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

Greenberg, Andrew S.; Egan, John J.; Wek, Sheree A.; Moos, Malcolm; Londos, Constantine; Kimmel, Alan R.

doi:10.1073/pnas.90.24.12035

Cited by 227 publications

(216 citation statements)

References 27 publications

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“…78,79 One plausible candidate gene in the 12 cM I-LOD unit drop support interval for the 15q linkage signal is perilipin (PLIN), a hormonally-regulated phospho-protein that encircles the lipid storage droplet in adipocytes. 80 It is the major cellular A-kinase substrate in adipocytes. Studies using knockout mice have demonstrated a major role for PLIN in adipose lipid metabolism and suggested PLIN as a potential target for obesity management.…”

Section: Discussionmentioning

confidence: 99%

Sex-specific findings from a genome-wide linkage analysis of human fatness in non-Hispanic whites and African Americans: The HyperGEN Study

et al. 2005

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OBJECTIVE: To conduct a full genome search for genes potentially influencing two related phenotypes: body mass index (BMI, kg/m 2 ) and percent body fat (PBF) from bioelectric impedance in men and women. DESIGN: A total of 3383 participants, 1348 men and 2035 women; recruitment was initiated with hypertensive sibpairs and expanded to first-degree relatives in a multicenter study of hypertension genetics. MEASUREMENTS: Genotypes for 387 highly polymorphic markers spaced to provide a 10 cM map (CHLC-8) were generated by the NHLBI Mammalian Genotyping Service (Marshfield, WI, USA). Quantitative trait loci for obesity phenotypes, BMI and PBF, were examined with a variance components method using SOLAR, adjusting for hypertensive status, ethnicity, center, age, age 2 , sex, and age 2 Â sex. As we detected a significant genotype-by-sex interaction in initial models and because of the importance of sex effects in the expression of these phenotypes, models thereafter were stratified by sex. No genotype-byethnicity interactions were found. RESULTS: A QTL influencing PBF in women was detected on chromosome12q (12q24.3-12q24.32, maximum empirical LOD score ¼ 3.8); a QTL influencing this phenotype in men was found on chromosome 15q (15q25.3, maximum empirical LOD score ¼ 3.0). These QTLs were detected in African-American and white women (12q) and men (15q). QTLs influencing both BMI and PBF were found over a broad region on chromosome 3 in men. QTLs on chromosomes 3 and 12 were found in the combined sample of men and women, but with weaker significance. CONCLUSION: The locations with highest LOD scores have been previously reported for obesity phenotypes, indicating that at least two genomic regions influence obesity-related traits. Furthermore, our results indicate the importance of considering context-dependent effects in the search for obesity QTLs.

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Section: Discussionmentioning

confidence: 99%

Sex-specific findings from a genome-wide linkage analysis of human fatness in non-Hispanic whites and African Americans: The HyperGEN Study

et al. 2005

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“…The adipocyte is able to accumulate astonishingly high amounts of TG, which can be stored anhydrously within intracellular lipid droplets coated with proteins called perilipins, without causing cellular lipotoxicity [25,26].…”

Section: Wat and Energy Homeostasismentioning

confidence: 99%

Fat poetry: a kingdom for PPARγ

2007

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Adipose tissue is not an inert cell mass contributing only to the storage of fat, but a sophisticated ensemble of cellular components with highly specialized and complex functions. In addition to managing the most important energy reserve of the body, it secretes a multitude of soluble proteins called adipokines, which have beneficial or, alternatively, deleterious effects on the homeostasis of the whole body. The expression of these adipokines is an integrated response to various signals received from many organs, which depends heavily on the integrity and physiological status of the adipose tissue. One of the main regulators of gene expression in fat is the transcription factor peroxisome proliferatoractivated receptor g (PPARg), which is a fatty acid-and eicosanoid-dependent nuclear receptor that plays key roles in the development and maintenance of the adipose tissue. Furthermore, synthetic PPARg agonists are therapeutic agents used in the treatment of type 2 diabetes.This review discusses recent knowledge on the link between fat physiology and metabolic diseases, and the roles of PPARg in this interplay via the regulation of lipid and glucose metabolism. Finally, we assess the putative benefits of targeting this nuclear receptor with still-to-be-identified highly selective PPARg modulators.

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“…These proteins are the most abundant PKA substrates in adipocytes (5), and both their subcellular location and polyphosphorylation by PKA suggest a role for the perilipins in PKAmediated lipolysis. In adipocytes, alternative mRNA splicing gives rise to perilipins A and B, the former at much higher levels than the latter (8). Thus far, functional studies point to a role for the perilipins in protecting stored TAG from hydrolysis by cellular lipases.…”

mentioning

confidence: 99%

Functional Studies on Native and Mutated Forms of Perilipins

Tansey¹,

Huml

Vogt

et al. 2003

Journal of Biological Chemistry

194

107

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Perilipin A coats the lipid storage droplets in adipocytes and is polyphosphorylated by protein kinase A (PKA); the fact that PKA activates lipolysis in adipocytes suggests a role for perilipins in this process. To assess whether perilipins participate directly in PKAmediated lipolysis, we have expressed constructs coding for native and mutated forms of the two major splice variants of the perilipin gene, perilipins A and B, in Chinese hamster ovary fibroblasts. Perilipins localize to lipid droplet surfaces and displace the adipose differentiation-related protein that normally coats the droplets in these cells. Perilipin A inhibits triacylglycerol hydrolysis by 87% when PKA is quiescent, but activation of PKA and phosphorylation of perilipin A engenders a 7-fold lipolytic activation. Mutation of PKA sites within the N-terminal region of perilipin abrogates the PKAmediated lipolytic response. In contrast, perilipin B exerts only minimal protection against lipolysis and is unresponsive to PKA activation. Since Chinese hamster ovary cells contain no PKA-activated lipase, we conclude that the expression of perilipin A alone is sufficient to confer PKA-mediated lipolysis in these cells. Moreover, the data indicate that the unique C-terminal portion of perilipin A is responsible for its protection against lipolysis and that phosphorylation at the N-terminal PKA sites attenuates this protective effect.Acute mobilization of adipose triacylglyerol stores for energy is regulated primarily by the activation state of cAMP-dependent protein kinase (PKA) 1 (1). Historically, this stimulation has been attributed to phosphorylation and activation of hormonesensitive lipase (HSL), but as noted previously (2, 3), the meager doubling of HSL activity upon phosphorylation in vitro falls far short of explaining the 30 -100-fold activation of cellular lipolysis upon elevation of PKA activity in isolated primary adipocytes. Although some the of differences between the magnitude of the in vitro and in vivo responses may be attributed to the PKA-induced translocation of HSL from the cytosol to the lipid storage droplets within adipocytes (4), it is likely that additional factors, notably the perilipins, contribute to the cellular response.The perilipins are a class of proteins found exclusively at the limiting surface of lipid storage droplets, i.e. at the lipid/aqueous interface, in adipocytes and in steroidogenic cells (5-7). These proteins are the most abundant PKA substrates in adipocytes (5), and both their subcellular location and polyphosphorylation by PKA suggest a role for the perilipins in PKAmediated lipolysis. In adipocytes, alternative mRNA splicing gives rise to perilipins A and B, the former at much higher levels than the latter (8). Thus far, functional studies point to a role for the perilipins in protecting stored TAG from hydrolysis by cellular lipases. Ectopic expression of perilipin A in 3T3-L1 adipoblasts results in perilipin A-coated lipid droplets and increases the half-life of stored TAG deposits by a factor of 4...

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

Cited by 227 publications

References 27 publications

Sex-specific findings from a genome-wide linkage analysis of human fatness in non-Hispanic whites and African Americans: The HyperGEN Study

Sex-specific findings from a genome-wide linkage analysis of human fatness in non-Hispanic whites and African Americans: The HyperGEN Study

Fat poetry: a kingdom for PPARγ

Functional Studies on Native and Mutated Forms of Perilipins

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