Detrimental weight loss: Scientists discover link between fat-cleaving enzymes and cancer-associated cachexia

Many serious diseases like cancer or AIDS cause cachexia, a life-threatening condition with extensive weight loss. The term cachexia is derived from the Greek word κακός ἕξις (kakos hexis), meaning bad condition. Cachexia is not caused by reduced calorie intake but is the result of a complex, pathological process not yet fully understood. Besides fat loss the patient also experiences massive muscle wasting. Weakened patients are less tolerant of treatment like radiation or chemotherapy and are more prone to infections. It is estimated that about one third of cancer patients do not die from their primary disease but from cachexia -- for some types of cancer the percentage is even higher.

Scientists from Graz, Austria, have now directly linked lipid metabolism and cancer-associated cachexia. The researchers report in Science Express (June 16, 2011) that mice deficient in the lipid degrading enzyme adipose triglyceride lipase (ATGL) are fully protected against cancer-associated cachexia. The research teams of Gerald Hoefler (Institute of Pathology, Medical University of Graz, Austria) and Rudolf Zechner (Institute of Molecular Biosciences, University of Graz, Austria) demonstrated that, despite unchanged growth of the tumor, neither loss of fat tissue nor muscle mass was observed in the animals. Mice lacking another key enzyme in the breakdown of fat, hormone sensitive lipase (HSL), were at least partly protected. This discovery seems to be relevant also for human patients: ATGL and HSL activities in cachectic cancer patients are significantly higher than in normal weight patients.

The close and interdisciplinary collaboration of researches from the Medical University of Graz and the University of Graz were the prerequisite for these ground-breaking findings. The scientists involved have been closely cooperating within the team grants SFB LIPOTOX (funded by the Austrian Science Foundation, FWF) and GOLD -- Genomics Of Lipid-associated Disorders within GEN-AU (funded by FFG and the Austrian Ministry of Science and Education).

In 2004 Zechner and his team published the discovery of a novel lipid cleaving enzyme in Science. They showed that ATGL is responsible for the first step in the breakdown of neutral lipids (triacylglycerols). The current findings provide a promising new therapeutic strategy for treating cachexia in cancer patients -- a patent application is pending. Drugs inhibiting the lipolytic activities of ATGL and HSL may prevent cachexia and significantly increase both the survival rate and the quality of life of patients affected.

/Science Daily/