Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact

Issue published November 1, 2001 Previous issue | Next issue

  • Volume 108, Issue 9
Go to section:
  • In this issue
  • Spotlight
  • Perspectives
  • Commentaries
  • Research Articles
  • Erratum
In this issue
In This Issue
John Ashkenas
John Ashkenas
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1241-1241. https://doi.org/10.1172/JCI119937.
View: Text | PDF

In This Issue

  • Text
  • PDF
Abstract

Authors

John Ashkenas

×
Spotlight
Spotlight on BACE: The secretases as targets for treatment in Alzheimer disease
Colin Dingwall
Colin Dingwall
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1243-1246. https://doi.org/10.1172/JCI14402.
View: Text | PDF

Spotlight on BACE: The secretases as targets for treatment in Alzheimer disease

  • Text
  • PDF
Abstract

Authors

Colin Dingwall

×
Perspectives
Autoimmune type 1 diabetes: resolved and unresolved issues
Abner Louis Notkins, Åke Lernmark
Abner Louis Notkins, Åke Lernmark
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1247-1252. https://doi.org/10.1172/JCI14257.
View: Text | PDF

Autoimmune type 1 diabetes: resolved and unresolved issues

  • Text
  • PDF
Abstract

Authors

Abner Louis Notkins, Åke Lernmark

×

Thyroid autoimmunity
Basil Rapoport, Sandra M. McLachlan
Basil Rapoport, Sandra M. McLachlan
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1253-1259. https://doi.org/10.1172/JCI14321.
View: Text | PDF

Thyroid autoimmunity

  • Text
  • PDF
Abstract

Authors

Basil Rapoport, Sandra M. McLachlan

×

Interplay between genetics and the environment in the development of celiac disease: perspectives for a healthy life
George K. Papadopoulos, … , Cisca Wijmenga, Frits Koning
George K. Papadopoulos, … , Cisca Wijmenga, Frits Koning
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1261-1266. https://doi.org/10.1172/JCI14344.
View: Text | PDF

Interplay between genetics and the environment in the development of celiac disease: perspectives for a healthy life

  • Text
  • PDF
Abstract

Authors

George K. Papadopoulos, Cisca Wijmenga, Frits Koning

×
Commentaries
Phosphatidylinositol 3-kinase and trypsin activation in pancreatitis
Craig Logsdon
Craig Logsdon
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1267-1268. https://doi.org/10.1172/JCI14272.
View: Text | PDF

Phosphatidylinositol 3-kinase and trypsin activation in pancreatitis

  • Text
  • PDF
Abstract

Authors

Craig Logsdon

×

Chemokines and atherosclerosis: what Adam Smith has to say about vascular disease
Barrett J. Rollins
Barrett J. Rollins
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1269-1271. https://doi.org/10.1172/JCI14273.
View: Text | PDF

Chemokines and atherosclerosis: what Adam Smith has to say about vascular disease

  • Text
  • PDF
Abstract

Authors

Barrett J. Rollins

×

Is it time to modify the reverse cholesterol transport model?
Alan R. Tall, … , Nan Wang, Phillip Mucksavage
Alan R. Tall, … , Nan Wang, Phillip Mucksavage
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1273-1275. https://doi.org/10.1172/JCI14342.
View: Text | PDF

Is it time to modify the reverse cholesterol transport model?

  • Text
  • PDF
Abstract

Authors

Alan R. Tall, Nan Wang, Phillip Mucksavage

×

Targeting aberrant transcriptional repression in leukemia: a therapeutic reality?
Jonathan D. Licht
Jonathan D. Licht
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1277-1278. https://doi.org/10.1172/JCI14343.
View: Text | PDF

Targeting aberrant transcriptional repression in leukemia: a therapeutic reality?

  • Text
  • PDF
Abstract

Authors

Jonathan D. Licht

×

Guanine nucleotides and acute renal failure
Joel M. Weinberg, Manjeri A. Venkatachalam
Joel M. Weinberg, Manjeri A. Venkatachalam
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1279-1281. https://doi.org/10.1172/JCI14320.
View: Text | PDF

Guanine nucleotides and acute renal failure

  • Text
  • PDF
Abstract

Authors

Joel M. Weinberg, Manjeri A. Venkatachalam

×
Research Articles
Identification of the CD4+ T cell as a major pathogenic factor in ischemic acute renal failure
Melissa J. Burne, … , Michael P. O’Donnell, Hamid Rabb
Melissa J. Burne, … , Michael P. O’Donnell, Hamid Rabb
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1283-1290. https://doi.org/10.1172/JCI12080.
View: Text | PDF

Identification of the CD4+ T cell as a major pathogenic factor in ischemic acute renal failure

  • Text
  • PDF
Abstract

Leukocytes have been implicated in the pathogenesis of ischemic acute renal failure (ARF), but the roles of the individual cell types involved are largely unknown. Recent indirect evidence suggests that T cells may play an important role in a murine model of ARF. In the current study, we found that mice deficient in T cells (nu/nu mice) are both functionally and structurally protected from postischemic renal injury. Reconstitution of nu/nu mice with wild-type T cells restored postischemic injury. We then analyzed the contribution of the individual T cell subsets to postischemic injury and found that mice deficient in CD4+ T cells, but not mice deficient in CD8+ T cells, were significantly protected from ARF. Direct evidence for a pathophysiologic role of the CD4+ T cell was obtained when reconstitution of CD4-deficient mice with wild-type CD4+ T cells restored postischemic injury. In addition, adoptive transfers of CD4+ T cells lacking either the costimulatory molecule CD28 or the ability to produce IFN-γ were inadequate to restore injury phenotype. These results demonstrate that the CD4+ T cell is an important mediator of ischemic ARF, and targeting this cell may yield novel therapies.

Authors

Melissa J. Burne, Frank Daniels, Asmaa El Ghandour, Shamila Mauiyyedi, Robert B. Colvin, Michael P. O’Donnell, Hamid Rabb

×

Guanosine supplementation reduces apoptosis and protects renal function in the setting of ischemic injury
K.J. Kelly, … , Zoya Plotkin, Pierre C. Dagher
K.J. Kelly, … , Zoya Plotkin, Pierre C. Dagher
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1291-1298. https://doi.org/10.1172/JCI13018.
View: Text | PDF

Guanosine supplementation reduces apoptosis and protects renal function in the setting of ischemic injury

  • Text
  • PDF
Abstract

Ischemic injury to the kidney is characterized in part by nucleotide depletion and tubular cell death in the form of necrosis or apoptosis. Recently, we linked anoxia-induced apoptosis in renal cell cultures specifically to the depletion of GTP. We therefore hypothesized that enhancing GTP repletion in vivo might protect function by reducing apoptosis in postischemic tubules. Male C57 black mice (the "I" group of animals) underwent bilateral renal artery clamp for 32 minutes to induce ischemia and then received either normal saline ("NS") or guanosine ("G"). After 1 hour of reperfusion, renal GTP levels in NS/I were reduced to nearly half of those in sham operated mice, whereas these levels were nearly unchanged in G/I mice. Morphologic examination of tubular injury revealed no significant differences between the two groups. However, there was a significant reduction in the number of apoptotic tubular cells in the medulla in the G/I group as compared with the NS/I group. At 24 hours, creatinine was significantly elevated in the NS/I group, compared to the G/I group. We conclude that guanosine protects against renal ischemic injury by replenishing GTP stores and preventing tubular apoptosis.

Authors

K.J. Kelly, Zoya Plotkin, Pierre C. Dagher

×

Reduced activity of 11β-hydroxysteroid dehydrogenase in patients with cholestasis
Cristiana Quattropani, … , Brigitte M. Frey, Felix J. Frey
Cristiana Quattropani, … , Brigitte M. Frey, Felix J. Frey
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1299-1305. https://doi.org/10.1172/JCI12745.
View: Text | PDF

Reduced activity of 11β-hydroxysteroid dehydrogenase in patients with cholestasis

  • Text
  • PDF
Abstract

Enhanced renal sodium retention and potassium loss in patients with cirrhosis is due to activation of mineralocorticoid receptors (MRs). Increased aldosterone concentrations, however, do not entirely explain the activation of MR in cirrhosis. Here, we hypothesize that cortisol activates MRs in patients with cholestasis. We present evidence that access of cortisol to MRs is a result of bile acid−mediated inhibition of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), an MR-protecting enzyme that converts cortisol to cortisone. Twelve patients with biliary obstruction and high plasma bile acid levels were studied before and after removal of the obstruction. The urinary ratio of (tetrahydrocortisol + 5α-tetrahydrocortisol)/tetrahydrocortisone, a measure of 11β-HSD2 activity, decreased from a median of 1.91 during biliary obstruction to 0.78 at 4 and 8 weeks after removal of the obstruction and normalization of plasma bile acid concentrations. In order to demonstrate that bile acids facilitate access of cortisol to the MR by inhibiting 11β-HSD2, an MR translocation assay was performed in HEK-293 cells transfected with human 11β-HSD2 and tagged MR. Increasing concentrations of chenodeoxycholic acid led to cortisol-induced nuclear translocation of MR. In conclusion, 11β-HSD2 activity is reduced in cholestasis, which results in MR activation by cortisol.

Authors

Cristiana Quattropani, Bruno Vogt, Alex Odermatt, Bernhard Dick, Brigitte M. Frey, Felix J. Frey

×

The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium
Yuqing Huo, … , Dan R. Littman, Klaus Ley
Yuqing Huo, … , Dan R. Littman, Klaus Ley
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1307-1314. https://doi.org/10.1172/JCI12877.
View: Text | PDF

The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium

  • Text
  • PDF
Abstract

In a reconstituted flow chamber system, preincubation with chemokines can trigger the arrest of rolling monocytes, suggesting that this interaction could help recruit these cells to early atherosclerotic lesions. To date, however, the contribution of endothelium–derived chemokines found in these lesion to monocyte arrests has not been investigated. The endothelium of lesion-prone carotid arteries from apolipoprotein E–deficient (ApoE–/–) mice, but not control mice, presents the chemokines KC (mouse GRO-α) and JE (mouse monocyte chemoattractant protein-1 [MCP-1]). Arrest of a monocytic cell line or mouse blood monocytes perfused through carotid arteries of ApoE–/– mice was reduced by treating with either pertussis toxin, an antagonist of CXCR2, or an antibody to KC, but this process was insensitive to agents that blocked CCR-2 or JE. Conversely, monocyte accumulation more than doubled upon pre-perfusion of the carotid artery with KC but not with mouse MCP-1. Blockade of α4β1 integrin (VLA-4) or vascular cell adhesion molecule-1, but not CD18 or intercellular adhesion molecule-1, almost completely inhibited the arrest of monocytes. We conclude that when presented by early atherosclerotic lesions, KC but not murine MCP-1 triggers VLA-4–dependent monocyte recruitment.

Authors

Yuqing Huo, Christian Weber, S.B. Forlow, Markus Sperandio, Jayant Thatte, Matthias Mack, Steffen Jung, Dan R. Littman, Klaus Ley

×

Monocyte/macrophage expression of ABCA1 has minimal contribution to plasma HDL levels
Mehrdad Haghpassand, … , Omar L. Francone, Robert J. Aiello
Mehrdad Haghpassand, … , Omar L. Francone, Robert J. Aiello
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1315-1320. https://doi.org/10.1172/JCI12810.
View: Text | PDF

Monocyte/macrophage expression of ABCA1 has minimal contribution to plasma HDL levels

  • Text
  • PDF
Abstract

Excess accumulation of cholesterol in macrophages results in foam cell production and lesion development. Recent studies have demonstrated that ATP-binding cassette protein A1 (ABCA1) is highly regulated in macrophages and mediates the efflux of cholesterol and phospholipids to apolipoproteins, a process necessary for HDL formation. The goal of this study was to determine the contribution of monocyte/macrophage ABCA1 to HDL formation in vivo. We generated mice expressing ABCA1 in macrophages and mice with selected inactivation of ABCA1 in macrophages by bone marrow transplantation in ABCA1-deficient (ABC1–/–) and wild-type (WT) mice. At all times, the level of HDL in ABC1–/– recipient mice remained low relative to WT recipient mice irrespective of the genotype of the donor macrophage ABCA1 or high-fat feeding. Expression of WT macrophage ABCA1 in ABC1–/– mice resulted in a small but significant increase in apoA-I levels starting 2 weeks after transplantation. No further increase in apoAI was observed up to 14 weeks after transplantation. The increase in apoAI was accompanied by a small but significant increase in HDL cholesterol 6 weeks after transplantation. The HDL formed as a consequence of the expression of WT macrophage ABCA1 migrated to the alpha position in a two-dimensional gel electrophoresis. These results demonstrate that monocyte/macrophage ABCA1 contributes to HDL formation; however, the contribution to the overall plasma HDL levels is minimal.

Authors

Mehrdad Haghpassand, Patricia-Ann K. Bourassa, Omar L. Francone, Robert J. Aiello

×

Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia
Li-Zhen He, … , Victoria M. Richon, Pier Paolo Pandolfi
Li-Zhen He, … , Victoria M. Richon, Pier Paolo Pandolfi
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1321-1330. https://doi.org/10.1172/JCI11537.
View: Text | PDF

Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia

  • Text
  • PDF
Abstract

Acute promyelocytic leukemia (APL) is associated with chromosomal translocations, invariably involving the retinoic acid receptor α (RARα) gene fused to one of several distinct loci, including the PML or PLZF genes, involved in t(15;17) or t(11;17), respectively. Patients with t(15;17) APL respond well to retinoic acid (RA) and other treatments, whereas those with t(11;17) APL do not. The PML-RARα and PLZF-RARα fusion oncoproteins function as aberrant transcriptional repressors, in part by recruiting nuclear receptor-transcriptional corepressors and histone deacetylases (HDACs). Transgenic mice harboring the RARα fusion genes develop forms of leukemia that faithfully recapitulate both the clinical features and the response to RA observed in humans with the corresponding translocations. Here, we investigated the effects of HDAC inhibitors (HDACIs) in vitro and in these animal models. In cells from PLZF-RARα/RARα-PLZF transgenic mice and cells harboring t(15;17), HDACIs induced apoptosis and dramatic growth inhibition, effects that could be potentiated by RA. HDACIs also increased RA-induced differentiation. HDACIs, but not RA, induced accumulation of acetylated histones. Using microarray analysis, we identified genes induced by RA, HDACIs, or both together. In combination with RA, all HDACIs tested overcame the transcriptional repression exerted by the RARα fusion oncoproteins. In vivo, HDACIs induced accumulation of acetylated histones in target organs. Strikingly, this combination of agents induced leukemia remission and prolonged survival, without apparent toxic side effects.

Authors

Li-Zhen He, Thomas Tolentino, Peter Grayson, Sue Zhong, Raymond P. Warrell Jr., Richard A. Rifkind, Paul A. Marks, Victoria M. Richon, Pier Paolo Pandolfi

×

Rules of chemokine receptor association with T cell polarization in vivo
Chang H. Kim, … , Lijun Wu, Eugene C. Butcher
Chang H. Kim, … , Lijun Wu, Eugene C. Butcher
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1331-1339. https://doi.org/10.1172/JCI13543.
View: Text | PDF

Rules of chemokine receptor association with T cell polarization in vivo

  • Text
  • PDF
Abstract

Current concepts of chemokine receptor (CKR) association with Th1 and Th2 cell polarization and effector function have largely ignored the diverse nature of effector and memory T cells in vivo. Here, we systematically investigated the association of 11 CKRs, singly or in combination, with CD4 T cell polarization. We show that Th1, Th2, Th0, and nonpolarized T cells in blood and tissue can express any of the CKRs studied but that each CKR defines a characteristic pool of polarized and nonpolarized CD4 T cells. Certain combinations of CKRs define populations that are markedly enriched in major subsets of Th1 versus Th2 cells. For example, although Th0, Th1, and Th2 cells are each found among blood CD4 T cells coordinately expressing CXCR3 and CCR4, Th1 but not Th2 cells can be CXCR3+CCR4–, and Th2 but only rare Th1 cells are CCR4+CXCR3–. Contrary to recent reports, although CCR7– cells contain a higher frequency of polarized CD4 T cells, most Th1 and Th2 effector cells are CCR7+ and thus may be capable of lymphoid organ homing. Interestingly, Th1-associated CKRs show little or no preference for Th1 cells except when they are coexpressed with CXCR3. We conclude that the combinatorial expression of CKRs, which allow tissue- and subset-dependent targeting of effector cells during chemotactic navigation, defines physiologically significant subsets of polarized and nonpolarized T cells.

Authors

Chang H. Kim, Lusijah Rott, Eric J. Kunkel, Mark C. Genovese, David P. Andrew, Lijun Wu, Eugene C. Butcher

×

Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site
Xue Liang Du, … , Chengyu Sui, Michael Brownlee
Xue Liang Du, … , Chengyu Sui, Michael Brownlee
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1341-1348. https://doi.org/10.1172/JCI11235.
View: Text | PDF

Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site

  • Text
  • PDF
Abstract

Endothelial nitric oxide synthase (eNOS) is activated by phosphorylation of serine 1177 by the protein kinase Akt/PKB. Since hyperglycemia-induced mitochondrial superoxide overproduction increases O-linked N-acetylglucosamine modification and decreases O-linked phosphorylation of the transcription factor Sp1, the effect of hyperglycemia and the hexosamine pathway on eNOS was evaluated. In bovine aortic endothelial cells, hyperglycemia inhibited eNOS activity 67%, and treatment with glucosamine had a similar effect. Hyperglycemia-associated inhibition of eNOS was accompanied by a twofold increase in O-linked N-acetylglucosamine modification of eNOS and a reciprocal decrease in O-linked serine phosphorylation at residue 1177. Both the inhibition of eNOS and the changes in its post-translational modifications were reversed by antisense inhibition of glutamine:fructose-6-phosphate amidotransferase, the rate-limiting enzyme of the hexosamine pathway, or by blocking mitochondrial superoxide overproduction with uncoupling protein-1 (UCP-1) or manganese superoxide dismutase (MnSOD). Immunoblot analysis of cells expressing myc-tagged wild-type human eNOS confirmed the reciprocal increase in O-linked N-acetylglucosamine and decrease in O-linked serine 1177 phosphorylation in response to hyperglycemia. In contrast, when myc-tagged human eNOS carried a mutation at the Akt phosphorylation site (Ser1177), O-linked N-acetylglucosamine modification was unchanged by hyperglycemia and phospho-eNOS was undetectable. Similar changes in eNOS activity and covalent modification were found in aortae from diabetic animals. Chronic impairment of eNOS activity by this mechanism may partly explain the accelerated atherosclerosis of diabetes.

Authors

Xue Liang Du, Diane Edelstein, Stefanie Dimmeler, Qida Ju, Chengyu Sui, Michael Brownlee

×

Antibacterial effect of human Vγ2Vδ2 T cells in vivo
Lisheng Wang, … , Lin Li, Jack F. Bukowski
Lisheng Wang, … , Lin Li, Jack F. Bukowski
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1349-1357. https://doi.org/10.1172/JCI13584.
View: Text | PDF

Antibacterial effect of human Vγ2Vδ2 T cells in vivo

  • Text
  • PDF
Abstract

Vγ2Vδ2 cells, a class of T cells found only in primates, are reactive to nonpeptide organophosphate and alkylamine antigens secreted by bacteria and parasites. These cells make up 2-5% percent of human peripheral blood T cells but expand to make up 8–60% of peripheral blood T cells during bacterial and parasitic infections. We show here, using a chimeric severe combined immunodeficiency (SCID) mouse (hu-SCID) model, that human Vγ2Vδ2 T cells mediate resistance to extracellular gram-positive (Staphylococcus aureus) and gram-negative (Escherichia coli and Morganella morganii) bacteria, as assessed by survival, body weight, bacterial loads, and histopathology. Surprisingly, this bacterial resistance was evident 1 day after infection, and bacteria were cleared well before γδ T cell expansion was detected 6 days after infection. Decreased resistance in Vδ2 T cell–depleted hu-SCID mice correlated with decreased serum IFN-γ titers. Intravenous treatment of infected, reconstituted hu-SCID mice with pamidronate, a human Vγ2Vδ2 T cell–specific aminobisphosphonate antigen, markedly increased the in vivo antibacterial effect of Vγ2Vδ2 T cells. Therefore, this large pool of antigen-specific, yet immediately reactive memory human Vγ2Vδ2 T cells is likely to be an important mediator of resistance against extracellular bacterial infection and may bridge the gap between innate and acquired immunity.

Authors

Lisheng Wang, Arati Kamath, Hiranmoy Das, Lin Li, Jack F. Bukowski

×

The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression
Jun Nakae, … , David L. Silver, Domenico Accili
Jun Nakae, … , David L. Silver, Domenico Accili
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1359-1367. https://doi.org/10.1172/JCI12876.
View: Text | PDF

The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression

  • Text
  • PDF
Abstract

Type 2 diabetes is characterized by the inability of insulin to suppress glucose production in the liver and kidney. Insulin inhibits glucose production by indirect and direct mechanisms. The latter result in transcriptional suppression of key gluconeogenetic and glycogenolytic enzymes, phosphoenolpyruvate carboxykinase (Pepck) and glucose-6-phosphatase (G6p). The transcription factors required for this effect are incompletely characterized. We report that in glucogenetic kidney epithelial cells, Pepck and G6p expression are induced by dexamethasone (dex) and cAMP, but fail to be inhibited by insulin. The inability to respond to insulin is associated with reduced expression of the forkhead transcription factor Foxo1, a substrate of the Akt kinase that is inhibited by insulin through phosphorylation. Transduction of kidney cells with recombinant adenovirus encoding Foxo1 results in insulin inhibition of dex/cAMP–induced G6p expression. Moreover, expression of dominant negative Foxo1 mutant results in partial inhibition of dex/cAMP–induced G6p and Pepck expression in primary cultures of mouse hepatocyes and kidney LLC-PK1-FBPase+ cells. These findings are consistent with the possibility that Foxo1 is involved in insulin regulation of glucose production by mediating the ability of insulin to decrease the glucocorticoid/cAMP response of G6p.

Authors

Jun Nakae, Tadahiro Kitamura, David L. Silver, Domenico Accili

×

DDR2 receptor promotes MMP-2–mediated proliferation and invasion by hepatic stellate cells
Elvira Olaso, … , Hsin Chieh Lin, Scott L. Friedman
Elvira Olaso, … , Hsin Chieh Lin, Scott L. Friedman
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1369-1378. https://doi.org/10.1172/JCI12373.
View: Text | PDF

DDR2 receptor promotes MMP-2–mediated proliferation and invasion by hepatic stellate cells

  • Text
  • PDF
Abstract

Type I collagen provokes activation of hepatic stellate cells during liver injury through mechanisms that have been unclear. Here, we tested the role of the discoidin domain tyrosine kinase receptor 2 (DDR2), which signals in response to type I collagen, in this pathway. DDR2 mRNA and protein are induced in stellate cells activated by primary culture or in vivo during liver injury. The receptor becomes tyrosine phosphorylated in response to either endogenous or exogenous type I collagen, whereas its expression is downregulated during cellular quiescence induced by growth on Matrigel. We developed stellate cell lines stably overexpressing either wild-type DDR2, a constitutively active chimeric DDR2 receptor (Fc-DDR2), a truncated receptor expressing the extracellular domain, or a kinase-dead DDR2 Cells overexpressing DDR2 showed enhanced proliferation and invasion through Matrigel, activities that were directly related to increased expression of active matrix metalloproteinase 2 (MMP-2). These data show that DDR2 is induced during stellate cell activation and implicate the phosphorylated receptor as a mediator of MMP-2 release and growth stimulation in response to type I collagen. Moreover, type I collagen-dependent upregulation of DDR2 expression establishes a positive feedback loop in activated stellate cells, leading to further proliferation and enhanced invasive activity.

Authors

Elvira Olaso, Kazuo Ikeda, Francis J. Eng, Lieming Xu, Li-Hsien Wang, Hsin Chieh Lin, Scott L. Friedman

×

The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue
Lucia A. de Jesus, … , P. Reed Larsen, Antonio C. Bianco
Lucia A. de Jesus, … , P. Reed Larsen, Antonio C. Bianco
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1379-1385. https://doi.org/10.1172/JCI13803.
View: Text | PDF

The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue

  • Text
  • PDF
Abstract

Type 2 iodothyronine deiodinase (D2) is a selenoenzyme, the product of the recently cloned cAMP-dependent Dio2 gene, which increases 10- to 50-fold during cold stress only in brown adipose tissue (BAT). Here we report that despite a normal plasma 3,5,3′-triiodothyronine (T3) concentration, cold-exposed mice with targeted disruption of the Dio2 gene (Dio2–/–) become hypothermic due to impaired BAT thermogenesis and survive by compensatory shivering with consequent acute weight loss. This occurs despite normal basal mitochondrial uncoupling protein 1 (UCP1) concentration. In Dio2–/– brown adipocytes, the acute norepinephrine-, CL316,243-, or forskolin-induced increases in lipolysis, UCP1 mRNA, and O2 consumption are all reduced due to impaired cAMP generation. These hypothyroid-like abnormalities are completely reversed by a single injection of T3 14 hours earlier. Recent studies suggest that UCP1 is primarily dependent on thyroid hormone receptor β (TRβ) while the normal sympathetic response of brown adipocytes requires TRα. Intracellularly generated T3 may be required to saturate the TRα, which has an approximately fourfold lower T3-binding affinity than does TRβ. Thus, D2 is an essential component in the thyroid-sympathetic synergism required for thermal homeostasis in small mammals.

Authors

Lucia A. de Jesus, Suzy D. Carvalho, Mirian O. Ribeiro, Mark Schneider, Sung-Woo Kim, John W. Harney, P. Reed Larsen, Antonio C. Bianco

×

Phosphatidylinositol 3-kinase-dependent activation of trypsinogen modulates the severity of acute pancreatitis
Vijay P. Singh, … , Lewis C. Cantley, Michael L. Steer
Vijay P. Singh, … , Lewis C. Cantley, Michael L. Steer
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1387-1395. https://doi.org/10.1172/JCI12874.
View: Text | PDF

Phosphatidylinositol 3-kinase-dependent activation of trypsinogen modulates the severity of acute pancreatitis

  • Text
  • PDF
Abstract

Intra-acinar cell activation of digestive enzyme zymogens including trypsinogen is generally believed to be an early and critical event in acute pancreatitis. We have found that the phosphatidylinositol 3-kinase inhibitor wortmannin can reduce the intrapancreatic activation of trypsinogen that occurs during two dissimilar experimental models of rodent acute pancreatitis, secretagogue- and duct injection-induced pancreatitis. The severity of both models was also reduced by wortmannin administration. In contrast, the NF-κB activation that occurs during the early stages of secretagogue-induced pancreatitis is not altered by administration of wortmannin. Ex vivo, caerulein-induced trypsinogen activation is inhibited by wortmannin and LY294002. However, the cytoskeletal changes induced by caerulein were not affected by wortmannin. Concentrations of caerulein that induced ex vivo trypsinogen activation do not significantly increase phosphatidylinositol-3,4-bisphosphate or phosphatidylinositol 3,4,5-trisphosphate levels or induce phosphorylation of Akt/PKB, suggesting that class I phosphatidylinositol 3-kinases are not involved. The concentration of wortmannin that inhibits trypsinogen activation causes a 75% decrease in phosphatidylinositol 3-phosphate, which is implicated in vesicle trafficking and fusion. We conclude that a wortmannin-inhibitable phosphatidylinositol 3-kinase is necessary for intrapancreatic activation of trypsinogen and regulating the severity of acute pancreatitis. Our observations suggest that phosphatidylinositol 3-kinase inhibition might be of benefit in preventing acute pancreatitis.

Authors

Vijay P. Singh, Ashok K. Saluja, Lakshmi Bhagat, Gijs J.D. van Acker, Albert M. Song, Stephen P. Soltoff, Lewis C. Cantley, Michael L. Steer

×

Role of protein kinase C-δ in the regulation of collagen gene expression in scleroderma fibroblasts
Sergio A. Jimenez, … , William R. Abrams, Joel Rosenbloom
Sergio A. Jimenez, … , William R. Abrams, Joel Rosenbloom
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1395-1403. https://doi.org/10.1172/JCI12347.
View: Text | PDF

Role of protein kinase C-δ in the regulation of collagen gene expression in scleroderma fibroblasts

  • Text
  • PDF
Abstract

Working with cultured dermal fibroblasts derived from control individuals and patients with systemic sclerosis (SSc), we have examined the effects of protein kinase C-δ (PKC-δ) on type I collagen biosynthesis and steady-state levels of COL1A1 and COL3A1 mRNAs. Rottlerin, a specific inhibitor of PKC-δ, exerted a powerful, dose-dependent inhibition of type I and type III collagen gene expression in normal and SSc cells. Optimal rottlerin concentrations caused a 70–90% inhibition of type I collagen production, a >80% reduction in COL1A1 mRNA, and a >70% reduction in COL3A1 mRNA in both cell types. In vitro nuclear transcription assays and transient transfections with COL1A1 promoter deletion constructs demonstrated that rottlerin profoundly reduced COL1A1 transcription and that this effect required a 129-bp promoter region encompassing nucleotides –804 to –675. This COL1A1 segment imparted rottlerin sensitivity to a heterologous promoter. Cotransfections of COL1A1 promoter constructs with a dominant-negative PKC-δ expression plasmid showed that suppression of this kinase silenced COL1A1 promoter activity. The results indicate that PKC-δ participates in the upregulation of collagen gene transcription in SSc and suggest that treatment with PKC-δ inhibitors could suppress fibrosis in this disease.

Authors

Sergio A. Jimenez, Svetlana Gaidarova, Biagio Saitta, Nora Sandorfi, David J. Herrich, Joan C. Rosenbloom, Umberto Kucich, William R. Abrams, Joel Rosenbloom

×
Erratum
Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3)
Kevin J. Leco, … , Tak W. Mak, Rama Khokha
Kevin J. Leco, … , Tak W. Mak, Rama Khokha
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1405-1405. https://doi.org/10.1172/JCI10947E1.
View: Text | PDF | Amended Article

Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3)

  • Text
  • PDF
Abstract

Authors

Kevin J. Leco, Paul Waterhouse, Otto H. Sanchez, Katrina L.M. Gowing, A. Robin Poole, Andrew Wakeham, Tak W. Mak, Rama Khokha

×
Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts