Barry M. Forman, M.D., Ph.D., Ruth B. and Robert K. Lanman Chair in Gene Regulation and Drug Discovery Research, is something of a locksmith. For him, however, matching the key to a given lock could help save lives.

Forman and his colleagues recently matched a gene-controlling protein with the naturally occurring hormone that activates it. The work marks the first-ever pairing of a naturally occurring hormone with an orphan nuclear receptor.

Barry Forman and a team of researchers were the first to find an orphan nuclear receptor’s true natural hormone. (Photo by Darrin S. Joy)

Nuclear receptors are proteins that act like locks to control the activity of genes, and the “keys” controlling the locks are hormones. When a hormone binds to a nuclear receptor, it unlocks it, so it can crank up or shut down a gene’s function.

An orphan nuclear receptor is a lock with an unknown hormone key. Researchers like Forman search for the mystery hormone, so they can better understand the orphan receptor and potentially find ways to control it.

In the current study, Forman and his colleagues showed that linoleic acid, an omega-6 fatty acid molecule, binds to the orphan nuclear receptor HNF4α, short for hepatocyte nuclear factor 4α.

HNF4α controls several metabolic pathways and has been linked to diabetes, atherosclerosis, cancer and other diseases.

“This is the first time anyone has found the true natural hormone that is interacting with a nuclear receptor within the cell,” said Forman.

Forman and the study team used a new process to look at HNF4α receptors from living cells and see what molecule naturally stuck to them.

Previous methods included using bacteria to make copies of the orphan nuclear receptor, which researchers crystallized and then examined to see what was bound to it.

“The molecule that stuck wasn’t the right one, which wasn’t surprising considering it was a human receptor grown in bacteria,” said Forman.

This was not the only problem, according to Forman. In the case of HNF4α, the material identified from bacterial cells was immovable, almost permanently bound to the receptor. This meant finding a drug that would bind to HNF4α would be pointless because drugs work by competing with the natural hormone, bumping it off the receptor. If the natural hormone cannot be bumped off, a drug will not work, so researchers lost interest in HNF4α as a possible drug target.

Forman and the team showed not only that linoleic acid is the natural hormone, but it can come off the receptor under normal conditions, reopening the door to finding possible drugs.

Forman also hopes to use the technique that matched linoleic acid with HNF4α to pair other orphan nuclear receptors to their natural hormones.

“There are 48 orphan receptors,” he said. “In principle, I don’t see why this technique couldn’t find the natural hormones for virtually all of them.”

Other City of Hope authors on the study, which was published in the May issue of the journal PLoS ONE, included Min Lin, Yinchen Dong, M.D., Mark A. Sherman, Ph.D., and Xiaohui Yuan, Ph.D.

Roberta Nichols contributed to this article.