Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Transcription factor may protect against hepatic injury caused by hepatitis C and alcohol

More damage seen when FOXO3 suppressed, according to report in The American Journal of Pathology

New data suggest that the transcription factor FOXO3 may protect against alcohol-induced liver injury. Researchers determined that alcohol given to mice deficient in FOXO3 caused severe liver injury resembling human alcoholic hepatitis.

Further they found that although hepatitis C virus (HCV) and alcohol independently activated FOXO3, in combination they suppressed FOXO3, reduced expression of cytoprotective genes, and worsened liver injury. The results are published in The American Journal of Pathology.

"There is emerging evidence that the FOXO transcription factor family plays a critical role in metabolic, antioxidant, and cell death responses in the liver. The role of FOXO in injury processes is complex as FOXO transcription programs can either be cytoprotective or cytotoxic, and well-documented examples of both phenomena are numerous," says Steven A. Weinman, MD, PhD, Department of Internal Medicine at the University of Kansas Medical Center.

Based on such emerging evidence, Dr. Weinman's group fed alcohol to FOXO3-deficient mice for three weeks. One third of these mice developed severe hepatic steatosis (infiltration of liver cells with fat), neutrophil infiltration, and necrosis, similar to that seen in patients with alcoholic hepatitis. In some mice, levels of the liver enzyme alanine aminotransferase (ALT) increased tenfold compared to controls.

Investigators also induced severe liver injury with alcohol in a mouse model of HCV (transgenic HCV/Sod2+/-). These animals had elevated ALT; increased ICAM-1 expression and caspase 3 cleavage, and severe steatosis, lobular inflammation, and ballooning degeneration of liver cells. In these mice, degree of liver injury correlated with levels of the mitochondrial antioxidant enzyme superoxide dismutase (SOD2). (SOD2 is also thought to play a part in protecting the liver from alcoholic injury.) Alcohol-treated HCV/Sod2+/- mice also showed a greater concentration of FOXO3 in the cytosol of the cell compared to the nuclear location found in other types of mice.

Weinman continues, "One of the important unanswered questions about alcoholic liver disease has been why only a minority of those who drink, including those who drink heavily, ever develop liver disease. In most people, the liver has efficient protection mechanisms against alcohol. Our results indicate that FOXO3 is a novel alcohol protection factor that is disrupted by the HCV-alcohol combination. We therefore think that modulation of the FOXO3 pathway is a potential therapeutic approach for HCV-alcohol-induced liver injury."

In cell culture, either HCV or alcohol alone produced an increase in FOXO3 transcriptional activity. However, Weinman and colleagues found that although the effects of both of these stress stimuli on FOXO3 were similar, the mechanisms of action were different. For example, although HCV activation was associated with translocation of FOXO3 from cytosol to the nucleus, alcohol produced transcriptional activation without a prominent change in the nuclear-cytosolic ratio. Another difference found was that HCV, but not alcohol, caused a miRNA-dependent suppression of SOD2 translation.

That HCV infection and alcohol exposure appear to work in synergy to produce effects that are different from those seen with either alone was a "novel and unexpected" finding, says Weinman. The suppression of FOXO3 by the combination of HCV and alcohol is attributed in part to nuclear export and a decreased protein half-life that does not occur with either HCV or alcohol alone. "The results indicate that FOXO3 is a novel alcohol protection factor that is disrupted by the HCV-alcohol combination," concludes Weinman.

In the same issue of The American Journal of Pathology, another team of investigators from the University of Kansas Medical Center, led by Dr. Wen-Xing Ding, PhD, Department of Pharmacology, Toxicology, and Therapeutics, also report that FOXO3 protects against acute ethanol-induced steatosis and liver injury. This study demonstrates that FOXO3 is necessary for activation of autophagy, a cellular degradation pathway that protects against alcohol-induced liver injury by removing damaged mitochondria. Acute alcohol-treated FOXO3-deficient mice developed more severe liver injury than that of wild-type mice, and this was attributed to decreased expression of autophagy-related genes.

"Our study," says Dr. Ding, "was an acute alcohol model whereas the study in Dr. Weinman's laboratory was a chronic alcohol feeding model; however, both studies show that FOXO3 is protective. Thus, these results indicate that FOXO3 is an important general mechanism by activating multiple cellular protective functions that the normal liver uses to resist the toxic effects of alcohol."

Eileen Leahy | EurekAlert!
Further information:

Further reports about: FoxO3 HCV-alcohol Pathology liver cells liver disease transcription factor

More articles from Health and Medicine:

nachricht Inflammation Triggers Unsustainable Immune Response to Chronic Viral Infection
24.10.2016 | Universität Basel

nachricht Resolving the mystery of preeclampsia
21.10.2016 | Universitätsklinikum Magdeburg

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: Light-driven atomic rotations excite magnetic waves

Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion

Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Oasis of life in the ice-covered central Arctic

24.10.2016 | Earth Sciences

‘Farming’ bacteria to boost growth in the oceans

24.10.2016 | Life Sciences

Light-driven atomic rotations excite magnetic waves

24.10.2016 | Physics and Astronomy

More VideoLinks >>>