Deactivating liver fibrosis

SAN DIEGO—In a paper recently published by Gastroenterology, a University of California, San Diego (UC San Diego) School of Medicine team posits that liver fibrosis progression could potentially be addressed by manipulating a special population of liver cells called hepatic stellate cells (HSCs). The researchers have identified several transcription factors that identify which liver cells produce potentially damaging collagen. More importantly, they have successfully manipulated those cells to arrest collagen production and promote the healing of fibrous scarring.

Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, that occurs in most types of chronic liver diseases. Brought on by hepatitis or chronic alcohol abuse, advanced liver fibrosis causes a buildup of collagen and scar tissue, resulting in cirrhosis, liver failure and portal hypertension—which often requires liver transplantation. Different forms of liver fibrosis include alcoholic liver disease, non-alcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD).

The UC San Diego team understood that in liver fibrosis, HSCs go from naïve (never-activated) to activated, thus causing collagen buildup and corresponding liver disease, and can also revert to non-activated or quiescent-like, meaning they still retain the cellular memory of having been activated. They began the study hoping to understand the etiology of the disease and to identify ways to “turn off” the cellular switch that changed the HSC phenotype.

“We are excited to discover that HSCs have this flexibility, and that we can change their type by manipulating the molecules involved,” said Dr. Tatiana Kisseleva, associate professor of surgery at UC San Diego School of Medicine, who led the study with first author Xiao Liu, a researcher in her lab. “We also learned that when injury to the liver stops, hepatic cells can actually revert from activated phenotype to a quiescent-like state.”

According to Kisseleva, the team compared different gene expression profiles and genetic markers, which allowed them to identify a number of transcription factors that proved to be critical in the cell phenotype. In fact, surprisingly, they found these transcription factors to be highly expressed in all phenotypes. Once identified, the team began efforts to prevent HSC activation in the first place, as well as to accelerate deactivation in compromised cells.

“Each of the transcription factors we found can be a target. If we identify and provide agonists for these transcription factors and can deliver them to specifically to stellate cells, we can stop collagen production by stellate cells,” asserts Kisseleva.

Once they had identified their targets, they began experiments on mice, using both mouse models and human cells injected into neonatal mice. The studies reinforced their contention that specific transcription factors served to prevent the activation of naïve cells, while others accelerated deactivation. Likewise, when levels of the associated transcription factors was reduced, HSCs became activated, increasing collagen production and exacerbating fibrosis.

Current efforts to control or cure liver fibrosis are lacking. Weight loss—oftentimes requiring bariatric surgery—can be effective, as can corticosteroids in some instances, and liver transplant in others. But these are largely stopgap measures, and given the high demand for organ transplants, patients can spend years waiting for a match. Kisseleva believes that future therapeutic interventions to arrest liver fibrosis will likely require multiple treatments, and that targeting stellate cells would be a direction for anti-fibrotic therapy.

“New therapeutic targets are urgently needed for liver fibrosis,” she concludes. “We know we still need to determine and eliminate the etiology of the disease, but in the meantime, if we can stop the progression of fibrosis, that represents a very big help for patients.”

Kisseleva says that she and her team are now exploring the role of other transcription factors involved in maintaining HSC naïveté, as well as searching for activators and inhibitors. They 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.