Science Editor

Scientists have identified a new pathway that controls key metabolic steps in the control of the liver's fat content, which in turn is tightly linked to blood sugar control. The pathway could be useful as a target for antidiabetic agents. They reported their findings in the May 25, 2011, issue of Nature.

The team, led by David Moore, of Baylor College of Medicine, identified the pathway by screening for compounds that affect the LRH receptor, a hormone receptor that sits in the cell nucleus. Moore and his team were searching for a tool to study the receptors, whose natural binding partner is unknown.

Indirect evidence suggested that the LRH receptor stimulates the production of bile acids – which in turn affect blood sugar – and so Moore and his team reasoned that an LRH agonist might be worth exploring for metabolic disorders.

Screening a number of phospholipids for such agonists, they identified two: dilauroyl phosphatidylcholine, or DLPC, and diundecanoyl phoshatidylcholine (DUPC), both of which are trace components of the nutritional supplement lecithin. "Lecithin, particularly for chemists, is a synonym for phosphatidylcholine," David Moore told BioWorld Today.

DLPC and DUPC in turn, are versions of phosphatidylcholine with specific side chain. That specificity is a key to their activity. Changes of a single carbon atom could make them ineffective at simulating the LRH receptor.

Moore, who is a professor of molecular and cellular biology at Baylor, and the paper's senior author, and his team tested the agonists in cell culture, and found that both activated LRH, but not other known antidiabetic receptors, most notably PPAR-gamma.

The team took the approach into mouse models of diabetes. When they fed mice with DLPC or DUPC, the level of bile acids increased; the level of fats in the animals' livers decreased; and their glucose control improved.

Moore and his colleagues next decided to focus on DLPC because it is a naturally occurring component of lecithin, and test its effects specifically in insulin-resistant mice. Such mice are not outright diabetic, but are insulin resistant.

A week of oral treatment with DLPC lowered the animals' blood sugar and levels of fat in the liver, without affecting their overall body weight.

Molecularly, DLPC does not appear to affect the metabolism of existing fat in the liver. Instead, it prevents the synthesis of new fat. DLPC appeared to work by putting the brakes on another protein, the transcription factor SREBP. "SREBP instructs the liver to make fat. LRH inhibits that," Moore summarized.

Using knockouts, Moore and his group found that SREBP's effects are "100 percent dependent on LRH receptor in the liver. When you knock out LRH in the liver, SREBP doesn't work anymore."

The LRH receptor's effects on SREBP are also a point of intersection with other antidiabetic approaches: PPAR gamma activators. Drugs such as Actos (pioglitazone, Takeda Pharmaceutical Co. Ltd.) and Avandia (rosiglitazone, GlaxoSmithKline plc) are thought to activate the PPAR-gamma receptor. And basic research has shown that PPAR-gamma, too, directly affects SREBP.

Moore's team itself will continue to focus more on the molecular aspects of the newfound pathway, "We're interested in the mechanisms of the antidiabetic effect – how it actually represses SREBP," Moore said.

Elsewhere at Baylor, the more clinical aspects of the findings are also being explored: A clinical trial enrolling individuals who are overweight, but have not been diagnosed with diabetes, is currently under way at Baylor to see whether treatment with DLPC will prevent diabetes. A total of 40 people will participate, and results are expected in November.

The trial is treating people with an approved form of lecithin that is part of or liposomes, fat droplets that are used as transporters for fat-soluble drugs. "This is already in people," Moore said. "That's the first thing that's different" from most compounds in preclinical studies, which can take years to even get into the clinical pipeline, let alone come out the other end as an approved therapeutic.