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<http://www.sciencedaily.com/releases/2011/03/110330192546.htm>
Cholesterol Regulator Plays Key Role in Development of Liver Scarring,
Cirrhosis
调节胆固醇在肝脏上的疤痕,
硬化
发展的关键作用
ScienceDaily (Apr. 4, 2011) — 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.
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Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily
staff) from materials provided by University of California - Los Angeles.
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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 |
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发表于 2011-4-7 11:52
