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JCI table of contents September 1, 2005

JCI Journals



72 years ago, the first evidence for end-product feedback regulation of a biosynthetic pathway was demonstrated when Rudolph Shoenheimer observed that mice synthesized large amounts of cholesterol when fed a low-cholesterol diet, but this synthesis stopped when the mice were fed cholesterol.

In later years, many details of this cholesterol feedback were worked out, but the main mechanism by which cells in the liver sense cholesterol and thus regulate cholesterol production remained unknown.

In a study appearing online on August 11 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Joseph Goldstein and Michael Brown finally solve the mystery of the Shoenheimer effect.

The authors show that Insig (insulin-induced gene) proteins are essential components of this cholesterol feedback response. They create mice lacking the two mammalian Insig genes -- Insig1 or Insig2 in the liver. On a normal chow diet, the mice overaccumulate cholesterol and fats in the liver, but levels of SREBP's and other SREBP target genes (molecules that sense cholesterol and regulate its synthesis) were not reduced. Normally, cholesterol intake reduces SREBP and the genes that synthesize cholesterol and fat, but this response was dysfunctional in the transgenic mice such that fat and cholesterol synthesis was not suppressed. The transgenic mice also had dysregulated levels of HMG-CoA reductase protein, the precursor for cholesterol synthesis.

The data presented indicate that the entire pathway for SREBP processing functions in the liver. Further, this pathway is responsible for the synthesis of cholesterol as well as the feedback suppression of synthesis when cholesterol is taken in from the diet.

Title: Schoenheimer Effect explained - Feedback regulation of cholesterol synthesis in mice mediated by Insig proteins

AUTHOR CONTACT: Joseph L. Goldstein
University of Texas Southwestern Medical Center, Dallas, TX USA
Phone: 214-648-2141; Fax: 214-648-8804; E-mail:

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Alzheimer disease (AD) is the most common form of senile dementia, with no effective treatment available. In a study appearing online on August 11 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Howard Weiner and colleagues from Harvard describe a novel immunologic approach for the treatment of AD.

Previous studies utilizing immunization against Abeta, a key pathogenic player in AD, to generate antibodies against Abeta were discontinued because of unacceptable side effects in AD patients.

Here, the researchers use a specific nasal vaccination to decrease AD burden in mice. The vaccine consists of an FDA-approved drug currently used to treat multiple sclerosis (called glatiramer acetate) plus a recently developed nasal adjuvant that has been shown to be safe in humans and activates microglia, cells which then clear beta-amyloid in the brain without evidence of toxic effects.

The findings have both basic and clinically relevant implications. The discovery of a non-antibody mediated method to clear Abeta could be used as a treatment for patients who already are showing signs of AD. Moreover, the compounds used have already been safely tested in humans.

Title: Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears beta-amyloid in a mouse model of Alzheimer's disease.

AUTHOR CONTACT: Howard L. Weiner
Harvard Medical School, Boston, MA USA
Phone: 617-525-5300; Fax: 617-525-5252; E-mail:

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Foxo proteins are involved in various cellular processes, but their precise roles in vivo were not clear because genetic loss of Foxo function had diverse effects. In a study appearing online on August 11 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Stefanie Dimmeler and colleagues from University of Frankfurt show that the Foxo transcription factors Foxo1 and Foxo3 specifically regulate angiogenesis in vivo, and regulate postnatal blood vessel formation.

The mechanism underlying these functions of Foxo1 and Foxo3 is through control over a variety of angiogenesis-related genes, including endothelial nitric oxide synthase (eNOS). The authors show that Foxo1 binds to the eNOS promoter to repress eNOS activity.

This is the first study to show that Foxo controls postnatal neovascularization and acts as a repressor of eNOS. The data suggest that Foxo proteins play an important role in blood vessel formation and vascular homeostasis.

Title: Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization

AUTHOR CONTACT: Stefanie Dimmeler
University of Frankfurt, Frankfurt, Germany
Phone: 49-60-6301-7440; Fax: 49-69-6301-7113; E-mail:

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Thyroid hormone (TH) exerts its actions by binding to TH receptors. In a study appearing online on August 11 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Frederic Wondisford and colleagues examine a poorly understood but major aspect of the mechanism of thyroid hormone action.

The authors have used mice with a knocked in a mutation in TH receptor beta2, which selectively impairs hormone dependent recruitment of a co-activator by TR. They show that there are a group of TR binding proteins that can confer negative, as well as positive, regulation in response to ligand interaction. These results enhance our understanding of hormone-dependent regulation by TR.

Title: Negative Regulation by Thyroid Hormone Receptor Requires an Intact Co-activator Binding Surface

AUTHOR CONTACT: Frederic Wondisford
Johns Hopkins Medical Institution, Baltimore, MD USA
Phone: 773-307-5416; E-mail:

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Mammalian viruses known as reoviruses cause programmed cell death that depends upon activation of a complex of molecules called NF-kappaB containing subunits known as p50 and p65/RelA. In a study appearing online on August 11 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Terence Dermody and colleagues from Vanderbilt University describe organ-specific roles for NF-kappaB in the pathogenesis of mammalian reovirus infection.

The authors use mice lacking the NF-kappaB p50 subunit to investigate the role of NF-kappaB activation in reovirus pathogenesis and disease. They show that NF-kappaB promotes programmed cell death during reovirus infection in the central nervous system yet suppresses programmed cell death in the heart. Absence of NF-kappaB results in striking cardiac pathology following reovirus infection, with extensive cell death and cardiac destruction. This data provide evidence for dual roles for NF-kappaB in viral infection.

Title: Organ-specific roles for transcription factor NF-kappaB in reovirus-induced apoptosis and disease

AUTHOR CONTACT: Terence Dermody
Vanderbilt University School of Medicine, Nashville, TN USA
Phone: 615-343-9943; Fax: 615-343-9723; E-mail:

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