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

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.

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.

Contact: Daniel Stolte
University of Arizona

Related biology news :

1. Scripps Florida scientists find connection between gene mutation, key symptoms of autism
2. Microscopic organism plays a big role in ocean carbon cycling, Scripps scientists discover
3. Cell resiliency surprises scientists
4. Scientists identify source of mysterious sound in the Southern Ocean
5. Scientists identify critical new protein complex involved in learning and memory
6. Scientists target receptor to treat diabetic retinopathy
7. Five scientists awarded prestigious Heineken Prizes
8. Neuroscientists: Brain activity may mark the beginning of memories
9. Scientists reconstruct ancient impact that dwarfs dinosaur-extinction blast
10. Scientists reveal potential link between brain development and breast cancer gene
11. Scientists disagree on responsible research
Post Your Comments:
Related Image:
Scientists at the UA make critical end-stage liver disease discovery
(Date:12/1/2015)... Calif. , Dec. 1, 2015 Synaptics ... human interface solutions, today announced a new agreement with ... OEMs with real-world test and development environments that combine ... solutions. The partnership reduces the complexity of FIDO certification ... software permits Synaptics and OEMs to verify FIDO enabled ...
(Date:11/30/2015)... BEACH, Fla. , Nov. 30, 2015 /PRNewswire/ ... as a finalist in this year,s Fierce Innovation Awards:  ... of FierceHealthIT , FierceHealthcare ... was recognized as a finalist in the category ... --> ...
(Date:11/26/2015)... Research and Markets ( ) has ... - Technology and Patent Infringement Risk Analysis" report ... --> Fingerprint sensors using capacitive technology represent ... sensor vendor Idex forecasts an increase of 360% of ... and of the fingerprint sensor market between 2014 and ...
Breaking Biology News(10 mins):
(Date:12/1/2015)... -- Twist Bioscience, a company focused on synthetic DNA, today announced ... selected as one of Foreign Policy,s 100 Leading ... of life . Each year, Foreign Policy selects ... have changed lives and are shaping the world. ... to be recognized among these incredible global leaders," said Leproust. ...
(Date:12/1/2015)... 2015 Oxford Finance LLC ("Oxford"), a specialty ... and healthcare services companies, today announced the closing of ... Inc. ("the Company"). Proceeds from the loan are being ... Company,s Rejuvaphyl™ and daily skincare products. ... brand of high potency skincare products that contain the ...
(Date:12/1/2015)... Dec. 01, 2015 ... of the "2016 Europe Cell Surface ... Technologies, Competitive Strategies, Opportunities for Suppliers--France, Germany, ... offering. --> ) has ... Europe Cell Surface Markers: Country Volume and ...
(Date:12/1/2015)... ... December 01, 2015 , ... Park Systems , ... add-on scanning ion conductance microscopy module to Park NX10 that is the only ... Park SICM benefits virtually all materials characterization that require measurements in liquid such ...
Breaking Biology Technology: