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Lipid droplets and adipose metabolism: a novel role for FSP27/CIDEC

Traini, Mathew; Jessup, Wendy

Current Opinion in Lipidology: April 2009 - Volume 20 - Issue 2 - p 147–149
doi: 10.1097/MOL.0b013e32832956c7
Bimonthly update: Edited by Alan Rees
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Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia

Correspondence to Wendy Jessup, Centre for Vascular Research, University of New South Wales, Sydney, NSW 2052, Australia Tel: +61 2 9385 1219; fax: +61 2 9385 1389; e-mail: w.jessup@unsw.edu.au

Lipid droplets are organelles responsible for the intracellular storage of triglycerides and steryl esters and are composed of a neutral lipid core covered by a phospholipid monolayer, which is studded with proteins. Lipid droplets are prominent features in a number of healthy and pathological cell types, such as adipocytes in both white adipose (WAT) and brown adipose tissue (BAT), steatotic hepatocytes, and macrophage foam cells. Once believed to be a static store of lipids to meet future energy demands, the lipid droplet is now recognized as a dynamic organelle, actively involved in lipid synthesis, turnover and trafficking. Further characterization of the lipid droplet, particularly of the proteins that decorate its surface, continues to uncover novel functions of this organelle [1•].

Examples that highlight this are several recent studies of murine fat-specific protein-27 (FSP27) and its closely related human homolog CIDEC. FSP27 and CIDEC belong to the ‘cell death inducing DNA fragmentation factor-a-like effector’ (CIDE) family. CIDE family members, which also include the human genes CIDEA and CIDEB, are characterized by the presence of N-terminal and C-terminal domains that are highly homologous to the pro-apoptotic Dffa and Dffb DNA fragmentation factors. Ectopic expression of CIDEC in 293T and COS cells results in its mitochondrial localization and the induction of apoptosis, although the exact mechanism by which this occurs remains unknown. In addition to its pro-apoptotic role, expression of FSP27/CIDEC is increased 50-fold in 3T3-L1 cell culture models during adipogenesis. More recently, expression of FSP27 mRNA and protein has been shown to be largely confined to WAT and BAT in mice, with minimal expression in other tissues tested [2••,3••]. Similarly, CIDEC is predominantly expressed in subcutaneous adipose tissue in humans, with the highest levels of mRNA found in adipocytes [4]. CIDEC expression is reduced in obese patients compared to normal-weight participants [5] and in patients undergoing caloric restriction as part of a special very low calorie diet [4].

These patterns of expression strongly hint at the involvement of CIDEC/FSP27 in the regulation of adipocyte metabolism, particularly with regards to caloric input, storage and demand. Consistent with this notion, a number of independent laboratories have recently demonstrated that FSP27 is localized to the surface of lipid droplets [2••,3••,5,6•]. Both a FSP27–GFP fusion protein and immunofluorescently labeled native FSP27 were observed outlining the circumference of Oil Red-O or Nile Red labeled lipid droplets in 3T3-L1 preadipocytes, HEK-293T and COS cells [5,6•]. FSP27–GFP was also found to co-localize with perilipin, a canonical lipid-droplet resident protein involved in controlling access of lipases to the neutral lipid core of the droplet. Strikingly, overexpression of FSP27–GFP in several cell models resulted in the accumulation of triglycerides and the appearance of significantly enlarged lipid droplets [2••,5,6•]. Conversely, knockdown of FSP27 mRNA in cultured adipocytes lead to the appearance of smaller, fragmented lipid droplets. Adipocytes isolated from FSP27−/− knockout mice also exhibit smaller multilocular lipid droplets rather than a large, unilocular droplet, which is a hallmark of white adipocytes [2••,3••]. Together, these results indicate that FSP27 plays a physically direct role in the modulation of lipid droplet size, in a variety of cell types.

FSP27 appears to have a far-reaching impact on energy storage and usage in addition to the regulation of lipid droplet size in adipocytes. FSP27−/− knockout mice exhibited a range of marked metabolic changes, including decreases in the mass of white fat pads, increased insulin sensitivity, and a lean phenotype, even when fed a high-fat diet [2••,3••]. These phenotypes were also observed in leptin-deficient ob/ob FSP27−/− double knockout animals [3••]. These effects were not simply due to a redistribution of triglycerides to other tissues or into the circulation, as is the case in perilipin knockout animals, as TAG levels were also lowered in skeletal and hepatic tissues [2••,3••]. Tellingly, FSP27−/− knockout mice exhibit increased whole body metabolism (measured by oxygen consumption), hinting at increased utilization of stored fatty acids. Indeed, mitochondrial size and count was increased in WAT of FSP27−/− knockout mice, but not in muscle cells or hepatocytes [2••,3••]. This mitochondrial proliferation was accompanied by a five-fold increase in the activity of cytochrome C oxidase and significant increases in the concentration of several mitochondrial marker proteins, including COXIV, CPT1, CPT2 and Hsp60, a mitochondrial matrix chaperone [3••]. These increased levels of mitochondrial activity in FSP27−/− knockout animals may be facilitated by the greater surface area available on multilocular lipid droplets, allowing more efficient access of lipases and mitochondria to stored fatty acids. Levels of the mitochondrial uncoupling protein Ubc1 were also dramatically increased in white adipose tissue [3••]. Ubc1 is responsible for the uncoupling of mitochondrial electron transport from ATP generation in BAT, routing electron flow towards thermogenesis rather than ATP production. The upregulation of Ubc1 in the WAT of FSP27−/− knockout animals suggests that WAT has acquired some of the characteristics of BAT, shifting from being an energy-storing tissue towards becoming an energy-consuming one (although it should be noted that the Ubc1 levels observed here are still only around 5% of those present in authentic BAT).

In addition to changes in the expression of mitochondrial genes, ablation of FSP27 also leads to substantial changes in the mRNA levels of several key transcription factors involved in regulation of lipid metabolism, such as PGC1α, PPARα, PPARγ, Rb, p107 and RIP140. Levels of important insulin signaling related genes GLUT4 and AKT2 mRNA were also significantly increased, providing a potential explanation for the enhanced insulin sensitivity of FSP27−/− knockout animals [3••]. As FSP27/CIDEC is itself known to be regulated by PPARγ [7,8], these results suggest that FSP27/CIDEC not only influences expression levels of master regulators of lipid metabolism, but is likely to be involved in a feedback-sensing system as well.

How might FSP27/CIDEC act in its apparent role as a bridge between the regulation of lipid droplet size, and the extensive downstream changes in adipocyte and whole-body metabolism which result from its deletion? FSP27 is a lipid droplet associated protein and is clearly important for the maintenance of large lipid droplet size. Might proteins involved in lipid droplet growth and fusion, such as SNAREs, require FSP27 to be present on the droplet surface in order to positively promote their activity? Does this interaction occur in a concentration-dependent manner, reflecting the multilocularization of droplets which occurs in not only where FSP27 expression is completely knocked out but also where levels are partially knocked down? Such questions might be resolved directly by a native purification of FSP27 and identification of physically interacting proteins which co-purify with it. It may also be interesting to examine FSP27/CIDEC expression levels for compensatory regulation in deletion mutants that exhibit either large droplet formation or droplet fragmentation.

These findings highlight a recurrent theme in previous studies of the lipid droplet proteome: the identification of ‘contaminating’ proteins normally associated with other organelles, such as the ER, mitochondria, peroxisome and even nuclear histones. Because lipid droplets can closely associate with these organelles, it is tempting to quickly dismiss such protein identifications as mere artifacts generated during the process of subcellular fractionation. The confirmation of CIDEC/FSP27 as a bona fide lipid droplet protein and the striking effects of its manipulation on both droplet and organism-wide metabolism highlight the need to rigorously characterize all putative protein localizations.

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References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

1• Goodman JM. The gregarious lipid droplet. J Biol Chem 2008; 283:28005–28009. Provides an up-to-date overview of the many facets of cell biology in which lipid droplets have been implicated.
2•• Nishino N, Tamori Y, Tateya S, et al. FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets. J Clin Invest 2008; 118:2808–2821. Demonstrates an in-vivo requirement for FSP27 for the formation of large lipid droplets in adipocytes and links the appearance of multilocular droplets to increases in mitochondrial activity.
3•• Toh SY, Gong J, Du G, et al. Up-regulation of mitochondrial activity and acquirement of brown adipose tissue-like property in the white adipose tissue of Fsp27 deficient mice. PLoS ONE 2008; 3:e2890, doi: 10.1371/journal.pone.0002890. Together with
3•• [2••] Together with
4 Magnusson B, Gummesson A, Glad CAM, et al. Cell death-inducing DFF45-like effector C is reduced by caloric restriction and regulates adipocyte lipid metabolism. Metab Clin Exp 2008; 57:1307–1313.
5 Keller P, Petrie JT, De Rose P, et al. Fat-specific protein 27 regulates storage of triacylglycerol. J Biol Chem 2008; 283:14355–14365.
6• Puri V, Konda S, Ranjit S, et al. Fat-specific protein 27, a novel lipid droplet protein that enhances triglyceride storage. J Biol Chem 2007; 282:34213–34218. The original report of FSP27 as a lipid droplet associated protein and its relationship to lipid droplet morphology.
7 Matsusue K, Kusakabe T, Noguchi T, et al. Hepatic steatosis in leptin-deficient mice is promoted by the PPARgamma target gene Fsp27. Cell Metab 2008; 7:302–311.
8 Kim YJ, Cho SJ, Yun CH, et al. Transcriptional activation of Cidec by PPARgamma2 in adipocytes. Biochem Biophys Res Commun 2008; 377:297–302.
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Further recommended reading

• Szymanski KM, Binns D, Bartz R, et al. The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. Proc Natl Acad Sci U S A 2007; 104:20890–20895. Together with the following papers by Fei
• Fei W, Shui G, Gaeta B, et al. Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeast. J Cell Biol 2008; 180:473–482. Mutant yeast cells lacking the protein seipin (ylr404wΔ) generate aberrant lipid droplets with a more irregular size distribution than in control cells. It is suggested that seipin plays a role in lipid droplet fusion.
• Payne VA, Grimsey N, Tuthill A, et al. The human lipodystrophy gene BSCL2/seipin may be essential for normal adipocyte differentiation. Diabetes 2008; 57:2055–2060. This study shows that expression of seipin expression is essential for adipocyte differentiation. This may be mediated through its effects on the expression and activity of lipid transcription factors PPARγ and C/EBPα, and of lipolytic enzymes AGPAT2 and DGAT2.
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