Scientists have identified a potential new target in the fight against hepatitis C: diacylglycerol acyl transferase 1, or DGAT-1, an enzyme that is involved in fat droplet synthesis in the liver.
In their studies, the authors showed that DGAT1 anchors a key viral protein to the fat droplets, which serve as a sort of staging ground for the assembly of new viral particles in the cell. Inhibiting the enzyme essentially keeps hepatitis C from getting its parts together into new virus particles after the virus has copied its genome.
Other studies had shown that inhibiting fat droplet synthesis prevents hepatitis C virus from assembling. But the inhibition of one specific enzyme "is a very tailored intervention," senior author Melanie Ott told BioWorld Today. "We don't touch . . . the ability of the cell to produce these very important fat droplets . . . we are excited about that." Ott is an investigator at the University of California, San Francisco's Gladstone Institute of Virology and Immunology.
Estimates of just how many people are infected with hepatitis C globally vary widely, from 160 million to almost twice that. But what is clear is that it is a large public health problem. The infection turns chronic in about 80 percent of those who contract it, and can lead to consequences including cirrhosis and liver cancer. And hepatitis C is one of the biggest headaches for HIV-infected individuals, particularly intravenous drug users who often contract both viruses at the same time.
To top it off, roughly half of treated patients respond to the standard treatment and doctors currently have no advance way to tell responders from nonresponders to the harsh regimen. Together, it translates into a need for better therapies.
Ott said her team's work, which was published in the Oct. 10, 2010, online edition of Nature Medicine, was enabled by advances in two separate areas. One is an increasing realization that fat droplets "are an important organelle," not just a cellular storage closet for triglycerides and cholesterol. Fat droplets "used to be thought of as completely uninteresting," she said.
The other is recent advances in the ability to work with the hepatitis C virus itself. "Until 2005, we couldn't really study the virus very well," because it replicated neither in cell culture nor in mice, meaning that studies had to be done in primates.
In their paper, senior author Ott and her team used a DGAT1 inhibitor to treat hepatitis-infected liver cells. They found that such cells did not have any fewer fat droplets than untreated counterparts, but that hepatitis C was able to check into such cells, but not check back out after viral replication.
Further experiments showed that DGAT1 inhibition appears to work by interfering with the hepatitis C virus core protein, which is required for assembling viral particles after replication. That assembly, it turns out, has to happen on the surface of the fat droplets that DGAT1 helps synthesize; without DGAT1 activity, the fat droplets still form, but the viral protein cannot bind to them. The fat droplets "serve as assembly platforms in the cell," Ott said.
DGAT1 has several advantages that could make it a good candidate for therapeutic inhibition.
For one thing, though it appears to be critical for viral assembly, it is not irreplaceable for synthesis of the fat droplets themselves, which have important roles in cellular life. Another enzyme, DGAT2, takes over their synthesis of the fat droplets when DGAT1 is inhibited.
For another, DGAT1 inhibitors are already being tested in the arena of metabolic disorders. Pfizer Inc. completed several Phase I studies of a DGAT1 inhibitor it is developing for the treatment of diabetes earlier this year, and at least one additional trial is ongoing. Other companies also are working on inhibitors, which could obviously also be tested against hepatitis.
Ott's team is also interested in learning more about the biological function of DGAT1. DGAT1 and DGAT2 are "structurally very different, but biochemically very similar," Ott said. Taken together, the available data "point to DGAT1 as something very unique" รข?? and from first biological principles, the enzyme's main function is surely not to enable the hepatitis C virus to ravage its owner's livers.
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