Mechanism of hormone-stimulated lipolysis in adipocytes: translocation of hormone-sensitive lipase to the lipid storage droplet.

Egan, John J.; Greenberg, Andrew S.; Chang, Mei-Wei; Wek, Sheree A.; Moos, Malcolm; Londos, Constantine

doi:10.1073/pnas.89.18.8537

Cited by 382 publications

(282 citation statements)

References 25 publications

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“…Recently, we demonstrated that hormonesensitive lipase, the rate-limiting enzyme of lipolysis, translocates to the lipid droplet surface upon lipolytic activation of adipocytes (27). One potential role for perilipin might be as a barrier to deny access ofthe lipase to the lipid ofunstimulated cells, whereas, upon phosphorylation of perilipin by A-kinase, the lipid surface may become exposed.…”

Section: Discussionmentioning

confidence: 99%

Isolation of cDNAs for perilipins A and B: sequence and expression of lipid droplet-associated proteins of adipocytes.

Greenberg

Egan

Wek

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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227

207

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The major cAMP-dependent protein kinase (A-kinase) substrate in adipocytes is perilipin, a protein found exclusively at the surface of the lipid storage droplets. Using anti-perilipin serum, we have isolated two related classes of funl-length coding cDNAs, designated perilipin A and B, from a rat adipocyte cDNA expression library. The two cDNAs derive from two mRNA species that arise by differential splicing. The mRNAs are predicted to encode perilipins A and B, proteins of 517 aa (56,870 Da) and 422 aa (46,420 Da), respectively, which share a common 406-aa N-terminal sequence. The predicted perilipin A contains peptides present in proteolytic digests ofthe purified 62-kDa form ofperilipin from rat adipocytes, as well as the requisite consensus A-kinase phosphorylation sites. Like perilipin A, the B form is expressed in adipocytes and is associated with lipid storage droplets. Modeling of predicted secondary structures fails to reveal an underlying basis for the tenacious association of perilipins with lipid droplets. These proteins exhibit a sicant sequence relationship (=65% similarity through 105 aa) with only one other known protein, the adipocyte differentiation-related protein (ADRP). Like the perilipins, ADRP appears to be adipocyte-specific, which suggests that they interact in a related intracellular pathway. The molecular probes for perilipins A and B described here will permit detailed analyses of their functional role(s) in lipid metabolism.The major reservoir of stored energy in animals is the triacylglycerol pool in lipid storage droplets of adipose cells. As reviewed briefly (1)

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Section: Discussionmentioning

confidence: 99%

Isolation of cDNAs for perilipins A and B: sequence and expression of lipid droplet-associated proteins of adipocytes.

Greenberg

Egan

Wek

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

227

207

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“…Increased release of NE from sympathetic nerves activates Adrb3 on the surface of adipocytes, increasing intracellular levels of cAMP that activates PKA, which mediates phosphorylation and activation of HSL [33,34]. Increased expression of Atgl and Perilipin is also required for fat mobilization [33,34].…”

Section: Discussionmentioning

confidence: 99%

ATF4 regulates lipid metabolism and thermogenesis

et al. 2010

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Activating transcription factor 4 (ATF4) has been shown to play key roles in many physiological processes. There are no reports, however, demonstrating a direct link between ATF4 and lipid metabolism. We noticed that Atf4-deficient mice are lean, suggesting a possible role for ATF4 in regulating lipid metabolism. The goal of our current study is to investigate the involvement of ATF4 in lipid metabolism and elucidate the underlying mechanisms. Studies using Atf4-deficient mice revealed increased energy expenditure, as measured by oxygen consumption. These mice also showed increases in lipolysis, expression of uncoupling protein 2 (UCP2) and β-oxidation genes and decreases in expression of lipogenic genes in white adipose tissue (WAT), suggesting increased utilization and decreased synthesis of fatty acids, respectively. Expression of UCP1, 2 and 3 was also increased in brown adipose tissue (BAT), suggesting increased thermogenesis. The effect of ATF4 deletion on expression of UCPs in BAT suggests that increased thermogenesis may underlie increased energy expenditure. Thus, our study identifies a possible new function for ATF4 in regulating lipid metabolism and thermogenesis.

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“…3A). We tested the possibility that the localization of CGI-58-GFP to lipid droplets may require the activation of PKA in a mechanism comparable to the translocation of PKA-phosphorylated hormone-sensitive lipase from the cytosol to the surfaces of lipid droplets in adipocytes (17,(31)(32)(33). Treatment of 3T3-L1 preadipocytes stably expressing CGI-58-GFP with forskolin and IBMX to elevate cAMP and activate PKA failed to alter the diffuse distribution of CGI-58-GFP (Fig.…”

Section: Cgi-58 Localizes To Cytosol In 3t3-l1 Preadipocytes and To Tmentioning

confidence: 99%

“…Because CGI-58 is a member of the ␣/␤-hydrolase fold family of proteins that includes many lipases, we were interested in studying the localization of CGI-58 under conditions when lipolysis is stimulated and hormone-sensitive lipase translocates from the cytosol to the surfaces of lipid droplets (17,(31)(32)(33). Fully differentiated 3T3-L1 adipocytes stably expressing ectopic CGI-58-GFP were treated with isoproterenol to stimulate ␤-adrenergic receptor signaling, and IBMX to inhibit phosphodiesterase activity and preserve elevated levels of cAMP.…”

Section: Cgi-58 Localizes To Cytosol In 3t3-l1 Preadipocytes and To Tmentioning

confidence: 99%

Perilipin A Mediates the Reversible Binding of CGI-58 to Lipid Droplets in 3T3-L1 Adipocytes

Subramanian

Rothenberg

Gómez

et al. 2004

Journal of Biological Chemistry

275

290

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Perilipins, the major structural proteins coating the surfaces of mature lipid droplets of adipocytes, play an important role in the regulation of triacylglycerol storage and hydrolysis. We have used proteomic analysis to identify CGI-58, a member of the ␣/␤-hydrolase fold family of enzymes, as a component of lipid droplets of 3T3-L1 adipocytes. CGI-58 mRNA is highly expressed in adipose tissue and testes, tissues that also express perilipins, and at lower levels in liver, skin, kidney, and heart. Both endogenous CGI-58 and an ectopic CGI-58-GFP chimera show diffuse cytoplasmic localization in 3T3-L1 preadipocytes, but localize almost exclusively to the surfaces of lipid droplets in differentiated 3T3-L1 adipocytes. The localization of endogenous CGI-58 was investigated in 3T3-L1 cells stably expressing mutated forms of perilipin using microscopy. CGI-58 binds to lipid droplets coated with perilipin A or mutated forms of perilipin with an intact C-terminal sequence from amino acid 382 to 429, but not to lipid droplets coated with perilipin B or mutated perilipin A lacking this sequence. Immunoprecipitation studies confirmed these findings, but also showed co-precipitation of perilipin B and CGI-58. Remarkably, activation of cAMP-dependent protein kinase by the incubation of 3T3-L1 adipocytes with isoproterenol and isobutylmethylxanthine disperses CGI-58 from the surfaces of lipid droplets to a cytoplasmic distribution. This shift in subcellular localization can be reversed by the addition of propanolol to the culture medium. Thus, CGI-58 binds to perilipin Acoated lipid droplets in a manner that is dependent upon the metabolic status of the adipocyte and the activity of cAMP-dependent protein kinase.Lipid droplets, organelles that store neutral lipids, are found in nearly all types of eukaryotic cells. The most highly studied lipid droplet-associated proteins are members of the PAT 1 (for perilipin, adipophilin (also called adipose differentiation-related protein or ADRP), and TIP47) family of proteins (1) that includes perilipin, adipophilin, TIP47, and a related but structurally divergent protein, S3-12 (2, 3). Three protein isoforms of perilipins, named perilipins A, B, and C, are translated from alternatively spliced forms of mRNA. Perilipin A and S3-12 localize to lipid droplets in adipocytes (3-5), where they are the most abundant structural proteins of large mature and small nascent lipid droplets, respectively. In contrast, most other types of cells have small lipid droplets covered with adipophilin (6, 7) and TIP47 (1, 8, 9). Perilipins A and C, and adipophilin, coat the lipid droplets of steroidogenic cells (6) that store cholesterol ester precursors for steroid hormone synthesis.The members of the PAT family comprise the major structural proteins of lipid droplets. Studies in perilipin knockout mice have established an important role for perilipins in regulating lipolysis in adipocytes, and hence, controlling the mass of triacylglycerol deposited in adipose tissue (10, 11). The mechanisms by which per...

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Mechanism of hormone-stimulated lipolysis in adipocytes: translocation of hormone-sensitive lipase to the lipid storage droplet.

Cited by 382 publications

References 25 publications

Isolation of cDNAs for perilipins A and B: sequence and expression of lipid droplet-associated proteins of adipocytes.

Isolation of cDNAs for perilipins A and B: sequence and expression of lipid droplet-associated proteins of adipocytes.

ATF4 regulates lipid metabolism and thermogenesis

Perilipin A Mediates the Reversible Binding of CGI-58 to Lipid Droplets in 3T3-L1 Adipocytes

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