Researchers 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. While explaining how NASH is initiated, our findings also offer a simple and effective way to treat or prevent this devastating disease.

Protein Misfolding

NASH is the most aggressive form of the non-alcoholic fatty liver 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.

Triglycerides

This results in an 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 a 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.

Caspase-2 Inhibitor

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.

They now know that by preventing caspase-2 expression or inhibiting its activity that biomarkers of NASH are mitigated. 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 activations by cleaving another protein called site-1 protease.

Moving forward, they would like to embark on the 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.

They hope to eventually translate and validate these study results using a much larger cohort of human subjects.