( ago. That enzyme now known to remove ...)Gene linked to rare disease activates fat breakdown

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.