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Helping the Liver Help Itself

Humans have practiced medicine for thousands of years, but the earliest results were decidedly mixed. Archaeological evidence reveals prehistoric physicians performed complicated tasks such as neurosurgery as far back as the Neolithic age. However, the evidence also suggests that prehistoric treatments may have done more harm than good, with the human body’s incredible capacity to heal itself the real reason most prehistoric patients got better. 

While science has fortunately made major advances since the time of stone tools, the human body’s remarkable powers of recovery remains an important part of modern medicine. Perhaps nowhere is this capacity for self-healing demonstrated better than in the liver. “Some of the damage to the liver that we thought was irreversible, like scarring, isn’t. It turns out that the liver can repair itself,” says Robert Dullea, a Director in Pfizer’s Internal Medicine Research Unit. “It’s a dynamic organ that, upon an insult or an injury, can revert to a state where it can replace injured cells.”

Unleashing the liver’s power to heal itself is an important part of an emerging strategy behind treating non-alcoholic steatohepatitis (NASH), an advanced form of fatty liver disease characterized by inflammation and liver injury that affects 3 to 5 percent of U.S. adults. Inflammation is the liver’s response to what Dullea calls “an insult,” or a condition that attacks the organ and leads to injury. While many things, including alcohol and viruses, can cause inflammation, NASH isn’t associated with infection or drinking to excess. In this case, the insult is related to the presence of excess fat in the liver. 

Over time, the inflammation can lead to scarring of the liver, including the most severe level of scarring called cirrhosis. Most people with NASH have very few symptoms of liver disease until they have advanced scarring, which is one reason why some investigational drugs being evaluated for NASH have tended to focus on controlling inflammation or directly blocking scarring. But other approaches to treating NASH are focused on controlling the insult that causes the injury.  

“We’re taking a different approach to NASH by addressing the metabolic underpinnings that drive the disease, rather than trying to treat the inflammation and fibrosis,” says William Esler, a Senior Director in Pfizer’s Internal Medicine Research Unit. “That gives us the opportunity to address the root causes of the disease instead of the downstream consequences.” 

We’re taking a different approach to NASH by addressing the metabolic underpinnings that drive the disease, rather than trying to treat the inflammation and fibrosis.

William Esler

In other words, the key to helping the liver help itself may be removing the conditions that are hurting the liver in the first place, giving the organ a chance to use its ability to recover from an insult. This means focusing on how to alter the metabolic factors that drive abnormal accumulation of fat in the liver in patients with NASH.
“The initial driving event is the accumulation of fat in the liver,” says Dullea. “We think that this what gets the whole process going.”

Scientists have a good idea of what metabolic pathways are dysregulated in NASH and lead to accumulation of fat in the liver. One approach is to inhibit the production of more fat in the liver, called lipogenesis, and drive the organ to burn off any excess fat it may already have. Pfizer’s lead NASH program, an inhibitor of an enzyme called acetyl-CoA carboxylase (or ACC), is being studied to do just that.

However, because metabolic pathways are so interconnected, researchers need to make sure that any changes to metabolism that allow the liver to get rid of its excess fat don’t result in unwanted changes in fat redistribution to other parts of the body. 

“One of our approaches is to understand the relationship between inhibition of lipogenesis, or fat production within the liver, and resulting increases in triglycerides in the blood. We want to narrow it down to a sweet spot, of where we have enough suppression of fat production in the liver to stop NASH without causing an increase in blood triglycerides,” says Esler. 

The process will be a careful balancing act, but one thing researchers are counting on is the liver’s ongoing ability to help itself. If scientists can come up with a way to remove the insult, then the liver could help heal the injury.

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