ATGL has a key role in lipid droplet/adiposome degradation in mammalian cells

Smirnova, Elena A.; Goldberg, Elysa B.; Makarova, Kira S.; Lin, Lin; Brown, William J.; Jackson, Catherine

doi:10.1038/sj.embor.7400559

Cited by 286 publications

(278 citation statements)

References 19 publications

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“…The sequential actions of ATGL, hormone-sensitive lipase, and monoglyceride lipase result in release of energy from stored lipid droplets as fatty acid and glycerol (43). In addition to its role in adipocyte hormone-sensitive triacylglycerol hydrolysis, ATGL has also been demonstrated to function in basal lipolysis (31). Ectopic expression of ATGL in oleic acid-cultured HeLa cells significantly diminished triacylglycerol stores and the size of lipid droplets, whereas knockdown of ATGL under these culture conditions resulted in enhanced triacylglycerol accumulation and the formation of markedly larger lipid droplets (31).…”

Section: Resultsmentioning

confidence: 99%

Functional analysis of FSP27 protein regions for lipid droplet localization, caspase-dependent apoptosis, and dimerization with CIDEA

Liu

Zhou

Kim

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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MS, Smas CM.Functional analysis of FSP27 protein regions for lipid droplet localization, caspase-dependent apoptosis, and dimerization with CIDEA. Am J Physiol Endocrinol Metab 297: E1395-E1413, 2009. First published October 20, 2009 doi:10.1152/ajpendo.00188.2009.-The adipocytespecific protein FSP27, also known as CIDEC, is one of three cell death-inducing DFF45-like effector (CIDE) proteins. The first known function for CIDEs was promotion of apoptosis upon ectopic expression in mammalian cells. Recent studies in endogenous settings demonstrated key roles for CIDEs in energy metabolism. FSP27 is a lipid droplet-associated protein whose heterologous expression enhances formation of enlarged lipid droplets and is required for unilocular lipid droplets typical of white adipocytes in vivo. Here, we delineate relationships between apoptotic function and lipid droplet localization of FSP27. We demonstrate that ectopic expression of FSP27 induces enlarged lipid droplets in multiple human cell lines, which is indicative that its mechanism involves ubiquitously present, rather than adipocyte-specific, cellular machinery. Furthermore, promotion of lipid droplet formation in HeLa cells via culture in exogenous oleic acid offsets FSP27-mediated apoptosis. Using transient cotransfections and analysis of lipid droplets in HeLa cells stably expressing FSP27, we show that FSP27 does not protect lipid droplets from action of ATGL lipase. Domain mapping with eGFP-FSP27 deletion constructs indicates that lipid droplet localization of FSP27 requires amino acids 174 -192 of its CIDE C domain. The apoptotic mechanism of FSP27, which we show involves caspase-9 and mitochondrial cytochrome c, also requires this 19-amino acid region. Interaction assays determine the FSP27 CIDE C domain complexes with CIDEA, and Western blot reveals that FSP27 protein levels are reduced by coexpression of CIDEA. Overall, our findings demonstrate the function of the FSP27 CIDE C domain and/or regions thereof for apoptosis, lipid droplet localization, and CIDEA interaction.fat-specific protein 27; cell death-inducing DFF45-like effector A; adipose OBESITY AND ITS RELATED COMORBIDITIES are approaching epidemic levels (1, 9). The development of new therapeutic inroads to treat these conditions would be greatly facilitated by a full understanding of lipid homeostasis (35,36). Lipotoxicity is a highly detrimental outcome of the obese state, leading to derangement of cell function and/or cell death in various tissues (34,35,37). White adipocytes present in white adipose tissue are the major site storage of excess energy in the form of triacylglycerol, contained within intracellular lipid droplets (7,38). Efficient storage of excess fatty acids within adipocyte lipid droplets also serves to protect other cells and tissues from their lipotoxic effects (7, 38). Lipid droplets are highly dynamic organelles consisting of a neutral lipid core, a phospholipid monolayer, and a large number of lipid droplet-associated proteins (7, 38). The role for the vast majority ...

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Section: Resultsmentioning

confidence: 99%

Functional analysis of FSP27 protein regions for lipid droplet localization, caspase-dependent apoptosis, and dimerization with CIDEA

Liu

Zhou

Kim

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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“…The NTE family has a distinct evolutionary origin from that of the other mammalian patatin-like lipase subfamilies that is consistent with the different domain architecture of NTE family members compared with other PNPLAs and its closer relation to bacterial patatin-like proteins (1,11). NTE possesses phospholipase activity for lysophosphatidylcholine (LPC) and, possibly, phosphatidylcholine (PC) (12)(13)(14).…”

mentioning

confidence: 82%

“…Patatin domain (Pfam01734)-containing enzymes comprise a large number of proteins from bacteria to men and can be divided by bootstrap techniques into six families (1). The patatin domain is characterized by comprising a canonical ␣/␤ hydrolase fold and a GXSXG motif, both common structural features of lipases.…”

mentioning

confidence: 99%

Identification of an Insulin-regulated Lysophospholipase with Homology to Neuropathy Target Esterase

Kienesberger

Lass

Preiss-Landl

et al. 2008

Journal of Biological Chemistry

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Neuropathy target esterase (NTE) is a member of the family of patatin domain-containing proteins and exhibits phospholipase activity in brain and cultured cells. NTE was originally identified as target enzyme for organophosphorus compounds that cause a delayed paralyzing syndrome with degeneration of nerve axons. Here we show that the structurally related murine protein NTErelated esterase (NRE) is a potent lysophospholipase. The enzyme efficiently hydrolyzes sn-1 esters in lysophosphatidylcholine and lysophosphatidic acid. No lipase activity was observed when triacylglycerols, cholesteryl esters, retinyl esters, phosphatidylcholine, or monoacylglycerol were used as substrates. Although NTE is predominantly expressed in the nervous system, we found the highest NRE mRNA levels in testes, skeletal muscle, cardiac muscle, and adipose tissue. Induction of NRE mRNA concentrations in these tissues during fasting suggested a nutritional regulation of enzyme expression and, in accordance with this observation, insulin reduced NRE mRNA levels in a dose-dependent manner in 3T3-L1 adipocytes. A green fluorescent protein-NRE fusion protein colocalized to the endoplasmic reticulum and lipid droplets. Thus, NRE is a previously unrecognized ER-and lipid droplet-associated lysophospholipase. Regulation of enzyme expression by the nutritional status and insulin suggests a role of NRE in the catabolism of lipid precursors and/or mediators that affect energy metabolism in mammals.

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“…LPL hydrolyses lipids in lipoproteins, such as chylomicrons and very low-density lipoproteins, into free fatty acids and monoacylglycerols (Mead et al, 2003). ATGL is a crucial lipase that catalyzes triglyceride hydrolysis and has a key role in lipid droplet degradation (Raben et al, 2006;Smirnova et al, 2006). Compared with group E2, there was a marked decrease in the expression of ATGL (P<0.01) and LPL (P<0.01) mRNAs in group E3.…”

Section: Gene Expression and Levels Of Proteins Associated With Lipidmentioning

confidence: 98%

The molecular mechanism of fat accumulation changes in Black-Bone chickens with different energy intakes

Qi¹,

Sun²,

HaiMing³

et al. 2012

J. Anim. Feed Sci.

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To investigate the molecular mechanism by which diets of different energy levels alter fat accumulation, 120 Black-Bone chickens were divided into 3 groups and fed diets with varying energy levels for six weeks (low: 3.02 Mcal/kg, moderate: 3.22 Mcal/kg, high: 3.42 Mcal/kg). The high-energy diet increased the concentration of blood lipids. Furthermore, high-energy intake inhibited the activities of several serum lipases. Histological sections showed over-synthesis of lipids in the livers of chickens fed high-energy diets. Data from western blotting and PCR analyses indicated that key factors for lipogenesis, regulatory transcription factors and fatty acid transporters, were up-regulated, while key factors for lipolysis were down-regulated. Chickens fed low-energy diets showed opposite results. In conclusion, varying energy levels of diets affect fat accumulation in Black-Bone chickens through changed expression of metabolic regulators.

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ATGL has a key role in lipid droplet/adiposome degradation in mammalian cells

Cited by 286 publications

References 19 publications

Functional analysis of FSP27 protein regions for lipid droplet localization, caspase-dependent apoptosis, and dimerization with CIDEA

Functional analysis of FSP27 protein regions for lipid droplet localization, caspase-dependent apoptosis, and dimerization with CIDEA

Identification of an Insulin-regulated Lysophospholipase with Homology to Neuropathy Target Esterase

The molecular mechanism of fat accumulation changes in Black-Bone chickens with different energy intakes

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