Caspase-2 enzyme inhibitor shows promise for ameliorating fatty liver disease

September 13, 2018, University of California - San Diego
Caspase-2 enzyme inhibitor shows promise for ameliorating fatty liver disease
Liver section that shows liver fibrosis revealed by staining of collagen accumulation in a mouse with human like NASH. Credit: UC San Diego Health

Researchers at University of California San Diego School of Medicine have discovered using mice and human clinical specimens, that caspase-2, a protein-cleaving enzyme, is a critical driver of non-alcoholic steatohepatitis (NASH), a chronic and aggressive liver condition. By identifying caspase-2's critical role, they believe an inhibitor of this enzyme could provide an effective way to stop the pathogenic progression that leads to NASH—and possibly even reverse early symptoms.

The findings are published in the September 13 online issue of Cell.

"Our results show that caspase-2 is a critical mediator of NASH pathogenesis, not only in mice but probably in humans as well," said Michael Karin, Ph.D., Distinguished Professor of Pharmacology at UC San Diego School of Medicine. "While explaining how NASH is initiated, our findings also offer a simple and effective way to treat or prevent this devastating disease."

NASH is the most aggressive form of non-alcoholic fatty disease (NAFLD), which includes a spectrum of chronic liver diseases and has become a leading cause of liver transplants. The cause of both NAFLD and NASH remains a mystery, but researchers believe one factor that accelerates the progression of benign NAFLD to aggressive NASH is elevated endoplasmic reticulum (ER) stress, induced by protein misfolding within the liver. This results in excessive buildup of cholesterol and triglycerides in liver tissue.

Applying this premise in mice, researchers first identified molecules involved in NASH pathogenesis by combining liver-specific ER stress and a high-fat diet to elicit NASH like disease, duplicating the cardinal features of human NASH, including fat accumulation in liver cells, liver damage, inflammation and scarring. Using this model, researchers found that the onset of NASH correlated with increased expression of caspase-2.

In the next phase, Karin and team examined human liver specimens collected from patients with benign NAFLD or aggressive NASH to confirm caspase-2 expression was also elevated in humans. By knocking out the caspase-2 gene in mice subjected to liver ER stress and high-fat diet or treating the mice with a specific caspase-2 inhibitor, they found that caspase-2 was responsible for all aspects of NASH, including lipid droplet accumulation, liver damage, inflammation and scarring.

"We now know that by preventing caspase-2 expression or inhibiting its activity that biomarkers of NASH are mitigated," said Juyoun Kim, Ph.D., senior fellow in the Karin laboratory and lead author. "This is exciting because now, we not only understand the role of caspase-2 in the disease, but also have a new avenue to find a potential drug treatment."

Through this study, Karin and team also discovered that caspase-2 has a critical role in activating SREBP1 and 2—the master regulators of lipogenesis, a process that takes place in the liver where nutrients like carbohydrates are turned into fatty acids, triglycerides and cholesterol. Caspase-2 was found to control SREBP1 and 2 activation by cleaving another protein called site-1 protease.

"In NASH-free individuals, the activities of SREBP1 and SREBP2 are kept under control, which is essential for preventing excessive lipid accumulation in the liver," said Karin. "However, in NASH patients, something goes awry and the liver continues to turn out excess amounts of triglycerides and cholesterol. This correlates with elevated SREBP1 and SREBP2 activities and increased caspase-2 expression."

Moving forward, Karin and team would like to embark on development of more effective drug-like caspase-2 inhibitors that could be used for NASH prevention, and ultimately provide a treatment option.

"This study was a great step forward in being able to understand the causes, and explore possible new treatments for patients with NASH and NAFLD," said co-author Rohit Loomba, MD, director of the UC San Diego NAFLD Research Center and director of hepatology at UC San Diego School of Medicine. "It is our hope to eventually translate and validate these study results using a much larger cohort of human subjects."

"This study was a great step forward in being able to understand the causes, and explore possible new treatments for patients with NASH and NAFLD," said co-author Rohit Loomba, MD, director of the UC San Diego NAFLD Research Center and director of hepatology at UC San Diego School of Medicine. "It is our hope to eventually translate and validate these study results using a much larger cohort of human subjects."

Explore further: Fatty liver: Turning off TAZ reverses disease

More information: Cell (2018). DOI: 10.1016/j.cell.2018.08.020

Related Stories

Fatty liver: Turning off TAZ reverses disease

October 27, 2016
Scientists at Columbia University Medical Center (CUMC) have identified a factor in liver cells that is responsible for turning a relatively benign liver condition, present in 30 percent of U.S. adults, into a serious disease ...

Gastrointestinal hormone measurably improved symptoms of non-alcoholic fatty liver disease

March 8, 2018
Through a randomized, double-blind, placebo-controlled phase II clinical trial, researchers at University of California San Diego School of Medicine report that small doses of NGM282, a non-tumorigenic variant of an endocrine ...

Emerging drug could help treat a common liver disease

December 22, 2017
Treating a liver disease called NASH (non-alcoholic steatohepatitis), which affects 10 to 15 percent of obese individuals with type-2 diabetes worldwide, is difficult. But now scientists believe they have found a pharmacologic ...

NASH associated with a 50 percent higher chance of death compared with NAFLD

April 24, 2015
Results from a large population-based cohort of almost a million people in the UK found that the chances of dying from non-alcoholic steatohepatitis (NASH), over a 14-year period, was approximately 50% higher than for those ...

MRI technology quantifies liver response in nonalcoholic steatohepatitis patients

August 19, 2016
Researchers at the University of California San Diego School of Medicine have found that a form of magnetic resonance imaging (MRI) that non-invasively measures fat density in the liver corresponds with histological (microscopic ...

Study sheds light on immune responses driving obesity-induced liver disease

June 28, 2017
New findings from mouse models reveal that the type of immune response that helps maintain healthy metabolism in fatty tissues, called type 2 immunity, also drives obesity-induced nonalcoholic fatty liver disease (NAFLD). ...

Recommended for you

Antibiotic prescribing influenced by team dynamics within hospitals

November 15, 2018
Antibiotic prescribing by doctors is influenced by team dynamics and cultures within hospitals.

Discovery suggests new route to fight infection, disease

November 14, 2018
New research reveals how a single protein interferes with the immune system when exposed to the bacterium that causes Legionnaires' disease, findings that could have broad implications for development of medicines to fight ...

Zika may hijack mother-fetus immunity route

November 14, 2018
To cross the placenta, Zika virus may hijack the route by which acquired immunity is transferred from mother to fetus, new research suggests.

Maternally acquired Zika immunity can increase dengue disease severity in mouse pups

November 14, 2018
To say that the immune system is complex is an understatement: an immune response protective in one context can turn deadly over time, as evidenced by numerous epidemiological studies on dengue infection, spanning multiple ...

New research aims to help improve uptake of hepatitis C testing

November 14, 2018
New research published in Scientific Reports shows persisting fears about HIV infection may impact testing uptake for the hepatitis C Virus (HCV).

Synthetic DNA-delivered antibodies protect against Ebola in preclinical studies

November 13, 2018
Scientists at The Wistar Institute and collaborators have successfully engineered novel DNA-encoded monoclonal antibodies (DMAbs) targeting Zaire Ebolavirus that were effective in preclinical models. Study results, published ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.