Lipolysis - a highly regulated multi-enzyme complex mediates the catabolism of cellular fat stores

Abstract

Lipolysis is the biochemical pathway responsible for the catabolism of triacylglycerol (TAG) stored in cellular lipid droplets. The hydrolytic cleavage of TAG generates non-esterified fatty acids, which are subsequently used as energy substrates, essential precursors for lipid and membrane synthesis, or mediators in cell signaling processes. Consistent with its central importance in lipid and energy homeostasis, lipolysis occurs in essentially all tissues and cell types, it is most abundant, however, in white and brown adipose tissue. Over the last 5years, important enzymes and regulatory protein factors involved in lipolysis have been identified. These include an essential TAG hydrolase named adipose triglyceride lipase (ATGL) [annotated as patatin-like phospholipase domain-containing protein A2], the ATGL activator comparative gene identification-58 [annotated as α/β hydrolase containing protein 5], and the ATGL inhibitor G0/G1 switch gene 2. Together with the established hormone-sensitive lipase [annotated as lipase E] and monoglyceride lipase, these proteins constitute the basic "lipolytic machinery". Additionally, a large number of hormonal signaling pathways and lipid droplet-associated protein factors regulate substrate access and the activity of the "lipolysome". This review summarizes the current knowledge concerning the enzymes and regulatory processes governing lipolysis of fat stores in adipose and non-adipose tissues. Special emphasis will be given to ATGL, its regulation, and physiological function.

Fig. 1

Schematic delineation of the coordinate breakdown of triacylglycerols. Abbreviations: ATGL, adipose triacylglycerol lipase; DAG, diacylglycerol; G, glycerol; HSL, hormone-sensitive lipase; MAG, monoacylglycerol; MGL, monoacylglycerol lipase; NEFA, non-esterified fatty acid; TAG, triacylglycerol.

Fig. 2

Conserved areas and domain organization of ATGL. Protein sequences of human and mouse ATGL were aligned using web-based “T-Coffee Multiple Sequence Alignments” tool . Identical amino acids in the protein sequences are depicted as black, differences in the sequence as white bars. Human ATGL as the longer orthologue (504 amino acids) was used as template. Domain organization is shown for the human protein.

Fig. 3

3D structure of Pat17 depicting sequence similarities with human ATGL. A region of human ATGL, commonly annotated as the patatin-domain of ATGL (Ile10–Lys179), shares sequence similarities with Pat17 (Leu32–Ser228). The 3D structure of this sequence area in Pat17 is depicted as colored cartoon . The remainder of the Pat17 3D structure is displayed in grey ribbon style. N- and C-terminal ends are indicated with capital letters. The insert shows the catalytic dyad of Pat17 with the catalytic residues Ser77 and Asp215 (corresponding to Ser47 and Asp166 in human ATGL) highlighted as yellow sticks. The figure was prepared using PyMol (The PyMOL Molecular Graphics System, Version 1.2, Schrödinger, LLC).

Fig. 4

Conserved areas and domain organization of CGI-58. Protein sequences of human and mouse CGI-58 were aligned using web-based “T-Coffee Multiple Sequence Alignments” tool . Identical amino acids in the protein sequences are depicted as black, differences in the sequence as white bars. Mouse CGI-58 as the longer orthologue (351 amino acids) was used as template. Domain organization is shown for the murine protein.

Fig. 5

3D model and domain organization of CGI-58. A homology model of CGI-58 was built using Swiss-Model based on Aspergillus niger epoxide hydrolase as template . The compact αβα sandwich containing the α/β-hydrolase core structure is depicted as cartoon in rainbow colors; residues of the putative catalytic triad in corresponding hydrolases are highlighted as yellow sticks (Asn155, His329, Asp303). The cap region covering the potential active site is depicted in magenta, whereas the N-terminal extension is depicted as a grey ribbon. N- and C-termini are indicated with capital letters. The figure was prepared using PyMol (The PyMOL Molecular Graphics System, Version 1.2, Schrödinger, LLC).