The missing link between obesity and a common liver disease

The high levels of obesity in the United States contribute to fatty liver disease, the most common form of liver disease. However, little is known about how obesity causes fatty liver. A new study by Yale researchers identifies molecular links between the two, and points to a possible therapy.

Fatty liver disease — also known as nonalcoholic steatohepatitis or NASH — frequently progresses to cirrhosis and liver cancer. Currently there are no approved therapies. A team of researchers, led by Dr. Wajahat Mehal, director of the Yale Weight Loss Program, conducted a study to examine how obesity triggers a receptor protein, TLR9, which plays a key role in NASH development.

First, the researchers confirmed the role of TLR9 by observing that TLR9-deficient mice did not develop fatty liver disease even after being fed a high-fat diet. They also identified the ligands, or TLR9-activating molecules, that are elevated in both mice and human subjects with NASH. Finally, in collaboration with Dynavax Technologies, they tested a TLR9 blocker in mice fed a high-fat diet and found that it protected them from the development of NASH.

The findings have important implications for this life-threatening disease. “TLR9 could be targeted as therapy for NASH,” said Mehal, adding that other drugs that target the same pathway could be potential therapies.

“From other clinical trials, we know humans can take this TLR9-blocking drug, and it’s not toxic,” he said. The next step for Mehal and his colleagues is to determine the appropriate dosage of the TLR9-blocking drug in animal models before conducting clinical trials for patients with NASH.

The study was published Jan. 25 in The Journal of Clinical Investigation. Mehal can be contacted at[email protected].

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