News Release

JCI table of contents: Nov. 8, 2007

Peer-Reviewed Publication

JCI Journals

EDITOR'S PICK: Atrogin breaks down the side effects of statins

Statins are a popular class of drugs used to successfully combat high cholesterol. However, the rare, but serious, and poorly understood side effect of skeletal muscle breakdown (a process known as atrophy) prevents more prevalent use of these drugs. New insight into the mechanism of statin-induced skeletal muscle atrophy has been provided by reserachers at Beth Israel Deaconess Medical Center, Boston.

In this study, the authors focused on the activity of atrogin-1, a gene highly associated with skeletal muscle atrophy. Following treatment with lovastatin, a commonly prescribed statin, atrogin-1 was induced in cultured mouse muscle cells and in zebrafish embryos. Furthermore, statin-induced muscle injury in the zebrafish was prevented by reducing the amount of atrogin-1 expressed. Finally, when the protein PGC-1a (which protects against skeletal muscle damage and atrophy) was expressed in zebrafish, both atrogin-1 expression and lovastatin-induced muscle damage were prevented. These data led the authors to conclude that atrogin-1 is a critical mediator of statin-induced muscle damage and that inhibiting atrogin-1 function might protect against this unwanted side effect of statins.

TITLE: The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity

Stewart H. Lecker,
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Phone: (617) 667-2147; Fax: (617) 667-5276; E-mail:

Vikas P. Sukhatme
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Phone: (617) 667-2147; Fax: (617) 667-5276; E-mail:

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EDITOR'S PICK: Sex, sugar, and metabolic disease

Overweight children and adults have low levels in their blood of a protein known as SHGB, which transports sex steroids and regulates their entry into tissues. Low levels of SHGB are a marker of the metabolic syndrome, a combination of medical disorders that increase an individual’s risk of developing type 2 diabetes and heart disease. An explanation as to why low levels of SHGB are such a good marker of the metabolic syndrome are now provided by Geoffrey Hammond and colleagues at the University of British Columbia, Vancouver.

In the study, exposure to glucose and fructose (monomeric sugar building blocks of carbohydrates) reduced the production of SHGB in vitro by a human liver cell line and in vivo by the liver of mice engineered to express human SHGB. Decreased production of SHGB was mediated by decreased expression of a protein that stimulates the gene that makes SHGB (HNF-4-alpha) and was associated with increased amounts of the fat palmitate in the liver cells. Importantly, glucose- and fructose-induced decreases in SHGB production were prevented by inhibiting palmitate generation. These data provide a mechanistic link between excess sugar and carbohydrate consumption and decreased levels of SHGB, indicating the reason it is a good marker of the metabolic syndrome.

TITLE: Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone–binding globulin gene

Geoffrey L. Hammond
Child & Family Research Institute, Vancouver, British Columbia, Canada.
Phone: (604) 875-2435; Fax: (604) 875-2496; E-mail:

Jennifer Kohm
Director, Communications
Child & Family Research Institute, Vancouver, British Columbia, Canada.
Phone: (604) 875- 2401; E-mail:

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TECHNICAL ADVANCE: New mouse strain teaches us about GPCRs

All mammals, including humans, have hundreds of proteins known as GPCRs. The function of some of these GPCRs is known — and in many cases has been shown to regulate disease processes. However, the function of very many GPCRs remains incompletely understood. A new tool to determine the in vivo function of GPCRs in mice has now been generated by Shaun Coughlin and colleagues from the University of California at San Francisco.

The authors generated mice (ROSA26PTX mice) that have the capacity to express a toxin known as PTX, which inhibits signaling by proteins that transmit signals from GPCRs (Gi and Go G proteins), in any tissue. However, expression of PTX only occurs in the presence of another protein known as Cre. The role of GPCRs in beta-cells in the pancreas was determined by mating ROSA26PTX mice with mice expressing Cre only in pancreatic beta cells. These mice had high levels of the hormone insulin in their blood and were resistant to diet-induced obesity. Further analysis determined new roles for the GPCRs alpha-2A-adrenergic receptor, Taar1, and Par2 in regulating insulin release by pancreatic beta cells. By mating ROSA26PTX mice with other strains of mice expressing Cre in a tissue or cell-type restricted manner it will be possible to determine the function of GPCRs in these specific tissues and cell types.

TITLE: Probing cell type–specific functions of Gi in vivo identifies GPCR regulators of insulin secretion

Shaun R. Coughlin
UCSF School of Medicine, San Francisco, California, USA.
Phone: (415) 476-6174; Fax: (415) 476-8173; E-mail:

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MYCOLOGY: Working together: C. albicans, epithelial cells, and PMNs control oral thrush

New data generated by Martin Schaller and colleagues at Eberhard Karls University Tübingen, Germany, using an in vitro epithelial model of oral thrush, have provided new insight into how infection with the fungus Candida albicans, the most common cause of oral thrush, might be controlled in the mouth.

In the study, immune cells known as PMNs were shown to protect oral reconstituted human epithelium from invasion by C. albicans and from cell injury. However, PMN-mediated protection was not provided directly, rather it was provided indirectly by the PMNs inducing the upregulation of a protein known as TLR4 in the epithelium. Further analysis revealed C. albicans induced epithelial cells to express soluble factors that attract and activate PMNs and that the soluble factor TNF-alpha had an important role in initiating PMN-induced epithelial cell upregulation of TLR4 expression. The authors therefore concluded that oral thrush is controlled by three-way communication between C. albicans, the epithelium, and PMNs.

TITLE: Human epithelial cells establish direct antifungal defense through TLR4-mediated signaling

Martin Schaller
Eberhard Karls University of Tübingen, Tübingen, Germany.
Phone: 49-7071-29-84555; Fax: 49-7071-29-5113; E-mail:

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CARDIOVASCULAR DISEASE: Two heads are better than one: ABCA1 and ABCG1 combine to enable HDL to protect us from cardiovascular disease

Individuals with an imbalance in the amount of cholesterol associated with the carrier complexes HDL and LDL have an increased risk of developing cardiovascular disease, a class of diseases that affect the heart and or blood vessels, including atherosclerosis. In this context, high levels of HDL protect against cardiovascular disease, but the mechanisms behind this protection are poorly understood. New insight into the antiatherogenic effects of HDL is provided by a study in mice by Laurent Yvan-Charvet and colleagues at Columbia University New York.

HDL is known to promote the efflux of cholesterol from cells known as macrophage foam cells via two proteins known as ABCA1 and ABCG1. Previous studies examining the role of each of these proteins individually have produced conflicting results as to the importance of this process for the antiatherogenic effects of HDL. In this study, mice lacking both ABCA1 and ABCG1 were generated. When bone marrow from these mice was transplanted into mice susceptible to developing atherosclerosis the recipients developed atherosclerosis more rapidly than recipients of normal bone marrow or bone marrow lacking either ABCA1 or ABCG1. These data indicate that efflux of cholesterol via ABCA1 and ABCG1 is central to the antiatherogenic properties of HDL.

TITLE: Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice

Laurent Yvan-Charvet
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: (212) 305-5789; Fax: (212) 305-5052; E-mail:

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HEMATOLOGY: Too many red blood cells spoil the mouse

A new mouse model of Chuvash polycythemia, an inherited disease characterized by increased numbers of red blood cells, generated by Celeste Simon and colleagues at the University of Pennsylvania, Philadelphia, has provided new insight into the mechanisms underlying Chuvash polycythemia and should provide a useful tool to assess the efficacy of potential therapies for the treatment of polycythemias.

A specific mutation in the gene that makes the protein VHL causes Chuvash polycythemia. In this study, mice expressing the same mutation (VhlR/R mice) were generated and shown to develop disease that almost recapitulated that observed in individuals with Chuvash polycythemia. The mice exhibited increased activity of the protein HIF-2-alpha in the spleen and this was associated with an increased number of red blood cells in the spleen due to their increased generation at that site. The authors therefore concluded that enhanced expression of HIF-2-alpha promotes the splenic production of red blood cells and that this causes the polycythemia in VhlR/R mice.

TITLE: von Hippel–Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2-alpha signaling and splenic erythropoiesis

M. Celeste Simon
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 746-5532; Fax: (215) 746-5511; E-mail:

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IMMUNOLOGY: Two faces for TNF-alpha in antiviral and antitumor immunity

Antagonists of the soluble factor TNF-alpha are used to treat individuals with inflammatory and autoimmune diseases mediated by immune cells known as T cells, e.g. rheumatoid arthritis. Despite this there are contradictory reports as to the effects of TNF-alpha on T cell responses. New research in mice by Pamela Ohashi and colleagues at the Ontario Cancer Institute, Toronto, has provided a potential explanation for these contradictory reports by demonstrating that the inflammatory milieu is a critical factor in determining the importance of TNF-alpha to the T cell response.

Mice lacking either TNF-alpha or one of its receptors (TNFR1 and TNFR2) were found to mount strong antiviral CD8+ T cell responses targeting the lymphocytic choriomeningitis virus glycoprotein (GP). By contrast, CD8+ T cell responses targeting tumors engineered to express the same GP protein were abrogated in TNF-alpha–deficient mice. Further analysis revealed that TNF-alpha was required for several steps of the antitumor CD8+ T cell response. These data led the authors to suggest that cancer might be a long-term complication of prolonged blockade of TNF-alpha, such as occurs in patients taking TNF-alpha antagonists.

TITLE: TNF-alpha is critical for antitumor but not antiviral T cell immunity in mice

Pamela S. Ohashi
Ontario Cancer Institute, Toronto, Ontario, Canada.
Phone: (416) 946-2357; Fax: (416) 946-2086; E-mail:

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PULMONARY: Making mice breathe easy: a role for IL-1 in lung damage

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown cause for which there is no effective treatment. Sequential episodes of acute lung injury that are followed by the formation of scar tissue (a process known as fibrosis) characterize IPF and ultimately lead to respiratory failure. In a new study, Isabelle Couillin and colleagues from the University of Orleans, France, have now identified some of the molecular mechanisms underlying inflammation-induced fibrosis in a mouse model of IPF.

When exposed to bleomycin, mice lacking either IL-1R1 or MyD88, which is crucial for the signaling cascade downstream of IL-1R1 and TLRs, exhibited decreased lung inflammation and fibrosis compared with normal mice. Consistent with a key role for IL-1R1 signaling in mediating bleomycin-induced lung damage, specific blockade of IL-1R1 by IL-1 receptor antagonist dramatically reduced bleomycin-induced inflammation in normal mice. Further analysis revealed that a protein known as ASC, which is part of a multiprotein complex known as the inflammasome, was required for the production of IL-1-beta by the lung in response to exposure to bleomycin. These data indicate a requirement for IL-1, the inflammasome, and IL-1R1/MyD88 signaling in bleomycin-induced lung damage, and led the authors to suggest that targeting this pathway might provide a new approach to treating chronic lung inflammation and fibrosis, such as occurs in individuals with IPF.

TITLE: IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice

Isabelle Couillin
University of Orleans and CNRS, Orleans, France.
Phone: 33-238-25-54-39; Fax: 33-238-25-79-79; E-mail:

Martine Hasler
Head of Press Office
Centre National De La Reserche Scientifique, France
Phone: 33-1-44-96-46-35; Email:

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NEPHROLOGY: A bone to pick with the parathyroid

A careful balance of mineral levels in the blood is necessary for life. A feedback loop between levels of phosphate, vitamin D, and the bone-derived hormone FGF23 helps to maintain this balance. FGF23 has been shown to bind cells in the kidneys, where it blocks the removal of phosphates from the blood and decreases vitamin D production. In a new study in rats, Justin Silver and his colleagues at Hadassah Hebrew University Medical Center, Israel, have demonstrated a link between FGF23 and the parathyroid gland, an organ that is vital in calcium homeostasis.

The parathyroid glands release parathyroid hormone (PTH), a small protein that stimulates the release of calcium from bone. Researchers identified the presence of Klotho, a protein required for FGF23 to bind to tissues, on rat parathyroid glands. Furthermore, the amount of Klotho on the parathyroid increased after injection of FGF23 into rats. FGF23 injection also resulted in decreased gene expression and serum levels of PTH. Because PTH modulates serum calcium levels, and FGF23 affects vitamin D and phosphate levels, the authors suggest a mineral homeostasis feedback loop connecting the bone, kidney, and parathyroid.

TITLE: The parathyroid is a target organ for FGF23 in rats

Justin Silver
Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Phone: 972-2-6436778; Fax: 972-2-6421234; E-mail:

Yael Bossem-Levi
Press Office
Hadassah Hospital, Jerusalem, Israel.
Phone: 972-2-6776220; E-mail:

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