Link between obesity and a common liver disease identified

Link between obesity and a common liver disease identified

The high levels of obesity 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 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.

Authors demonstrated that plasma from mice and patients with NASH contains high levels of mitochondrial DNA (mtDNA) and intact mitochondria and has the ability to activate TLR9. Most of the plasma mtDNA was contained in microparticles (MPs) of hepatocyte origin, and removal of these MPs from plasma resulted in a substantial decrease in TLR9 activation capacity.

Finally 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 the author, 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,” author said.