Sometimes the mundane mechanisms that keep the human body functioning can yield the most intriguing therapeutic possibilities.
So it is with TGR5, a protein that plays a backup role protecting the liver during the everyday process of digestion.
More than that, activating TGR5 appears to reduce inflammation and burn energy. These promising properties suggest that therapies targeting the molecule could fight liver cancer, diabetes and even obesity.
Wendong Huang studies receptors active in the liver. (Photo by Walter Urie)
Wendong Huang, Ph.D., associate professor in the Division of Gene Regulation and Drug Discovery, is looking more closely at the receptor to understand how it works and identify molecules that trigger its action. His investigations place him among a cadre of City of Hope scientists advancing research into the overlap between cancer and diabetes.
The two diseases seem to share risk factors and some underlying mechanisms. The picture is becoming clearer through the efforts of a few dedicated City of Hope researchers, including Huang and collaborator Barry Forman, M.D., Ph.D., holder of the Ruth B. and Robert K. Lanman Chair in Gene Regulation and Drug Discovery Research.
According to Huang, TGR5 is expressed highly in brown adipose tissue — the “good fat” recently shown to help burn calories. He says the receptor’s potential against obesity is associated with its action in brown fat. TGR5 also holds promise against type 2 diabetes, which is closely linked to obesity.
Additionally, TGR5’s anti-inflammatory effects bolster its potential as a target for diabetes treatments and make it a likely target for new agents to fight liver cancer.
“Inflammation can cause or worsen diabetes. And many cancers are known to be highly related to inflammation. In the liver, it’s often related to hepatitis, which causes inflammation,” Huang noted.
His research follows two intertwining paths. He and his colleagues are trying to discover the downstream signaling that enables TGR5 to burn energy and suppress inflammation when activated. They also seek to identify new, potent agents to turn on the receptor and potentially become therapies.
The work fits perfectly into his ongoing research: For a decade, Huang has been investigating receptors that reside in the nucleus of cells and bind with hormones to control metabolism.
His major target is FXR, the main protein tool the body uses to keep bile acids from building up in the liver. Huang has found that FXR also may play a role in protecting against liver cancer.
In 2005, a few years after Japanese researchers discovered TGR5, Huang began to study the receptor as a natural complement to his FXR work.
He and his colleagues recently found that the receptor helped regulate a type of inflammation caused by B cells in a mouse model, suggesting TGR5 could be a target for drugs to fight inflammatory or immune liver disease. Findings were published in the journal Hepatology. And work continues to investigate its role in obesity.
The work shows the wide-ranging influence of basic science research on potential therapies for a variety of diseases and conditions — not only for cancer, but also as a potential tool to fight some of the world’s other most common health problems.
“We wondered about the function of this alternative receptor,” he said. “TGR5 is more related to diabetes and obesity. Clinicians have observed that bile acids have an anti-obesity function. TGR5 seems to be the reason.”