Liver fibrosis results from an excessive accumulation of tough, fibrous scar tissue and occurs in most types of chronic liver diseases. In industrialized countries, the main causes of liver injury leading to fibrosis include chronic hepatitis virus infection, excess alcohol consumption and, increasingly, nonalcoholic steatohepatitis (NASH).
This image shows mouse liver tissue with fibrosis (red), a type of scarring caused by chronic liver diseases and injuries. Salk researchers found that a drug already approved by the FDA for the treatment of psoriasis deactivates the switch governing the fibrotic response in mouse liver cells, suggesting a potential new therapy for fibrotic diseases in humans.
Credit: Image: Courtesy of the Salk Institute for Biological Studies
Now, in a new study published in the journal Cell, scientists at the Salk Institute for Biological Studies have discovered that a synthetic form of vitamin D, calcipotriol (a drug already approved by the FDA for the treatment of psoriasis), deactivates the switch governing the fibrotic response in mouse liver cells, suggesting a potential new therapy for fibrotic diseases in humans.
"Because there are currently no effective drugs for liver fibrosis, we believe our findings would open a new door for treatment," says senior author Ronald M. Evans, a professor in Salk's Gene Expression Laboratory and lead researcher in the Institute's new Helmsley Center for Genomic Medicine.
The Salk study focused on a star-shaped "stellate" cell in the liver that serves as a beacon for damage. When called into action, stellate cells produce fibrotic proteins in an attempt to heal an injury. Under chronic stress, however, localized fibrosis expands, eventually leading to cirrhosis, increased risk of liver cancer, and the need for a liver transplant in advanced cases.
The Evans lab discovered a genetic switch through which vitamin D-related ligands such as calcitriol, a hormonally active form of the vitamin, can put the brakes on fibrosis. "Preclinical results suggest the 'vitamin D brake' is highly efficacious and led us to believe that the time is right to consider a trial in the context of chronic liver disease," says Evans, a Howard Hughes Medical Institute Investigator and holder of the March of Dimes Chair in Molecular and Developmental Biology.
Previous studies have shown a physiologic role for vitamin D in liver function, but "it was our discovery of high levels of vitamin D receptor (VDR) in the stellate cell that led us to consider it as a possible off switch for liver fibrosis," says lead author Ning Ding, a research associate in the Gene Expression Laboratory.
"Current therapeutic approaches, which treat the symptoms of liver disease, don't stop liver fibrosis from progressing," says Michael Downes, a senior staff scientist in the Gene Expression Laboratory and co-corresponding author on the paper. "In liver diseases where the underlying cause cannot be cured, progression to cirrhosis is currently inevitable in some people. What we have discovered is that by acting on the genome, VDR can simultaneously defend against multiple fibrotic activators. This is important because many different pro-fibrotic signaling pathways converge on the genome to affect their fibrotic response."
The Salk discovery that calcipotriol counters the fibrotic response in stellate cells illuminates a potentially safer, more effective strategy capable of neutralizing multiple convergent fibrotic triggers.
The Salk scientists say that clinical trials of the vitamin D analog for the treatment of liver fibrosis are being planned. The synthetic vitamin D analog is better than natural vitamin D, they say, for a couple of reasons. First, natural vitamin D, which is found in small amounts in a few foods and produced in the body by exposure to sunlight, degrades quickly, while synthetic versions of vitamin D are less susceptible to breakdown. Second, too much natural vitamin D can cause hypercalcemia, or elevated calcium in the blood, which can lead to nausea and vomiting, frequent urination, muscle weakness and joint aches and pain. The synthetic vitamin D analog, on the other hand, produces a strong response without adding calcium to the blood.
In addition, the researchers say this new model for treating liver fibrosis may also be helpful in treating other diseases with a fibrotic component, including those of the lung, kidney and pancreas.
Other researchers on the study were Ruth T. Yu, Mara H. Sherman, Mathias Leblanc, Mingxiao He, Annette R. Atkins and Grant D. Barish, from the Salk Institute; Nanthakumar Subramaniam, Caroline Wilson, Renuka Rao, Sally Coulter and Christopher Liddle, of the University of Sydney (Australia); and Sue L. Lau , Christopher Scott and Jenny E. Gunton, of the Garvan Insitute for Medical Research (Australia).
The work was supported by grants from the National Institutes of Health, the Howard Hughes Medical Institute, the National Health and Medical Research Council of Australia, the Genentech Foundation,the Leona M. and Harry B. Helmsley Charitable Trust, the Samuel Waxman Cancer Research Foundation, Stand Up to Cancer and Ipsen/Biomeasure.
About the Salk Institute for Biological Studies:
The Salk Institute for Biological Studies is one of the world's preeminent basic research institutions, where internationally renowned faculty probe fundamental life science questions in a unique, collaborative, and creative environment. Focused both on discovery and on mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer's, diabetes and infectious diseases by studying neuroscience, genetics, cell and plant biology, and related disciplines.
Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit organization and architectural landmark.
Andy Hoang | EurekAlert!
Further reports about: > Cancer > Expression > Gates Foundation > Gene Expression > Liver fibrosis > Medical Wellness > Nonalcoholic steatohepatitis > Vitamin D > chronic hepatitis virus infection > chronic liver disease > excess alcohol consumption > health services > liver disease > signaling pathway
Penn vet research identifies new target for taming Ebola
12.01.2017 | University of Pennsylvania
The strange double life of Dab2
10.01.2017 | University of Miami Miller School of Medicine
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
17.01.2017 | Earth Sciences
17.01.2017 | Materials Sciences
17.01.2017 | Architecture and Construction