Biology Reference
In-Depth Information
in the past decade has revealed that phosphorylation of lipid droplet coat protein
perilipin 1 by cAMP-dependent protein kinase (PKA) plays a critical role in control-
ling the lipid droplet localization of HSL in adipocytes (
Brasaemle, Levin, Adler-
Wailes, &Londos, 2000; Egan et al., 1992; Sztalryd et al., 2003
). Others and we have
demonstrated that ATGL also undergoes perilipin 1-dependent lipid droplet translo-
cation upon
-adrenergic stimulation (
Bezaire et al., 2009; Wang et al., 2011; Yang
et al., 2010
). While HSL is mainly regulated by PKA phosphorylation (
Brasaemle
et al., 2000; Egan et al., 1992; Sztalryd et al., 2003; Wang et al., 2009
), ATGL's ac-
tivity is coactivated by the protein comparative gene identification-58 (CGI-58) and
inhibited by the protein G0/G1 switch gene 2 (
Lass et al., 2006; Yang et al., 2010
).
Recent reports have indicated a mechanism for ATGL activation in adipocytes that
involves the dissociation of CGI-58 from phosphorylated perilipin 1 (
Granneman
et al., 2007; Granneman, Moore, Krishnamoorthy, & Rathod, 2009; Miyoshi
et al., 2007; Subramanian et al., 2004; Yamaguchi, Omatsu, Matsushita, &
Osumi, 2004
). Experiments reconstituting interactions using ectopically expressed
proteins have demonstrated that in unstimulated cells, CGI-58 is in complex with
perilipin 1 at the surface of LDs and therefore is separated from ATGL. Upon stim-
ulation, perilipin is phosphorylated on Ser492 or Ser517 by PKA, thereby releasing
CGI-58 to act on ATGL (
Granneman, Moore, Krishnamoorthy, & Rathod, 2009
).
Although the basic mechanisms for lipolysis have been elucidated, the regulative
signaling pathways are much more complicated. Lipolysis is now known to be
regulated by various extracellular signals, namely adenosine, atrial natriuretic
peptide,
b
-hydroxybutyrate, endothelin-1, insulin, glucocorticoids, growth hormone,
lactate, leptin, melanocortins, neuropeptide Y, peptide YY, prostaglandin
E2, thyroid-stimulating hormone, and tumor necrosis factor
b
(
Carmen & Victor,
2006; Chaves, Frasson, & Kawashita, 2011; Duncan, Ahmadian, Jaworski,
Sarkadi-Nagy, & Sul, 2007
). When and how these signals exert their regulation
remains largely unclear. Moreover, comparative mass spectrometry analysis has
revealed proteins differentially associated with lipid droplets in adipocytes under
basal and lipolytically stimulated conditions. For example, 17-hydroxysteroid dehy-
drogenase (type 7) was identified only in basal condition, whereas ACSL3/4 and two
short-chain reductase/dehydrogenases were found on lipid droplets upon stimulation
(
Brasaemle, Dolios, Shapiro, &Wang, 2004
). The function of these proteins in lipol-
ysis is still unknown. Furthermore, it is likely that the development of new technol-
ogies such as mass spectrometry of higher sensitivity and small interfering RNA
(siRNA) library screening will lead to future discovery of more and more proteins
involved in the lipolytic control in adipocytes. Consequently, a reliable system
model for the functional characterization of proteins regulating lipolysis in mature
adipocytes is highly desirable if not imperative.
During the past decade, loss- and gain-of-function studies using genetically engi-
neered animals have greatly advanced our knowledge on lipolysis. Most notably, the
lack of obese phenotypes in HSL-null mice prompted an intense search for a separate
TG lipase (
Haemmerle et al., 2002; Okazaki et al., 2002; Wang et al., 2001;
Zimmermann et al., 2003
) and led to the eventual discovery of ATGL (
Jenkins
a
