'Fatostatin' A Turnoff for Fat Genes

Reported August 31, 2009

(Ivanhoe Newswire) -- A small molecule earlier found to have both anti-fat and anti-cancer properties is a literal turnoff for fat-making genes, according to a new report.

The chemical, which the researchers call fatostatin, blocks a well known master controller of fat synthesis, a transcription factor known as SREBP. That action in mice that are genetically prone to obesity causes the animals to become leaner. It lowers the amount of fat in their livers, as well as their blood sugar and cholesterol levels. "We are frankly very excited about it," Salih Wakil of Baylor College of Medicine is quoted as saying. "It goes to the origin of [fat synthesis] – all the way back to gene expression."

Unlike cholesterol-lowering statins in use today, which block a single enzyme in the pathway, fatostatin "hits fat from the very beginning," Motonari Uesugi, who is now at Kyoto University is quoted as saying. In this way, fatostatin influences many of the genes involved in fat production and in various aspects of the metabolic syndrome that controls a collection of risk factors including obesity, high cholesterol and insulin resistance.

Studies in cell culture showed that fatostatin significantly lowers the activity of 63 genes, including 34 directly associated with fatty acid or cholesterol synthesis. Many of those were known to be under the control of SREBP.

More detailed analysis reveals that fatostatin blocks SREBP by preventing it from entering the cell nucleus, where it would otherwise switch on the fat-making program. It operates by binding another protein called SCAP, which serves as SREBP's escort into the nucleus.

Obese mice injected with fatostatin show noticeable reductions in their weight despite little difference in their eating habits, the researchers report. After four weeks of treatment, the animals weighed 12 percent less and had 70 percent lower blood sugar levels. Their cholesterol levels (both LDL and HDL) were down, too. The concentration of fatty acids in their blood was actually higher, a sign of their greater demand for fat to burn. While the livers of the obese mice were heavy and pale with fat, treated animals' livers weighed more than 30 percent less and were a healthy-looking red.

Although less obvious, the SREBP-blocking ability might also explain fatostatin’s reported effects against prostate cancer cells in culture. Cells need fatty acids and cholesterol to build their cell membranes and continue growing, the researchers explained.

Fatostatin is not the first molecule to act on SREBP, according to the researchers, but it appears to do so in a different way than those described previously. Many steps remain, but researchers are optimistic that fatostatin could be clinically useful in the context of obesity and perhaps of cardiovascular disease and diabetes, as well.

"Hopefully down the road, fatostatin or a derivative of fatostatin may be helpful," said Wakil, who has been studying the enzymes involved in fat synthesis ever since he discovered them in the late 1950s. "It could have a broad impact on the key diseases we all suffer from."

SOURCE: Chemistry and Biology, August 28, 2009