JCI table of contents November 1, 2004


Mutations in Transporter Protein Effect HDL Levels in the General Population

High cholesterol levels are a major contributor to heart disease in particular atherosclerosis. High density lipoprotein (HDL) has an essential role in reducing cholesterol levels, and therefore has a cardioprotective effect. There is therefore a great deal of research into the genetic underpinnings that control HDL blood levels. Individuals with Tangier disease have essentially no HDL in the blood. Recently the mutation underlying this disorder was identified in the ABC transporter A1 (ABCA1) gene, which is essential for the first step in the synthesis of HDL. When both ABCA1genes become nonfunctional, Tangier disease develops. Given the ABCA1 transporter's essential role in HDL synthesis, researchers have theorized that mutations in one of the ABCA1 genes may alter HDL levels in the normal population. Anne Tybjærg-Hansen and colleagues at Copenhagen University Hospital now provide the evidence that indeed alterations in the ABCA1 gene affect HDL levels in the general population. The authors found that approximately 10% of individual with low HDL levels in the general population have a mutation or nucleotide modification in one of their ABCA1 genes. Furthermore, the researchers showed that the 4 out of 9 individuals with low HDL specifically carry 1 of the 2 mutations identified in families with Tangier disease. These data provide insight into the genetic changes that can contribute to variation of HDL in the general population and add to our current understanding of the variety of mechanisms that together contribute to increased or decreased susceptibility to cardiovascular disease.

An accompanying commentary places this study in the context of the function of the ABCA1 transporter and its impact on HDL production along with studies of the genetics and molecular mechanisms relating to Tangier disease.

TITLE: Genetic variation in ABC transporter A1 contributes to HDL cholesterol in the general population

Anne Tybjærg-Hansen
Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark
Phone: 45-3545-4159; Fax: 45-3545-4160; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/20361.pdf

ACCOMPANYING COMMENTARY: Do DNA sequence variants in ABCA1 contribute to HDL cholesterol levels in the general population?

Päivi Pajukanta
University of California, Los Angeles, 695 Charles E. Young Dr South, Los Angeles, CA 90095, USA
Phone: 310-267-2011; Fax: 310-794-5446; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/23466.pdf

Gene that Blocks Free Radical Damage Protects Against Emphysema

Emphysema is a major manifestation of chronic obstructive lung disease, which affects more than 16 million Americans and is the fourth highest cause of death in the United States. This disease is primarily cigarette smoke induced, but oxidative stress, a harmful condition that occurs when there is an excess of free radicals, has recently been alleged to play an important role in lung susceptibility to cigarette smoke-induced damage. To investigate the impact of oxidative stress on emphysema development, Shyam Biswal and colleagues, from Johns Hopkins University, disrupted in mice the nuclear factor, erythroid-derived 2, like 2 (Nrf2) gene, which makes a protein that regulates genes involved in protecting the body from free radical damage. The authors found that cigarette smoke-induced emphysema was of earlier onset and more widespread in the Nrf2–/– mice than in their wild-type littermates. The Nrf2–/– mice also had a greater number of alveolar cells that underwent programmed cell death, and had more prominent bronchoalveolar inflammation. Microarray analysis provided evidence of about 50 Nrf2-dependent antioxidant and cell-protective genes in the lung that might function together to protect the lung from cigarette smoke-induced emphysema. These data suggest that the Nrf2 pathway provides protection from emphysema by turning on antioxidants and suppressing inflammation and cell death in the lung.

TITLE: Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke–induced emphysema in mice

Shyam Biswal
Johns Hopkins University, Baltimore, MD 21205, USA
Phone: 410-955-4728; Fax: 410-955-0116; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/21146.pdf

Ethical Paradigm: Relating Embryonic Stem Cell Use to Organ Donation

The conflict over allowing the creation of embryonic stem cells for therapeutic purposes pits the value of early human life against that of potentially life-saving therapies. This has deeply polarized each side of the argument, ultimately resulting in an arena that disregards common interest or points of view. Donald Landry and Howard Zucker, of the University of Columbia, now offer a commentary that presents a potential means for creating common ground in this debate. The authors propose applying the ethics and standards of organ donation, which has a long history of debate, legal definition, and ethical resolution, to that of embryonic cell use. Landry and Zucker detail the development of laws and practices surrounding the establishment of the definition of death for a fully developed human. At the point that brain function is irretrievably lost, even if other cells and organs remain alive, humans are considered organismically dead. At this time organs and tissues may be harvested as needed and allowed by . The authors propose a similar mechanism might be used for embryonic cells. At this stage, however, no definition for death has been defined for unformed humans. The authors highlight the point that many embryos created for in vitro fertilization are not used because they are unable to properly produce a fetus due to inherent genetic or mechanical defects. These embryos, however, often contain some normal cells that, while unable to create a fully formed human, can be donated for use. The arguments defined by Landry and Zucker are laid out with historical background both on the history of organ donation and in vitro fertilization. The commentary offers a potential path for both sides of the embryonic stem cell argument to follow to common ground in the discussion for determining an ethically and medically sound future for stem cell research.

TITLE: Embryonic death and the creation of human embryonic stem cells

Donald W. Landry
Columbia University, 630 West 168th St, New York, NY 10032, USA
Phone: 212-305-2436; Fax: 212-305-3475; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/23065.pdf

Diabetes Drug Works by Enhancing Fat Cell Energy Production

Energy homeostasis is controlled by a complex series of cellular and hormonal interactions. White fat tissue has been shown by mouse-knockout studies and the identification of fat-specific secreted factors to be central to this process. Drugs for type 2 diabetes that enhance sensitivity to insulin, such as rosiglitazone, work through mechanisms that involve fat. Cell culture work has indicated that rosiglitazone alters the mitochondria of fat cells, both in their structural features and in the types of proteins they produce. Mitochondria are what make the cell's energy. Silvia Corvera and colleagues, from University of Massachusetts Medical School, examined in live animals the effects of rosiglitazone through studies on white fat tissue in an obesity mouse model called ob/ob mice. The authors found that at the onset of obesity in the ob/ob mice, there was decreased expression of about 50% of the mitochondrial protein genes. When these mice were treated with rosiglitazone, half of these genes showed increased expression. Additionally, the mitochondria in the white fat cells of treated ob/ob mice had increased size and altered structure. The oxygen consumption, reflecting energy use, of these cells was also significantly higher. The work here provides live animal evidence that rosiglitazone treatment works by modifying mitochondrial structure and increasing white fat cell tissue energy, which indicates that increased lipid utilization by fat cells improves insulin sensitivity and alters whole-body energy homeostasis.

TITLE: Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone

Silvia Corvera,
University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01601, USA
Phone: 508-856-6898; Fax: 508-856-1617; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/21752.pdf

Imatinib May Aid in Combating Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a rapidly progressing lung disease that has a survival rate of fewer than three years. Recent work suggests an underlying mechanism of pathogenesis of IPF may work through cytokines that can promote the formation of excessive fiberous tissue, such as TGF-b and PDGF. Edward Leof and colleagues , from the Mayo Clinic, examined TGF-b–induced fibrosis to determine if it is mediated through the action of c-Abl, which is already known to mediate PDGF action. The authors show that c-Abl is a direct target of TGF-b and that its kinase activity is stimulated by TGF-b in a Smad2/3-independent manner. Further, TGF-b stimulation of c-Abl kinase activity did not require PDGFR phosphorylation or expression. Use of imatinib, an FDA-approved treatment for chronic myelogenous leukemia that inhibits c-Abl family kinases, blocked TGF-b–induced fibroblast morphological changes and proliferation in culture. In vivo, imatinib treatment in a bleomycin-induced pulmonary fibrosis mouse model resulted in reduced collagen deposition and tissue destruction in addition to a lower number of inflammatory cells in lung tissue compared with that found in untreated mice. This study provides evidence that c-Abl family members may be primary targets of profibrotic cytokine signaling and that imatinib represents a potentially effective in vivo therapy for growth-dependent fibrosis in an animal model.

TITLE: Imatinib mesylate inhibits the profibrogenic activity of TGF-b and prevents bleomycin-mediated lung fibrosis

Edward B. Leof
Mayo Clinic, Rochester, MN 55905, USA
Phone: 507-284-5717; Fax: 507-284-4521; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/19603.pdf

Gene that Inhibits Cancer Metastasis Identified

Melanoma is the deadliest form of skin cancer, primarily because of its highly metastatic nature. One class of proteins called semaphorins could play a role in the development of tumor metastasis as they have been shown to block the migration of some cell types in culture. Michael Klagsbrun and colleagues, from Harvard Medical School, examined semaphorin 3F (SEMA3F) expression in human metastatic cancer cell lines and found that it was markedly lower both in cell culture and in implanted tumors in mice. The authors then put the SEMA3F gene into human melanoma cells. In culture, these cells had a reduced ability to adhere to and migrate on fibronectin, a standard test of cellular motility. For analysis in live animals, the authors implanted these SEMA3F-expressing tumor cells in mice. In drastic contrast to the tumors whose cells did not contain SEMA3F, the SEMA3F-containing tumors did not metastasize. Furthermore, the resultant primary tumors resembled benign nevi that had reduced vascularization and had an increased number of cells that underwent programmed cell death. Hyperplasia was inhibited in overlying epidermal cells, and the tumors were encapsulated in well-defined thick layers of fibroblast and collagen matrix. Together, these data indicate that SEMA3F is a strong inhibitor of metastasis that affects both tumor and stromal cells, which suggests that it may have therapeutic potential.

TITLE: Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype

Michael Klagsbrun
Harvard Medical School, 300 Longwood Ave Boston, MA 02115, USA
Phone: 617-919-2157; Fax: 617-730-0233; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/21378.pdf


Cellular Markers of Aging Identified

TITLE: Ink4a/Arf expression is a biomarker of aging

Norman E. Sharpless
The University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Phone: 919-966-1185, or 919-966-4067; Fax: 919-966-8212; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/22475.pdf

ACCOMPANYING COMMENTARY: p16 and ARF: activation of teenage proteins in old age

Karl Lenhard Rudolph
Medical School Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
Phone: 49-511-532-6999; Fax: 49-511-532-6998; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/23437.pdf

Protein that Degrades Cell Surface Receptors Involved in Obesity

TITLE: c-Cbl–deficient mice have reduced adiposity, higher energy expenditure, and improved peripheral insulin action

David E. James
Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia
Phone: 61-2-9295-8210; Fax: 61-2-9295-8201; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/21480.pdf

New Gene Identified in Control of Diet-Induced Obesity

TITLE: Mice lacking the syndecan-3 gene are resistant to diet-induced obesity

April D. Strader
University of Cincinnati, 2170 East Galbraith Rd,, Reading, OH 45237, USA
Phone: 513-558-4703; Fax: 513-558-8990; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/20631.pdf

DNA Vaccine Enhances Dendritic Cells and Improves Immune Response

TITLE: Recruitment and expansion of dendritic cells in vivo potentiate the immunogenicity of plasmid DNA vaccines

Dan H. Barouch
Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA
Phone: 617-667-4434; Fax: 617-667-8210; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/22608.pdf

ACCOMPANYING COMMENTARY: Developing DNA vaccines that call to dendritic cells

David Weiner
University of Pennsylvania School of Medicine, 422 Curie Blvd, Philadelphia, PA 19104, USA
Phone: 215-662-2352; Fax: 215-573-9436; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/23467.pdf

Blocking Ras-1 Protects Intestines from Inflammation

TITLE: Kinase suppressor of Ras-1 protects intestinal epithelium from cytokine-mediated apoptosis during inflammation

D. Brent Polk
Vanderbilt University, Medical Center North, 21st and Garland Avenues, Nashville, TN 37232, USA
Phone: 615-322-7449; Fax: 615-343-8915; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/21022.pdf

ACCOMPANYING COMMENTARY: Inflammatory bowel disease reveals the kinase activity of KSR1

Richard Kolesnick
Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA
Phone: 212-639-7558; Fax: 212-639-2767; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/23441.pdf

Inflammation-Related Protein Enhances Tumor Growth

TITLE: Mast cell–derived angiopoietin-1 plays a critical role in the growth of plasma cell tumors

Giovanna Tosato
National Cancer Institute, NIH, 10 Center Dr., Bethesda, MD 20892, USA
Phone: 301-594-9596; Fax: 301-594-9585; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/22089.pdf

Viral Protein Mimics Self Protein and Accelerates Autoimmune Diabetes

TITLE: A viral epitope that mimics a self antigen can accelerate but not initiate autoimmune diabetes

Matthias G. von Herrath
La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr, San Diego, CA 92121, USA
Phone: 858-558-3671; Fax: 858-558-3579; E-mail: [email protected]

View the PDF of this article at: https://www.the-jci.org/press/22557.pdf

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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