Liver fibrosis 'off switch' discovered in mice

January 23, 2020

Chronic alcohol abuse and hepatitis can injure the liver, often leading to a buildup of collagen and scar tissue. Understanding this process, known as liver fibrosis, could help researchers develop new ways to prevent or treat conditions such as alcoholic liver disease, non-alcoholic steatohepatitis (NASH) and nonalcoholic flatty liver disease (NAFLD).

In a study published January 23, 2020 by Gastroenterology, researchers at University of California San Diego School of Medicine demonstrated for the first time that liver fibrosis progression could potentially be addressed by manipulating a special population of liver cells called hepatic stellate cells (HSCs).

In the liver, HSCs are found in three forms: naïve in healthy people, activated in people with liver disease and inactivated in people who have recovered from liver fibrosis. In both mouse and human liver tissue, the researchers discovered they can control this cellular switch by activating or inhibiting specific transcription factors, molecules that turn genes "on" or "off."

"We are excited to discover that HSCs have this flexibility, and that we can change their type by manipulating the molecules involved," said Tatiana Kisseleva, MD, PhD, associate professor of surgery at UC San Diego School of Medicine. "These insights may allow us to develop new ways to stop the progression of liver fibrosis." Kisseleva led the study with first author Xiao Liu, a researcher in her lab.

In healthy people, naïve HSCs store vitamin A and support normal liver function -- filtering blood, metabolizing drugs and producing bile acids to aid digestion. But in alcoholic liver disease or hepatitis, HSCs become activated and start producing collagen, a hallmark of fibrosis.

The goals of the study, Kisseleva said, were to 1) understand the mechanism that switches HSCs from their naïve to their active state and 2) find ways to stop the process and inactivate collagen-producing HSCs.

Kisseleva and her team identified several transcription factors that distinguish active HSCs from naïve HSCs, and studied them in human liver samples and mouse models. Some of the transcription factors they found prevent activation of HSCs or inactivate them. When the levels of each of these naïve-associated transcription factors were reduced in mouse HSCs, the cells became activated, increased their collagen production and promoted fibrosis. Liver fibrosis was more severe in mice lacking these transcription factors.

The researchers also took the opposite approach, stimulating one of these transcription factors, PPARγ, with a chemical called rosiglitazone. In mice treated with rosiglitazone, the researchers observed liver fibrosis regression and faster resolution of fibrous scars than in untreated mice.

"We essentially found that we can help PPARγ put a stop to collagen production by activated HSCs," Kisseleva said.

New therapeutic targets are urgently needed for liver fibrosis, she said. According to the US National Institutes of Health, weight loss is the only known method for reducing liver fibrosis associated with NAFLD and NASH. Therapeutic drugs to slow the progression of disease are only available in advanced stages, where NASH has led to liver cirrhosis. Alcoholic liver disease is most commonly treated with corticosteroids, but they are not highly effective. Early liver transplantation is the only proven cure, but is offered only at select medical centers to a limited number of patients.

To further their efforts, Kisseleva and team are now exploring the role of other transcription factors involved in maintaining HSC naïveté, and searching for activators and inhibitors. They also plan to take a closer look at the genes these transcription factors are regulating, and determine if they can be directly targeted to inactivate HSCs.
Co-authors of the study include: Jun Xu, Sara Rosenthal, Ryan McCubbin, Nairika Meshgin, Linshan Shang, Yukinori Koyama, Hsiao-Yen Ma, Sven Heinz, Chris K. Glass, Chris Benner, David A. Brenner, UC San Diego; Ling-juan Zhang, UC San Diego and Xiamen University; and Sonia Sharma, La Jolla Institute for Immunology.

University of California - San Diego

Related Liver Disease Articles from Brightsurf:

Fatty liver disease despite a normal weight
Researchers from the University of Tsukuba found significant differences in the clinical presentation of non-obese patients with non-alcoholic fatty liver disease (NAFLD) based on their sex and body mass index.

Sobering reminder about liver disease
Alcohol's popularity and its central place in socialising in Australia obscures the dangers of excessive drinking and possible liver disease, Flinders University experts warn.

Giant leap in diagnosing liver disease
A collaborative team of Salk Institute and UC San Diego scientists have created a novel microbiome-based diagnostic tool that, with the accuracy of the best physicians, quickly and inexpensively identifies liver fibrosis and cirrhosis over 90 percent of the time in human patients.

Link between liver and heart disease could lead to new therapeutics
A newly published study of flies found that protecting liver function also preserves heart health.

Fatty liver disease is underdiagnosed in the US
According to an analysis published in Alimentary Pharmacology & Therapeutics, nonalcoholic fatty liver disease (NAFLD) is grossly underdiagnosed in the United States.

Possible new treatment strategy for fatty liver disease
Researchers at Karolinska Institutet in Sweden have identified a molecular pathway that when silenced could restore the normal function of immune cells in people with fatty liver disease.

Longevity protein SIRT6 also protects against fatty liver and fatty liver disease
SIRT6 regulates fat metabolism by activating another protein called peroxisome proliferator-activated receptor alpha (PPAR-alpha).

Fresh insights could lead to new treatments for liver disease
The fight against liver disease could be helped by the discovery of cells that cause liver scarring.

Better methods needed for predicting risk of liver disease
While blood samples can reliably identify people with a low risk of developing severe liver disease, better methods are needed in primary care for identifying people in most need of care.

Lab-on-a-chip may help identify new treatments for liver disease
Investigators have developed a 'lab on a chip' technology that can simulate different levels of non-alcoholic fatty liver disease progression.

Read More: Liver Disease News and Liver Disease Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to