Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers Find a New Role for a 'Foxy Old Gene'

05.08.2008
Researchers at the University of Pennsylvania School of Medicine have discovered that a protein called FOXA2 controls genes that maintain the proper level of bile in the liver.

FOXA2 may become the focus for new therapies to treat diseases that involve the regulation of bile salts. The study was published online this week in Nature Medicine.

Bile, although made in the liver, is stored in the gall bladder and transported through ducts to the small intestine where it helps to digest fats from food. Bile salts, chemicals in bile that help digest fats and also keep cholesterol dissolved in the bile, are reabsorbed from the intestine and returned to the liver where they are broken up. The liver maintains a balance of bile salts by degrading old bile salts and synthesizing new ones. Problems arise when too many bile salts accumulate in the liver.

Diseases of bile regulation, such as primary sclerosing cholangitis (PSC), are characterized by problems with bile transport from the liver to the gut. The researchers found that in both children with biliary atresia and adults with PSC, syndromes of different etiologies, expression of FOXA2 in the liver is severely reduced. FOXA2 regulates expression of transporter proteins responsible for moving bile out of the liver, as well as several enzymes that function in bile acid detoxification. The study suggests that strategies to maintain FOXA2 expression might be a novel therapeutic goal.

... more about:
»Cells »DNA »FOXA2 »PSC »duct

In PSC, blockage of bile transport leads to inflammation of the bile duct and, over time, liver damage. The causes of PSC and related syndromes are not known, but may be autoimmune-related. PSC is associated with an increased risk of liver cirrhosis and liver cancer. Biliary atresia is a birth defect in which the bile ducts do not have normal openings, preventing bile from leaving the liver. The condition causes jaundice and cirrhosis of the liver.

Senior author Klaus Kaestner, PhD, Professor of Genetics, named the family of FOX genes and previous work in his lab showed that FOXA2 was important for glucose metabolism in the liver.

“Our interest in using genomics to study metabolic diseases led us to screen DNA from liver cells that expressed FOXA2 with an assay called ChIP on Chip,” explains first author Irina Bochkis, a doctoral student in Genomics and Computational Biology in the Kaestner lab, which resides in the Department of Genetics and the Institute for Diabetes, Obesity, and Metabolism at Penn.

ChIP-on-Chip assay stands for Chromatin ImmunoPrecipitation on a gene Chip.
First, in the two-step assay, chromatin (DNA and protein) was extracted from liver cells and an antibody specific for FOXA2 was used to recognize the protein and immunoprecipitate the FOXA2 protein-DNA complex. The antibody made a sandwich with FOXA2 in the middle and DNA on the sides. Then FOXA2 and its antibody were degraded, but the DNA that was bound to FOXA2 was put on a gene chip. The genes encoded by this DNA were then identified from this remaining DNA.

“We were surprised that a cluster of genes involved in lipid and steroid metabolism was identified by being bound to FOXA2,” says Bochkis.

This study also used mice that expressed no FOXA2 in their liver cells. Compared to normal littermates, the mutant mice accumulated bile salts and failed to detoxify them properly, which resulted in liver damage. In addition, liver biopsies from patients with PSC and biliary atresia, had no detectable levels of FOXA2. These findings suggest that low FOXA2 levels exacerbate liver injury.

Drug or DNA therapies that increase the expression of FOXA2 in liver cells may offer a new means of treating PSC and other similar syndromes. “In order to lay the groundwork for developing new treatments, we have to determine how FOXA2 itself is regulated,” notes Bochkis.

Co-authors are Nir Rubins, Peter White, and Emma Furth, of Penn and Joshua Friedman, of Children's Hospital of Philadelphia. The work was supported by the National Institutes of Health and a Penn Genomics Institute Graduate Fellowship.

PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three hospitals — its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s “Honor Roll” hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center — a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

Karen Kreeger | Newswise Science News
Further information:
http://www.uphs.upenn.edu/

Further reports about: Cells DNA FOXA2 PSC duct

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>