November 2010

From Lipolysis to the Lipolysome

For decades, textbooks taught that two enzymes are responsible for the complete hydrolysis of triacylglycerol, hormone-sensitive lipase and monoglyceride lipase, originally described by Steinberg and colleagues in 1964. Recently, lipolysis attracted renewed attention when the complexity and systemic physiological importance of this biochemical pathway became apparent.


Lipid Droplets

Localization of ATGL on lipid droplets of cos-7 cells. Cellular localization of YFP-tagged ATGL (yellow) was determined by Nipkow®-based array confocal laser scanning microscopy. Neutral lipids in cells (red) were stained with Bodipy® 558/568 C12. (Courtesy of W. Graier, R. Malli and M. Schweiger.)

Fatty acids are essential in all organisms as precursors for lipids involved in the formation of biological membranes and in cell signaling processes. Additionally, FA are important energy substrates in animals, most insects and micro-organisms. However, increased cellular concentrations of FA are toxic. Due to their amphipatic nature, they form micelles, disrupt membrane architecture and affect the cellular acid/base homeostasis. To prevent increased cellular FA concentrations, essentially all cells “detoxify” FA by their esterification and storage as triacylglycerol in lipid droplets. In mammals, adipose tissue is the most efficient organ for fat storage. When needed, FA are released from TG by enzymatic hydrolysis mediated by lipases. This process commonly is called lipolysis.

For decades, textbooks taught that two enzymes are responsible for the complete hydrolysis of TG, hormone-sensitive lipase and monoglyceride lipase, originally described by Steinberg and colleagues in 1964. Recently, lipolysis attracted renewed attention when the complexity and systemic physiological importance of this biochemical pathway became apparent.

The lipolytic pathway required the first revision in 2004 when three laboratories reported the discovery of a previously overlooked TG hydrolase (1-3). Due to its enzymatic function and its high abundance in adipose tissue, the enzyme was named adipose triglyceride lipase (2). The critical role of ATGL in fat catabolism became evident when ATGL-deficient mice accumulated massive amounts of fat in many tissues, including adipose, cardiac and skeletal, muscle, liver, kidney and testis. Soon after it was shown that ATGL activity is controlled by a mandatory co-activator (CGI-58) and a potent co-repressor (G0/G1 switch gene 2) (4, 5). The relevance for human physiology was established when mutations in ATGL and CGI-58 were found to be causative for two variants of a rare, autosomal hereditary disease called “neutral lipid storage disease” (6, 7).

In an early, ground-breaking observation, Londos, Greenberg and colleagues demonstrated that perilipin, the “prototype” of structural lipid droplet proteins, regulates HSL access to the TG substrate. On the basis of this finding, numerous proteins recently have been shown to act in a “gate-keeping” role for both HSL and ATGL. The list includes additional members of the perilipin family, members of the CideN family of proteins such as Fsp27 or pigment epithelium-derived factor. Additionally, specific vesicle transport systems (such as Arf1-COP1) also regulate the access of ATGL to lipid droplets by mechanisms that are understood insufficiently (8, 9). Although the list of regulatory factors affecting lipolysis still is incomplete, it is safe to say that lipolysis requires the large regulatory network of a “lipolysome” to function appropriately in various cell types.

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COMMENTS:

Great article that summarizes lipolysis and its importance, and emphasizes the complex nature of the process.

 

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