New study upends thinking about how liver disease develops

Dec 20, 2010

In the latest of a series of related papers, researchers at the University of California, San Diego School of Medicine, with colleagues in Austria and elsewhere, present a new and more definitive explanation of how fibrotic cells form, multiply and eventually destroy the human liver, resulting in cirrhosis. In doing so, the findings upend the standing of a long-presumed marker for multiple fibrotic diseases and reveal the existence of a previously unknown kind of inflammatory white blood cell.

The results are published in this week's early online edition of the .

In all types of , healthy, functioning tissues are progressively replaced by fibrous scarring, which renders the tissues or larger organ increasingly dysfunctional until, eventually, it fails. The process is called . In the human liver, the end result is cirrhosis, the 12th leading cause of death by disease in the United States with roughly 27,000 deaths annually. Fibrosis occurs in other organs as well, such as the heart, kidneys and lungs, with comparable deadly effect.

Scientists do not fully understand the process of fibrosis, particularly how problematic fibroblast cells are created. For years, conventional wisdom has posited that fibroblasts are likely to be transformed epithelial cells, a conversion called "epithelial to mesenchymal transition" or EMT. A protein called fibroblast-specific protein 1 (FSP1) has long been considered to be a reliable indicator of fibroblasts in injured organs undergoing tissue remodeling and has been broadly used to identify the presence of fibrotic disease.

The new research undermines the validity of prevailing assumptions about EMT and FSP1, but also opens the door to new avenues of investigation that could ultimately lead to improved detection and treatment of cirrhosis and similar conditions.

"This work, along with earlier papers, puts into question a whole area of research – at least in terms of the liver" said David Brenner, MD, Vice Chancellor for Health Sciences, dean of the UC San Diego School of Medicine and co-author of the paper. "The old evidence and assumptions about the source of fibroblasts and the role of FSP1 as a marker are not valid."

Specifically, in experiments using cell cultures, human liver samples and mouse models, the researchers found no evidence of EMT – that transformed epithelial cells became liver fibroblasts. Rather, endogenous stellate cells appear to be the culprit, though the scientists note many types of cells seem to contribute, directly or indirectly, to liver fibrosis.

Likewise, experiments proved FSP1 to be an unreliable marker for fibrosis. Cells containing FSP1 increased in human and experimental liver disease and in liver cancer, but researchers found that liver do not express the protein, nor do hepatic stellate cells – a major cell type involved in fibrosis. Similarly, FSP1 was determined not to be a marker for myofibroblasts (a fibroblast with some properties of a smooth muscle cell) or any precursors of myofibroblasts.

"There have been hundreds of papers based on FSP1 as a marker," said Brenner. "That thinking now seems to have been a mistake. One of the take-home messages of this paper is that FSP1 clearly can't be reliably used as a marker."

On the other hand, the scientists discovered that FSP1 is a consistent marker for a previously unknown subset of inflammatory or macrophages found in injured livers. The protein appears to also perform biological functions in the macrophages, though these remain to be determined.

"It's a whole new class of monocytes," said Brenner. "We don't know what they do, but they're worth investigating."

Explore further: US scientists make embryonic stem cells from adult skin

Related Stories

Scientists Uncover Protective Mechanism Against Liver Cancer

Dec 14, 2009

(PhysOrg.com) -- A team of scientists from the UC San Diego School of Medicine and Osaka University in Japan have identified a protein switch that helps prevent liver damage, including inflammation, fibrosis and cancer. The ...

Spice in curry could prevent liver damage

Oct 29, 2010

Curcumin, a chemical that gives curry its zing, holds promise in preventing or treating liver damage from an advanced form of a condition known as fatty liver disease, new Saint Louis University research suggests.

Recommended for you

Leeches help save woman's ear after pit bull mauling

Apr 18, 2014

(HealthDay)—A pit bull attack in July 2013 left a 19-year-old woman with her left ear ripped from her head, leaving an open wound. After preserving the ear, the surgical team started with a reconnection ...

New pain relief targets discovered

Apr 17, 2014

Scientists have identified new pain relief targets that could be used to provide relief from chemotherapy-induced pain. BBSRC-funded researchers at King's College London made the discovery when researching ...

User comments : 0

More news stories

Less-schooled whites lose longevity, study finds

Barbara Gentry slowly shifts her heavy frame out of a chair and uses a walker to move the dozen feet to a chair not far from the pool table at the Buford Senior Center. Her hair is white and a cough sometimes interrupts her ...

How to keep your fitness goals on track

(HealthDay)—The New Year's resolutions many made to get fit have stalled by now. And one expert thinks that's because many people set their goals too high.

Low tolerance for pain? The reason may be in your genes

Researchers may have identified key genes linked to why some people have a higher tolerance for pain than others, according to a study released today that will be presented at the American Academy of Neurology's 66th Annual ...

Growing app industry has developers racing to keep up

Smartphone application developers say they are challenged by the glut of apps as well as the need to update their software to keep up with evolving phone technology, making creative pricing strategies essential to finding ...

Making graphene in your kitchen

Graphene has been touted as a wonder material—the world's thinnest substance, but super-strong. Now scientists say it is so easy to make you could produce some in your kitchen.