Crucial Role of CGI-58/.ALPHA./.BETA. Hydrolase Domain-Containing Protein 5 in Lipid Metabolism

Yamaguchi, Tomohiro

doi:10.1248/bpb.33.342

Cited by 32 publications

(27 citation statements)

References 32 publications

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“…Other enzymes are involved in mobilizing TG from its storage depot within adipocyte lipid droplets during WAT lipolysis, including Pnpla2 and CGI-58 (Abhd5), both of which are implicated in diseases associated with aberrant lipolysis (33,34). We found that DEX treatment stimulated an increase in the overall abundance of Pnpla2 within the WAT of WT mice despite some variability in expression levels between individual mice.…”

Section: Glucocorticoid Action Is Required For Fasting-induced Angptl4mentioning

confidence: 73%

Angiopoietin-like 4 (Angptl4) Protein Is a Physiological Mediator of Intracellular Lipolysis in Murine Adipocytes

Gray

Lam

Yang

et al. 2012

Journal of Biological Chemistry

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Background: Angiopoietin-like 4 (Angptl4) is a secreted protein involved in triacylglycerol homeostasis. Results: Angptl4 was required for fasting, glucocorticoids, and catecholamines to stimulate cAMP-dependent signaling and triacylglycerol hydrolysis in murine fat, a response reproduced by treating adipocytes with purified ANGPTL4. Conclusion: Angptl4 is a physiological mediator of lipolysis. Significance: This finding may impact aberrant lipolytic states like insulin resistance.

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Section: Glucocorticoid Action Is Required For Fasting-induced Angptl4mentioning

confidence: 73%

Angiopoietin-like 4 (Angptl4) Protein Is a Physiological Mediator of Intracellular Lipolysis in Murine Adipocytes

Gray

Lam

Yang

et al. 2012

Journal of Biological Chemistry

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“…44 It is of interest to explore the role of Plin5 in regulating expression of ATGL and abhd5 in HSC. Passaged HSC were transducted with LV-Plin5-YFP, or LV-YFP, or no transduction.…”

Section: Plin5 Restores Ld Formation In Hsc J Lin and A Chenmentioning

confidence: 99%

“…For fully activation, ATGL must be associated with the activator abhd5. 44 Abhd5 in cytosol is directed to LDs by LD proteins. 41 Interruption of their interactions could greatly affect the activity of ATGL.…”

Section: Plin5 Restores Ld Formation In Hscmentioning

confidence: 99%

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Lin

Chen

2016

Laboratory Investigation

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Hepatic stellate cells (HSC) are major effectors during hepatic fibrogenesis. The activation of HSC is coupled to the loss of lipid droplets (LDs), which are specialized organelles composed of neutral lipids surrounded by perilipins. LDs have emerged as a focal point of interest in understanding the metabolic regulation of intrahepatic lipids during lipid-mediated liver fibrogenesis. Perilipin 5 (Plin5) is a newly identified LD protein in the perilipin family, which plays a key role in regulating aspects of intracellular trafficking, signaling, and cytoskeletal organization in hepatocytes. Recent work in Plin5 knockout mice suggests a role in high fat diet-induced hepatic lipotoxicity. The current report is to evaluate the impact of Plin5 on HSC activation and to elucidate the underlying mechanisms. We now show that high fat diet-induced liver fibrosis is accompanied by an approximate 75% reduction in Plin5 in HSC, and that spontaneous activation of primary HSC produces temporally coincident loss of Plin5 expression and LD depletion. As modulating lipid content in HSC is a suggested strategy for inhibition of HSC activation and treatment of hepatic fibrosis, we asked whether exogenous Plin5 expression in primary HSC would reverse the activation phenotype and promote LD formation. Recombinant lentiviral Plin5 expression in primary mouse HSC restored the formation of LDs, increased lipid content by inducing expression of pro-lipogenic genes and suppressing expression of pro-lipolytic genes, and suppressed HSC activation (~two fold reduction in expression of procollagen and α-smooth muscle actin, two unique biomarkers for activated HSC). In addition, the expression of exogenous Plin5 in HSC attenuated cellular oxidative stress by reducing cellular reactive oxygen species, elevating cellular glutathione, and inducing gene expression of glutamate-cysteine ligase. Taken together, our results indicate that expression of Plin5 plays a critical role in the formation of LDs, the elevation of lipid content in HSC, and the inhibition of the activation of HSC.

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“…Excess energy is primarily stored as TAG in LDs of adipose tissue, and the TAG reserves are hydrolyzed by a process called lipolysis, to supply fatty acids (FAs) to various tissues in cases of energy demand such as starvation and exercise. The prevailing pathway of regulated lipolysis involving several lipases and LD-associated proteins are summarized as follows (Brasaemle, 2007;Granneman and Moore, 2008;Granneman et al, 2009;Yamaguchi, 2010;Zechner et al, 2009). In quiescent adipocytes, perilipin binds to comparative gene identification (CGI)-58 (also called a,b-hydrolase domain-containing [ABHD] 5), a coactivator of adipose triacylglycerol lipase (ATGL), on the surface of LDs, hence preventing CGI-58 from interacting with ATGL.…”

Section: Introductionmentioning

confidence: 99%

Active involvement of micro-lipid droplets and lipid-droplet-associated proteins in hormone-stimulated lipolysis in adipocytes

Hashimoto

Segawa

Okuno

et al. 2012

Journal of Cell Science

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SummaryThe regulation of lipolysis in adipocytes involves coordinated actions of many lipid droplet (LD)-associated proteins such as perilipin, hormone sensitive lipase (HSL), adipose triglyceride lipase (ATGL), and its activator protein, CGI-58. Here, we describe the cellular origin and physiological significance of micro LDs (mLDs) that emerge in the cytoplasm during active lipolysis, as well as the roles of key lipolytic proteins on mLDs in differentiated 3T3-L1 adipocytes. Multiplex coherent anti-Stokes Raman scattering (CARS) microscopy demonstrated that mLDs receive the fatty acid (FA) moiety of triglyceride from pre-existing LDs during lipolysis. However, when FA re-esterification was blocked, mLDs did not emerge. Time-lapse imaging of GFP-tagged LD-associated proteins and immunocytochemical analyses showed that particulate structures carrying LD-associated proteins emerged throughout the cells upon lipolytic stimulation, but not when FA re-esterification was blocked. Overall lipolysis, as estimated by glycerol release, was significantly lowered by blocking re-esterification, whereas release of free FAs was enhanced. ATGL was co-immunoprecipitated with CGI-58 from the homogenates of lipolytically stimulated cells. Following CGI-58 knockdown or ATGL inhibition with bromoenol lactone, release of both glycerol and FA was significantly lowered. AICAR, an activator of AMP-activated protein kinase, significantly increased FA release, in accordance with increased expression of ATGL, even in the absence of CGI-58. These results suggest that, besides on the surface of pre-existing central LDs, LD-associated proteins are actively involved in lipolysis on mLDs that are formed by FA reesterification. Regulation of mLDs and LD-associated proteins may be an attractive therapeutic target against lipid-associated metabolic diseases.

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Crucial Role of CGI-58/.ALPHA./.BETA. Hydrolase Domain-Containing Protein 5 in Lipid Metabolism

Cited by 32 publications

References 32 publications

Angiopoietin-like 4 (Angptl4) Protein Is a Physiological Mediator of Intracellular Lipolysis in Murine Adipocytes

Angiopoietin-like 4 (Angptl4) Protein Is a Physiological Mediator of Intracellular Lipolysis in Murine Adipocytes

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Active involvement of micro-lipid droplets and lipid-droplet-associated proteins in hormone-stimulated lipolysis in adipocytes

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