements taken included whole-body magnetic resonance imaging for quantification of regional fat, anthropometric measurements, central laboratory analysis of metabolites, and assessment of symptoms, sociodemographic factors, and lifestyle. Similar measurements were repeated among FRAM participants 4 years later (FRAM 2) for investigation of the progression of fat distribution changes, insulin resistance, and hyperlipidemia. In FRAM 2, which is ongoing, investigators are also determining the associations of subclinical cardiovascular disease, as measured by carotid intimal-medial wall thickness, with HIV infection, fat distribution changes, insulin resistance, and other proatherogenic changes in serum lipid levels. The demographic characteristics of HIV-infected FRAM men and women were comparable to those reported from a national random sampling of HIV-infected men and women receiving medical care in the United States. The representativeness of the FRAM sample increases its value as a resource for studies on fat distribution, metabolic changes, and atherosclerosis in HIV infection.

Adipose Tissue↗
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↗
PubMed2006

Waist circumference correlates with metabolic syndrome indicators better than percentage fat.

OBJECTIVE: Percent fat is often considered the reference for establishing the magnitude of adipose tissue accumulation and the risk of excess adiposity. However, the increasing recognition of a strong link between central adiposity and metabolic disturbances led us to test whether waist circumference (WC) is more highly correlated with metabolic syndrome components than percent fat and other related anthropometric measures such as BMI. RESEARCH METHODS AND PROCEDURES: BMI, WC, and percent fat, measured by DXA, were evaluated in 1010 healthy white and African-American men and women [age, 48.3 +/- 17.2 (standard deviation) years; BMI, 27.0 +/- 5.3 kg/m(2)]. The associations of BMI, WC, and percent fat with age and laboratory-adjusted health risk indicators (i.e., serum glucose, insulin, triglycerides, high-density lipoprotein cholesterol, blood pressure) in each sex and ethnicity group were examined. RESULTS: For 18 of 24 comparisons, the age- and laboratory-adjusted correlations were lowest for percent fat and in 16 of 24 comparisons were highest for WC. Fifteen of the between-method differences reached statistical significance. With health risk indicator as the dependent variable and anthropometric measures as the independent variable, the contribution of percent fat to the WC regression model was not statistically significant; in contrast, adding WC to the percent fat regression model did make a significant independent contribution for most health risk indicators. DISCUSSION: WC had the strongest associations with health risk indicators, followed by BMI. Although percent fat is a useful measure of overall adiposity, health risks are best represented by the simply measured WC.

Adiposity↗
PubMed2006

Oxandrolone in the treatment of HIV-associated weight loss in men: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and safety of oxandrolone in promoting body weight and body cell mass (BCM) gain in HIV-associated weight loss. METHODS: Randomized, double-blind, placebo-controlled trial. Two hundred sixty-two HIV-infected men with documented 10% to 20% weight loss or body mass index < or =20 kg/m were randomized to placebo or to 20, 40, or 80 mg of oxandrolone daily. After 12 weeks, subjects were allowed to receive open-label oxandrolone at a dose of 20 mg for another 12 weeks. RESULTS: Body weight increased in all groups, including the group receiving placebo, during the double-blind phase (1.1 +/- 2.7, 1.8 +/- 3.9, 2.8 +/- 3.3, and 2.3 +/- 2.9 kg in placebo and 20-, 40-, and 80-mg oxandrolone groups, respectively; all P < 0.014 vs. baseline). BCM increased from baseline in all groups (0.45 +/- 1.7, 0.91 +/- 2.2, 1.5 +/- 2.5, and 1.8 +/- 1.8 kg in placebo and 20-, 40-, and 80-mg oxandrolone groups, respectively). At 12 weeks, only the gain in weight at the 40-mg dose of oxandrolone and the gain in BCM at the 40- and 80-mg doses of oxandrolone were greater than those in the placebo group, however. Oxandrolone treatment was associated with significant suppression of sex hormone-binding globulin, luteinizing hormone, follicle-stimulating hormone, and total and free testosterone levels. Treatment was generally well tolerated but accompanied by significant increases in transaminases and low-density lipoprotein as well as decreases in high-density lipoprotein. CONCLUSION: Oxandrolone administration is effective in promoting dose-dependent gains in body weight and BCM in HIV-infected men with weight loss.

Adult↗
PubMed2005

Fat distribution in men with HIV infection.

OBJECTIVE: Both peripheral fat loss and central fat gain have been reported in HIV infection. Which changes are specific to HIV were determined by comparison with control subjects and the associations among different adipose tissue depots were determined. METHODS: Cross-sectional analysis of HIV-positive and control men from the study of Fat Redistribution and Metabolic Change in HIV Infection. Lipoatrophy or lipohypertrophy was defined as concordance between participant report of change and examination. Regional adipose tissue volume was measured by magnetic resonance imaging (MRI). RESULTS: HIV-positive men reported more fat loss than controls in all peripheral and most central depots. Peripheral lipoatrophy was more frequent in HIV-positive men than in controls (38.3% vs. 4.6%, P < 0.001), whereas central lipohypertrophy was less frequent (40.2% vs. 55.9%, P = 0.001). Among HIV-positive men, the presence of central lipohypertrophy was not positively associated with peripheral lipoatrophy (odds ratio = 0.71, CI: 0.47 to 1.06, P = 0.10). On MRI, HIV-positive men with clinical peripheral lipoatrophy had less subcutaneous adipose tissue (SAT) in peripheral and central sites and less visceral adipose tissue (VAT) than HIV-positive men without peripheral lipoatrophy. HIV-positive men both with and without lipoatrophy had less SAT than controls, with legs and lower trunk more affected than upper trunk. Use of the antiretroviral drugs stavudine or indinavir was associated with less leg SAT but did not appear to be associated with more VAT; nevirapine use was associated with less VAT. CONCLUSION: Both peripheral and central subcutaneous lipoatrophy was found in HIV infection. Lipoatrophy in HIV-positive men is not associated with reciprocally increased VAT.

Adipose Tissue↗
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

Body composition and metabolic changes in antiretroviral-naive patients randomized to didanosine and stavudine vs. abacavir and lamivudine.

Comparisons of body composition and metabolic changes among antiretroviral-naive patients randomly assigned to didanosine and stavudine- (ddI+d4T) vs. abacavir and lamivudine- (ABC+3TC) containing regimens were assessed in a nested substudy of an ongoing multicenter randomized trial. At baseline and every 4 months, body cell mass and total body fat were calculated, anthropometric measurements were performed, and fasting metabolic parameters were obtained. The rates of change (unit/mo) estimated using the slopes of regression lines and overall mean changes from baseline were compared by study assignment. Among 96 patients enrolled, 46 received ddI+d4T- and 50 received ABC+3TC-containing regimens with a median follow-up of 32.4 months. For both study arms, an overall increase in the rates of change was seen for body cell mass. For ddI+d4T, after an initial increase, the rates of change declined for regional fat and total body fat compared with an increase for ABC+3TC, with the 2 arms being significantly different (P<0.05). For high-density lipoprotein cholesterol rates of change, ddI+d4T decreased, while ABC+3TC increased. For both arms, low-density lipoprotein cholesterol decreased, while triglycerides increased. Early and sustained increases in insulin and insulin resistance were seen only for ddI+d4T. In this prospective study, metabolic and body composition changes varied according to whether subjects received ddI+d4T or ABC+3TC.

Adult↗
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↗
PubMed2005

The effects of HIV protease inhibitors on carbohydrate and lipid metabolism.

Since the introduction of HIV protease inhibitors (PIs), disorders of glucose and lipid metabolism have emerged. In dissecting out the direct effect on lipid and glucose metabolism, it has become apparent that individual PIs have different effects on metabolism. Some PIs such as indinavir acutely induce insulin resistance. PIs have also been shown to cause other disorders of glucose metabolism, including impairment of insulin secretion and increased endogenous glucose production. Individual PIs also have different effects on lipid metabolism. Ritonavir predominantly increases triglyceride and very low-density lipoprotein cholesterol levels. Limited studies in HIV-negative volunteers suggest that several of the PIs do not increase low-density lipoprotein cholesterol levels. This review examines the direct effects of PIs on glucose and lipid metabolism by assessing prospective studies of HIV-infected and healthy normal volunteers, and in vitro studies.

Blood Glucose↗
PubMed2005

Sex differences in the associations of HIV disease characteristics and body composition in antiretroviral-naive persons.

BACKGROUND: Data on associations of body composition with HIV disease characteristics are limited. OBJECTIVE: We compared sex-specific associations between HIV disease characteristics and body composition in an racially-ethnically diverse cohort of antiretroviral-naive patients. DESIGN: The study was a cross-sectional analysis of participants enrolled in a metabolic substudy of a multicenter trial. Regional fat was measured, and total body fat (TBF) was derived by using the Durnin-Womersley formula (DWF) and bioelectrical impedance analysis (BIA). Body cell mass (BCM) was measured by BIA. RESULTS: Among 422 participants, 22% were women, 60% were African American, and 36% had prior AIDS-defining illnesses. Mean (+/-SD) age was 38.2 +/- 9.6 y, CD4+ count was 215 +/- 184 cells/mm3, and HIV RNA log10 was 5.0 +/- 0.8 copies/mL. On multivariate analysis, women with AIDS-defining illness had significantly (P < 0.005) lower regional body fat and TBF (BIA: -9.5 kg; DWF: -7.3 kg) but nonsignificantly lower BCM (-1.3 kg) than did women without such illnesses, whereas men with AIDS-defining illness had significantly (P < 0.005) lower BCM (-1.7 kg) but nonsignificantly lower TBF (BIA: -1.3 kg; DWF: -1.83 kg) than did men without such illnesses (P < 0.05 for sex differences in TBF). Significant negative associations of HIV RNA with BCM (-0.9 kg/log RNA; P = 0.03), TBF by BIA (-1.4 kg/log RNA; P = 0.05) and by DWF (-1.6 kg/log RNA; P = 0.01), and regional fat were observed in men only. CONCLUSIONS: The effect of prior AIDS illness on body fat differed significantly between the sexes: women with prior AIDS-defining illness had significantly less fat than did women without such illnesses. An independent effect of HIV viremia on BCM and fat was seen in men. These distinctions may be due to inherent biological differences between the sexes.

Adipose Tissue↗