FYI...Cholesterol Regulator Plays Key Role in Development of Liver Scarring, Cirrhosis

[Guest guest]

http://www.sciencedaily.com/releases/2011/03/110330192546.htm

Cholesterol Regulator Plays Key Role in Development of Liver Scarring, Cirrhosis

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 Geffen School of Medicine at UCLA.

The research was done in the laboratory of senior author Dr. Tontonoz, a

professor of pathology and laboratory medicine at the Geffen School of Medicine

and a 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 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. Tontonoz of the

Medical Institute; Wroblewski and 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

Bensinger of the department of pathology at the Geffen School of Medicine

at UCLA.

--------------------------------------------------------------------------------

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff)

from materials provided by University of California - Los Angeles.

--------------------------------------------------------------------------------

Journal Reference:

1.Simon W. Beaven, Wroblewski, Jiaohong Wang, Hong,

Bensinger, Hide Tsukamoto, 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

[Guest guest]

http://www.sciencedaily.com/releases/2011/03/110330192546.htm

Cholesterol Regulator Plays Key Role in Development of Liver Scarring, Cirrhosis

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 Geffen School of Medicine at UCLA.

The research was done in the laboratory of senior author Dr. Tontonoz, a

professor of pathology and laboratory medicine at the Geffen School of Medicine

and a 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 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. Tontonoz of the

Medical Institute; Wroblewski and 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

Bensinger of the department of pathology at the Geffen School of Medicine

at UCLA.

--------------------------------------------------------------------------------

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff)

from materials provided by University of California - Los Angeles.

--------------------------------------------------------------------------------

Journal Reference:

1.Simon W. Beaven, Wroblewski, Jiaohong Wang, Hong,

Bensinger, Hide Tsukamoto, 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