Gene linked to rare disease activates fat breakdown

A gene earlier linked to a rare disease plays a critical role in the body's "finely tuned balance" of fat storage and break down, new evidence reported in the May Cell Metabolism reveals. The findings elucidate the mechanism underlying healthy fat metabolism and explain why people with the genetic condition known as Chanarin-Dorfman Syndrome (CDS), who carry a mutant version of the gene, suffer from the widespread buildup of fat in tissues throughout their bodies.

The group found that the gene "CGI-58" is a strong activator of one of three lipid-degrading enzymes, or lipases, that disassemble triacylglycerol. Triacylglycerol is perhaps more commonly known as triglycerides. In vertebrates including humans, excess nutritional carbohydrates and fat are efficiently converted into triglycerides and deposited in fat tissue.

The team, led by Rudolf Zechner of the University of Graz in Austria, now reports that CGI-58 boosts the activity of so-called adipose triglyceride lipase (ATGL) up to 20-fold.

"We knew that the enzyme responsible for CDS must be very important for fat breakdown, but its involvement in neutral lipid catabolism remained unexplained," Zechner said. "The discovery that CGI-58 acts as a very potent activator offers a new picture of how stored fat is broken down in adipose and other tissues."

The finding solves a puzzle first raised in 2001 with the discovery that CGI-58 caused the lipid storage disease CDS in some patients, Zechner said. The symptoms characteristic of the disorder coupled with the structure of the enzyme encoded by CGI-58 led researchers to suspect that the enzyme itself acted as a lipase. However, studies failed to confirm its lipid-busting activity and its role remained mysterious.

Triglycerides consist of three fatty acids, each of which is removed in a "step-wise affair" from its glycerol backbone, Zechner explained. One of the lipases responsible, hormone-sensitive lipase, was discovered decades ago. That enzyme, now known to remove the second of the fatty acids from triglyceride, was long thought to be the critical rate-limiting step in the lipid break down.

Much later, however, it became clear from research done by Zechner's team and others that another "missing lipase" must act ahead of hormone-sensitive lipase. That prediction led to the discovery of ATGL as the enzyme that specifically removes the first fatty acid from triglyceride. A third lipase finishes the job, Zechner said.

The researchers now find that CGI-58 interacts with ATGL, stimulating its activity up to 20-fold. In contrast, CGI-58 variants with the mutations found in patients with CDS fail to activate ATGL, they found. Moreover, the joint expression of CGI-58 and ATGL limits lipid accumulation in cultured cells, while treatments that block CGI-58 in fat cells inhibit the removal of stored triglycerides. Finally, the addition of normal CGI-58 in cells having the CDS mutation restores lipid breakdown and reverses the abnormal triglyceride accumulation typical of patients with the lipid storage disease.

"These data establish an important biochemical function for CGI-58 in the lipolytic degradation of fat, implicating this lipolysis activator in the pathogenesis of CDS," the researchers wrote.

Further study will examine how CGI-58 activation of the lipase affects energy metabolism in various tissues. As disruption of the equilibrium of lipid synthesis and degradation can result in prevalent metabolic diseases, such as obesity and type 2 diabetes, the findings might have important implications for understanding these increasingly common disorders as well, Zechner said.

Source : Cell Press