Featured Research

from universities, journals, and other organizations

Cholesterol regulator plays key role in development of liver scarring, cirrhosis

Date:
April 4, 2011
Source:
University of California - Los Angeles
Summary:
Researchers have demonstrated that a key regulator of cholesterol and fat metabolism in the liver also plays an important role in the development of liver fibrosis -- the build-up of collagen scar tissue that can develop into cirrhosis.

Treated with a control substance, livers from normal and LXR-deficient mice appear identical and undamaged (top left and right). The bottom images show the greater degree of fibrosis (blue bands) in the livers of mice lacking LXRs (right) compared to normal mice (left) after liver injury.
Credit: UCLA

UCLA researchers have demonstrated that a key regulator of cholesterol and fat metabolism in the liver also plays an important role in the development of liver fibrosis -- the build-up of collagen scar tissue that can develop into cirrhosis. Cirrhosis, in turn, is a major cause of premature death and is incurable without a liver transplant.

Published in the March issue of the journal Gastroenterology, the study shows that liver X receptors (LXRs), master regulators of cholesterol, fat and inflammatory gene expression, also control the fibrosis-making cells of the liver, known as hepatic stellate cells.

In the face of chronic liver injury -- due to excess fat, chronic viral hepatitis or alcohol abuse, for example -- stellate cells become activated and launch an inflammatory and fibrotic cascade that eventually results in the build-up of collagen scar tissue in the liver.

LXRs, when stimulated, "turn on" several hundred genes that hold instructions to create proteins for carrying out bodily processes in cells, from transporting and excreting cholesterol to synthesizing fat in the liver. They have also been shown to suppress inflammatory processes in several contexts.

"Our work sets the stage for looking at new ways to modulate cholesterol and/or fat metabolism in order to have therapeutic potential for the treatment of fibrosing liver diseases," said lead author Dr. Simon Beaven, an assistant professor of digestive diseases at the David Geffen School of Medicine at UCLA.

The research was done in the laboratory of senior author Dr. Peter Tontonoz, a professor of pathology and laboratory medicine at the Geffen School of Medicine and a Howard Hughes Medical Institute investigator.

Beaven noted that the recent rise in obesity has resulted in a surge in the prevalence of a condition known as fatty liver, which can be a precursor to fibrosis and chronic liver disease. Simple fatty liver, also known as non-alcoholic fatty liver disease, or NAFLD, is one of the most common reasons patients consult a liver doctor in the United States. Cirrhosis due to fatty liver is skyrocketing and within a decade may become the most common indication for liver transplantation.

Beaven said the need to find better treatments for liver disease is crucial.

"A 'holy grail' for liver researchers is to develop anti-fibrotic treatments that target activated stellate cells in order to slow or prevent the development of cirrhosis," Beaven said. "Our study offers the first detailed look at how LXRs specifically impact the activation of hepatic stellate cells and the subsequent development of liver fibrosis in animal models."

UCLA researchers have found that LXRs normally play a role in helping to reduce the collagen-producing actions of stellate cells when the cells are "activated" by liver damage. For the study, UCLA scientists first tested how activated stellate cells taken from mice would react when a chemical that induces LXR activity was added to the cell culture.

In stellate cells from normal mice, LXRs suppressed the inflammatory and fibrosis-promoting program. But in those taken from mice genetically lacking LXRs, that same program of genes significantly increased because the inhibitory effect of LXRs was no longer present.

"We showed that LXRs dampen stellate cell activation by repressing inflammatory and collagen-producing genes," Beaven said.

To further gauge the strength of the response, scientists took the medium from the cultures of LXR-deficient cells and added it to stellate cells from normal mice. These cells then showed a markedly exaggerated inflammatory and collagen-producing response, suggesting that LXR-deficient stellate cells are secreting signals to promote fibrosis.

The researchers noted that these experiments demonstrate that LXRs control a fibrotic response in stellate cells that can have a wide influence on neighboring cells.

The scientists also found that after replicating chronic liver injury, mice without LXRs had dramatically more liver fibrosis than normal mice.

"The genetic loss of LXRs rendered the mice susceptible to developing fibrotic liver disease," Beaven said.

But LXRs are also known to have important functions in the immune system. The researchers then wanted to know whether the effects they were seeing in animals were due to changes in stellate cell activity specifically or whether immune cells -- derived from bone marrow -- accounted for most of the effect. After extensive testing, the researchers found no differences

in the level of liver fibrosis among normal mice and animals lacking LXRs, suggesting that the contribution from the immune system was negligible.

"This finding, along with the cell culture studies, suggests that LXRs' influence on fibrosis most likely resides in altering stellate cell function in the liver," Beaven said. "This is a critical finding and opens an entire new field of study for stellate cell biologists."

Additional studies will further identify which genes in stellate cells are activated by LXRs and help researchers better understand the role of cholesterol metabolism in the fibrotic response.

This study was funded primarily by grants from the National Institutes of Health and the Howard Hughes Medical Institute. Collaborators from the University of Southern California were funded by core grants from the NIH and the Southern California Research Center for ALPD and Cirrhosis.

Other study authors included senior investigator Dr. Peter Tontonoz of the Howard Hughes Medical Institute; Kevin Wroblewski and Cynthia Hong from Tontonoz's lab; Jiaohong Wang and Hide Tsukamoto of the Southern California Research Center for ALPD and Cirrhosis, USC's Keck School of Medicine and the Department of Veterans Affairs Greater Los Angeles Healthcare System; and Steven Bensinger of the department of pathology at the David Geffen School of Medicine at UCLA.


Story Source:

The above story is based on materials provided by University of California - Los Angeles. Note: Materials may be edited for content and length.


Journal Reference:

  1. Simon W. Beaven, Kevin Wroblewski, Jiaohong Wang, Cynthia Hong, Steven Bensinger, Hide Tsukamoto, Peter Tontonoz. Liver X Receptor Signaling Is a Determinant of Stellate Cell Activation and Susceptibility to Fibrotic Liver Disease. Gastroenterology, 2011; 140 (3): 1052 DOI: 10.1053/j.gastro.2010.11.053

Cite This Page:

University of California - Los Angeles. "Cholesterol regulator plays key role in development of liver scarring, cirrhosis." ScienceDaily. ScienceDaily, 4 April 2011. <www.sciencedaily.com/releases/2011/03/110330192546.htm>.
University of California - Los Angeles. (2011, April 4). Cholesterol regulator plays key role in development of liver scarring, cirrhosis. ScienceDaily. Retrieved September 30, 2014 from www.sciencedaily.com/releases/2011/03/110330192546.htm
University of California - Los Angeles. "Cholesterol regulator plays key role in development of liver scarring, cirrhosis." ScienceDaily. www.sciencedaily.com/releases/2011/03/110330192546.htm (accessed September 30, 2014).

Share This



More Health & Medicine News

Tuesday, September 30, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

How 'Yes Means Yes' Defines Sexual Assault

How 'Yes Means Yes' Defines Sexual Assault

Newsy (Sep. 29, 2014) Aimed at reducing sexual assaults on college campuses, California has adopted a new law changing the standard of consent for sexual activity. Video provided by Newsy
Powered by NewsLook.com
Scientists May Have Found An Early Sign Of Pancreatic Cancer

Scientists May Have Found An Early Sign Of Pancreatic Cancer

Newsy (Sep. 29, 2014) Researchers looked at 1,500 blood samples and determined people who developed pancreatic cancer had more branched chain amino acids. Video provided by Newsy
Powered by NewsLook.com
Colo. Doctors See Cluster of Enterovirus Cases

Colo. Doctors See Cluster of Enterovirus Cases

AP (Sep. 29, 2014) Doctors at the Children's Hospital of Colorado say they have treated over 4,000 children with serious respiratory illnesses since August. Nine of the patients have shown distinct neurological symptoms, including limb weakness. (Sept. 29) Video provided by AP
Powered by NewsLook.com
Dr.'s Unsure of Cause of Fast-Spreading Virus

Dr.'s Unsure of Cause of Fast-Spreading Virus

AP (Sep. 29, 2014) Doctors at the Children's Hospital of Colorado say they have treated over 4,000 children with serious respiratory illnesses since August. Nine of the patients have shown distinct neurological symptoms, including limb weakness. (Sept. 29) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins