Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists at the UA make critical end-stage liver disease discovery

28.04.2014

The discovery of an unknown cellular pathway has helped scientists and physicians better understand end-stage liver disease and offers a potential target for new therapeutics

A team of researchers in the University of Arizona's College of Pharmacy has discovered a molecular pathway that could be key to creating new therapeutics that would slow or even reverse the progression of end-stage liver disease.


Zhang's research group studies the molecular mechanisms cells use to protect themselves from damage caused by toxicants and carcinogens.

Credit: Daniel Stolte/ University of Arizona News

Although cirrhosis of the liver is most commonly associated with alcohol or drug abuse, the condition – marked by scar tissue replacing healthy liver tissue – also can result from viral hepatitis, obesity and diabetes, as well as certain inherited diseases.

According to the National Institutes of Health, cirrhosis is the 12th leading cause of death by disease in the U.S. As with many other human pathologic conditions, end-stage liver disease goes hand in hand with oxidative stress, which refers to damage inflicted to biological tissues by reactive oxygen molecules.

Such molecules, also called free radicals, occur naturally as a byproduct of metabolic processes in the body and are associated with many chronic diseases including cancer, diabetes, neurodegenerative and cardiovascular diseases.

"Cells keep oxidative stress under control through various mechanisms," said Donna Zhang, a professor in the UA Department of Pharmacology and Toxicology, explaining that most of these mechanisms involve Nrf2, a protein present in virtually every cell that acts as a molecular switch. Nrf2 activates various biochemical mechanisms inside the cell that capture reactive oxygen molecules or dispose of damaged cellular components before they can cause more trouble. The antioxidants found in many fruits and vegetables exert their healthful benefits by capturing reactive oxygen molecules.

Under normal, healthy conditions, when no oxidative stress response is needed, an enzyme called Keap1 constantly chews up Nrf2, keeping its level low.

"Then, under stress from reactive oxygen molecules, or when you eat antioxidants from certain plants like broccoli sprouts, it prevents Keap1 from eating up Nrf2, allowing it to accumulate in the cell," explained Zhang, who is also a member of the UA BIO5 Institute. "Nrf2 then activates the cellular antioxidant response. That is how antioxidants work." According to conventional wisdom, our bodies turn on their Nrf2-mediated protection pathway when subjected to high oxidative stress to limit the damage from the destructive oxygen compounds. During liver cirrhosis, Nrf2 should be induced by oxidative stress, but for reasons unclear until this study, this does not happen.

"This was a puzzle before we did our study," she said. "Somehow the protective mechanism mediated by Nrf2 is compromised by another factor, other than Keap1, in liver cirrhosis." Adding to the mystery is the fact that drugs aimed at inhibiting Keap1 from chewing up Nrf2 have proven ineffective in a cirrhotic liver.

When Zhang and her colleagues studied tissue samples from a human cirrhotic liver, they discovered the reason behind the inexplicably low Nrf2 levels in the face of rampant oxidative stress.

It turned out that another enzyme chews up Nrf2 and prevents the much-needed antioxidant response, exacerbating the disease process. That protein, Hrd1, is part of the cells' garbage disposal – it specializes in destroying misfolded proteins before they can accumulate and damage cell components.

Under normal conditions, Hrd1 levels are low, so it does not interfere much with Nrf2, explained Zhang. As liver cirrhosis progresses, excessive inflammation triggers the garbage-mediated stress response and Hrd1 becomes very abundant and begins chewing up Nrf2.

The study is published in the April 1 issue of the journal Genes and Development. The first author of the report is Tongde Wu, a graduate of the UA Department of Pharmacology and Toxicology, who developed the project as part of her dissertation research. Fei Zhao and Eli Chapman, in the same department, also contributed to the research. The work resulted from a collaboration between Zhang's research group and Deyu Fang, Beixue Gao and Can Tan at Northwestern University Feinberg School of Medicine in Chicago. Other contributors are Naoko Yagishita and Toshihiro Nakajima of St. Marianna University School of Medicine in Kawasaki, Japan, and Pak K. Wong of the UA College of Engineering.

The discovery could change the way scientists develop therapeutics, as it provides a new target for future drugs. In laboratory experiments, Zhang and her colleagues were able to restore Nrf2 levels in cirrhotic liver tissue by inactivating Hrd1, effectively reversing liver cirrhosis in mice.

"Previous efforts only focused on the Keap1 protein and tried to prevent it from breaking down Nrf2," Zhang said. "Now we know there is a second player in the game – Hrd1 – that we need to inhibit in order to restore Nrf2 levels.

"Boosting Nrf2 is good for protection in general, which is why you should always eat your broccoli," she stressed.

###

The study, "Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis," is published in the April 1 issue of the journal Genes and Development: http://genesdev.cshlp.org/content/28/7/708.abstract

Daniel Stolte | UA News
Further information:
http://www.arizona.edu

Further reports about: Department Development Medicine Toxicology damage death diseases drugs enzyme healthy liver pathway protein

More articles from Health and Medicine:

nachricht Nanotubes are beacons in cancer-imaging technique
23.05.2016 | Rice University

nachricht More light on cancer
20.05.2016 | Lomonosov Moscow State University

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Worldwide Success of Tyrolean Wastewater Treatment Technology

A biological and energy-efficient process, developed and patented by the University of Innsbruck, converts nitrogen compounds in wastewater treatment facilities into harmless atmospheric nitrogen gas. This innovative technology is now being refined and marketed jointly with the United States’ DC Water and Sewer Authority (DC Water). The largest DEMON®-system in a wastewater treatment plant is currently being built in Washington, DC.

The DEMON®-system was developed and patented by the University of Innsbruck 11 years ago. Today this successful technology has been implemented in about 70...

Im Focus: Computational high-throughput screening finds hard magnets containing less rare earth elements

Permanent magnets are very important for technologies of the future like electromobility and renewable energy, and rare earth elements (REE) are necessary for their manufacture. The Fraunhofer Institute for Mechanics of Materials IWM in Freiburg, Germany, has now succeeded in identifying promising approaches and materials for new permanent magnets through use of an in-house simulation process based on high-throughput screening (HTS). The team was able to improve magnetic properties this way and at the same time replaced REE with elements that are less expensive and readily available. The results were published in the online technical journal “Scientific Reports”.

The starting point for IWM researchers Wolfgang Körner, Georg Krugel, and Christian Elsässer was a neodymium-iron-nitrogen compound based on a type of...

Im Focus: Atomic precision: technologies for the next-but-one generation of microchips

In the Beyond EUV project, the Fraunhofer Institutes for Laser Technology ILT in Aachen and for Applied Optics and Precision Engineering IOF in Jena are developing key technologies for the manufacture of a new generation of microchips using EUV radiation at a wavelength of 6.7 nm. The resulting structures are barely thicker than single atoms, and they make it possible to produce extremely integrated circuits for such items as wearables or mind-controlled prosthetic limbs.

In 1965 Gordon Moore formulated the law that came to be named after him, which states that the complexity of integrated circuits doubles every one to two...

Im Focus: Researchers demonstrate size quantization of Dirac fermions in graphene

Characterization of high-quality material reveals important details relevant to next generation nanoelectronic devices

Quantum mechanics is the field of physics governing the behavior of things on atomic scales, where things work very differently from our everyday world.

Im Focus: Graphene: A quantum of current

When current comes in discrete packages: Viennese scientists unravel the quantum properties of the carbon material graphene

In 2010 the Nobel Prize in physics was awarded for the discovery of the exceptional material graphene, which consists of a single layer of carbon atoms...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Networking 4.0: International Laser Technology Congress AKL’16 Shows New Ways of Cooperations

24.05.2016 | Event News

Challenges of rural labor markets

20.05.2016 | Event News

International expert meeting “Health Business Connect” in France

19.05.2016 | Event News

 
Latest News

11 million Euros for research into magnetic field sensors for medical diagnostics

27.05.2016 | Awards Funding

Fungi – a promising source of chemical diversity

27.05.2016 | Life Sciences

New Model of T Cell Activation

27.05.2016 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>