3:26 PM
May 18, 2017
 |  BC Innovations  |  Targets & Mechanisms

Degrading NASH

How TMBIM1 could calm inflammation in NASH

Inflammation is one of the primary drivers of non-alcoholic steatohepatitis (NASH), but decreasing inflammation without creating susceptibility to infection remains a challenge for the field. In Nature Medicine this month, a Chinese team described how TMBIM1, a transmembrane regulator of vesicle trafficking, triggers breakdown of excess levels of a major inflammatory mediator of NASH when it is up-regulated during the disease, leaving normal levels of TLR4 to respond to infections.

NASH is a major complication of non-alcoholic fatty liver disease (NAFLD). As fat deposits accumulate in the liver -- a process known as steatosis --, some patients progress to full-blown NASH, developing chronic inflammation that ultimately leads to fibrosis.

The excess fat primarily accumulates in hepatocytes, causing the cells to release cytokines that activate a variety of immune cells in liver and blood, leading to chronic inflammation. In turn, cytokine release from the immune cells causes liver stellate cells to become fibrotic.

The study, which was led by Hongliang Li, a professor of medicine at Wuhan University, found that TMBIM1 interacts with TLR4 and directs it to lysosomes for degradation. TLR4 is a major mediator of inflammation in NASH.

"In the end I think it's going to be a disease that's going to get treated by a combination of drugs that act at different stages."

Sanjay Bhanot, Ionis Pharmaceuticals Inc.

TLR4 is found on hepatocytes and liver macrophages (Kupfer cells) and is expressed at abnormally high levels in the livers of patients; preclinical studies have shown genetic or pharmacological inhibition of TLR4 can treat a variety of symptoms in mice.

There are not yet any approved therapies for NASH. And while TLR4 has been on the radar as a possible target in several inflammatory disorders, to date no TLR4 inhibitors have been approved by FDA for any indication, though at least six inhibitors are in trials for a variety of indications including sepsis, atherosclerosis, rheumatoid arthritis and skin cancer.

However, due to the central role of TLR4 in innate immunity, blocking it raises infection risk concerns.

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