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JCI online early table of contents: Nov. 15, 2010

EDITOR'S PICK: At-TRIB(1)-uting a gene a new function in the liver

Specific, relatively uncommon variations at a region of human chromosome 8 have recently been linked to fat (lipid) levels in the blood that decrease an individual's risk of atherosclerosis (a disease of the major arterial blood vessels that is a main cause of heart attack and stroke). The only currently described gene in this region of chromosome 8 is TRIB1, but it has not been previously linked in any way to regulation of lipid levels. Now, a team of researchers, led by Jan Breslow, at The Rockefeller University, New York, and Daniel Rader, at the University of Pennsylvania School of Medicine, Philadelphia, has identified in mice a role for this gene in regulating lipid production by the liver. Specifically, overexpression of Trib1 in the liver decreased levels of lipids such as cholesterol in the blood, while lack of Trib1 increased levels of the same lipids. These data suggest that TRIB1 is the gene responsible for the associations between chromosome 8 and lipid levels in the blood.

TITLE: Trib1 is a lipid- and myocardial infarctionassociated gene that regulates hepatic lipogenesis and VLDL production in mice

Jan L. Breslow
The Rockefeller University, New York, New York, USA.
Phone: 212.327.7700; Fax: 212.327.7165; E-mail:

Daniel J. Rader
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 215.573.4176; Fax: 215.573.8606; E-mail:

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VIROLOGY: The proteins PD-1 and Tim-3: double trouble for hepatitis C virus immune cells

In a large proportion of patients who become infected with hepatitis C virus (HCV), the virus evades the anti-viral immune response to establish a persistent infection. In these individuals, the function of HCV-specific immune cells known as CTLs is impaired as a result of inhibitory signals emanating from proteins such as Tim-3 and PD-1 on their surface. A team of researchers, led by Hugo Rosen, at the University of Colorado Denver, Aurora, has now generated data that suggest that blocking the inhibitory proteins Tim-3 and PD-1 might provide a new approach to treating individuals with a persistent HCV infection.

The team determined that expression of PD-1 and Tim-3 on HCV-specific CTLs was characteristic of individuals acutely infected with HCV who were more likely to develop persistent HCV infection. Importantly, blockade of either PD-1 or Tim-3 enhanced the in vitro proliferation of HCV-specific CTLs, while blockade of Tim-3 increased the ability of these cells to kill cells expressing HCV proteins. The authors therefore conclude that coexpression of PD-1 and Tim-3 on HCV-specific CTLs is associated with the development of persistent HCV infection and suggest that simultaneous blockade of PD-1 and Tim-3 might be therapeutically useful.

TITLE: Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity

Hugo R. Rosen
University of Colorado Denver, Aurora, Colorado, USA.
Phone: 303.724.1858; Fax: 303.724.1891; E-mail:

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PHYSIOLOGY: Patients explain exactly why we need the chemical element selenium

The trace element selenium is essential for cellular function. This is predominantly because it must be incorporated into some proteins, in the form of selenocysteine, for them to function. A multiprotein complex that includes the protein SECISBP2 is responsible for incorporating selenocysteine into proteins. A team of researchers, led by Krishna Chatterjee, at the University of Cambridge, United Kingdom, has now identified two individuals with distinct mutations in their two SECISBP2 genes and characterized their clinical defects. These individuals had reduced levels of most of the 25 known human selenoproteins and this led to a complex multisystem disorder that included, but was not limited to, a lack of sperm, muscle wasting, increased sensitivity to UV light, and impaired thyroid function. This analysis has provided new insight into the diverse biological processes in which selenoproteins are involved.

TITLE: Mutations in the selenocysteine insertion sequencebinding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans

V. Krishna K. Chatterjee
University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
Phone: 44.1223.336842; Fax: 44.1223.330598; E-mail:

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TUMOR IMMUNOLOGY: Genetic modification: the secret to a long-lived antitumor immune response

One anticancer approach many researchers are seeking to develop is the transfer into patients of immune cells known as T cells that have been manipulated such that they attack and destroy the patient's tumor. Although this approach has proven beneficial in some individuals, in most, the antitumor immune response has not been long-lived enough to be of benefit. However, a team of researchers, led by Christopher Touloukian, at Indiana University School of Medicine, Indianapolis, has developed an approach that led to long-lived antitumor immune responses by CD4+ T cells in a mouse model of melanoma skin cancer. They hope that it might be possible to one day translate this approach for clinical benefit.

TITLE: Transplantation of mouse HSCs genetically modified to express a CD4-restricted TCR results in long-term immunity that destroys tumors and initiates spontaneous autoimmunity

Christopher E. Touloukian
Indiana University School of Medicine, Indianapolis, Indiana, USA.
Phone: 317.278.9945; Fax: 317.274.7592; E-mail:

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METABOLIC DISEASE: Uncovering new way to stop fat accumulation in mice

The most common cause of liver dysfunction in the United States is a condition known as nonalcoholic fatty liver disease (NAFLD). A form of NAFLD known as hepatic steatosis is associated with obesity and type 2 diabetes. It arises as a result of increased generation and accumulation of lipids (fats) in the liver. Renaud Dentin and colleagues, at Institut Cochin, France, have now provided new insight into the mechanisms underlying hepatic steatosis in mice. Specifically, they find a role for the proteins p300 and SIK2 in regulating lipid production in the liver. Taken together, all the data lead the authors to suggest that SIK2 activators and specific p300 inhibitors might provide new approaches to treating hepatic steatosis in individuals with obesity and type 2 diabetes.

TITLE: Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice

Renaud Dentin
Institut Cochin, Universit Paris Descartes, CNRS, UMR 8104, INSERM, U1016, Paris, France.
Phone:; Fax:; Email:

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AUTOIMMUNITY: Attacking the symptoms of SLE

Systemic lupus erythematosus (SLE) is a relatively common autoimmune disorder, i.e., a disorder caused by a person's immune system turning on that person's body and inflicting tissue damage. The disease can affect the skin, joints, kidneys, and other organs. There is no cure for SLE, although there are good treatments to combat many of the symptoms. A team of researchers, led by Liliana Schaefer, at the Institut fr Allgemeine Pharmakologie und Toxikologie/ZAFES, Germany, has now identified, through work in mice, a potential new target for treating the symptoms of SLE

One marker of disease activity in individuals with SLE is CXCL13, which is a protein that attracts immune cells known as B cells. The team has now identified a mechanism by which CXCL13 is induced in a mouse model of SLE. Specifically, increased levels of the molecule biglycan interacted with proteins known as TLR2/4 to trigger production of CXCL13. Importantly, biglycan deficiency was associated with reduced disease. Further, as levels of biglycan were elevated in patients with SLE, the authors suggest that targeting biglycan-TLR2/4 interactions might provide a new approach to treating the symptoms of SLE.

TITLE: The proteoglycan biglycan regulates expression of the B cell chemoattractant CXCL13 and aggravates murine lupus nephritis

Liliana Schaefer
Institut fr Allgemeine Pharmakologie und Toxikologie/ZAFES, Frankfurt am Main, Germany.
Phone: 49.69.6301.7899; Fax: 49.69.6301.83027; E-mail:

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METABOLISM: How the hormone glucagon tips the balance to increase blood glucose levels

A team of researchers, led by Alan Cherrington, at Vanderbilt University Medical Center, Nashville, has provided new insight into the mechanisms by which blood levels of glucose one of the main sources of energy for the cells in our body are regulated.

Given the importance of glucose as a source of energy for cells, maintaining adequate levels of glucose in the blood is extremely important. The opposing effects of the hormones insulin and glucagon are key to this: insulin induces liver, muscle, and fat cells to take up glucose from the blood and store it, while glucagon induces the liver to release stored glucose into the blood. In the study, Cherrington and colleagues show in dogs that although insulin potently inhibits the effects of glucagon when blood glucose levels are normal, glucagon overcomes the inhibitory effects of insulin when blood glucose levels are low. Further analysis provided insight into the mechanisms underlying this critical regulatory process.

TITLE: Insulin-induced hypoglycemia increases hepatic sensitivity to glucagon in dogs

Alan D. Cherrington
Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Phone: 615.322.7013; Fax: 615.343.0490; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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