Perilipin1 promotes unilocular lipid droplet formation through the activation of Fsp27 in adipocytes

Sun, Zhiqi; Gong, Jingyi; Wu, Hanjiang; Xu, Wenyi; Wu, Lizhen; Xu, Duanyi; Gao, Jinlan; Wu, Jiawei; Yang, Hongyuan; Yang, Maojun; Li, Peng

doi:10.1038/ncomms2581

Cited by 218 publications

(241 citation statements)

References 56 publications

(86 reference statements)

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“…In a prior work, we found that leptin constitutes a positive regulator of fat browning process through the upregulation of Prdm16, Ucp1, and Cidec in murine subcutaneous adipocytes 71 . Accordingly, leptin deficiency was associated with a downregulation of Prdm16, a zinc-finger protein involved in the expression of brown fat-selective genes, and Ucp1, a brown-and beige-specific marker, together with an upregulation of Cidec, which promotes lipid droplet formation in subcutaneous AT 72 , suggesting an impaired fat browning in the context of leptin deficiency. Interestingly, the deletion of iNOS upregulated Prdm16 mRNA levels and tended to increase Ucp1 transcript levels.…”

Section: Discussionmentioning

confidence: 99%

Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C

et al. 2018

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Background/Objectives: Obesity is related to a dynamic extracellular matrix (ECM) remodeling, which involves the synthesis and degradation of different proteins, such as tenascin C (TNC) in the adipose tissue (AT). Given the functional relationship between leptin and inducible nitric oxide synthase (iNOS), our aim was to analyze the impact of the absence of the iNOS gene in AT inflammation and ECM remodeling in ob/ob mice. Subjects/Methods: The expression of genes involved in inflammation and ECM remodeling was evaluated in 10-week-old male double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes as well as in ob/ob mice classified into three groups [control, leptin-treated (1 mg kg −1 day −1 ) and pair-fed]. Results: Leptin deficiency increased inflammation and fibrosis in AT. As expected, leptin treatment improved the obesity phenotype. iNOS deficiency in ob/ob mice improved insulin sensitivity, AT inflammation, and ECM remodeling, as evidenced by lower AT macrophage infiltration and collagen deposition, a downregulation of proinflammatory and profibrogenic genes Tnf, Emr1, Hif1a, Col6a1, Col6a3, and Tnc, as well as lower circulating TNC levels. Interestingly, leptin upregulated TNC expression and release in 3T3-L1 adipocytes, and iNOS knockdown in 3T3-L1 fat cells produced a significant decrease in basal and leptin-induced Tnc expression. Conclusions: Ablation of iNOS in leptin-deficient mice improved AT inflammation and ECM remodeling-related genes, attenuating fibrosis, and metabolic dysfunction. The activation of iNOS by leptin is necessary for the synthesis and secretion of TNC in adipocytes, suggesting an important role of this alarmin in the development of AT inflammation and fibrosis.

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Section: Discussionmentioning

confidence: 99%

Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C

et al. 2018

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“…Both CIDEA and CIDEC catalyse a slow fusion mechanism in which a donor LD transfers its content to a larger LD in a process driven by their internal pressure gradient [34]. CIDE proteins stabilize LD pairs by the formation of trans homodimers at the LD-LD contact site [19, 34,35], where they facilitate the transport of neutral lipids through the phospholipid monolayer. The lipid transfer step requires the presence of a cationic amphipathic helix, which by interacting with PA could interfere with the phospholipid barrier to increase its permeability to TAG [19].…”

Section: Ld-ld Fusionmentioning

confidence: 99%

“…The lipid transfer step requires the presence of a cationic amphipathic helix, which by interacting with PA could interfere with the phospholipid barrier to increase its permeability to TAG [19]. CIDEC activity is enhanced and regulated by accessory proteins such as PLIN1 and Rab8a [35,36]. However, CIDE proteins alone are probably sufficient to fulfil the full process as the expression of murine CIDEA in yeast produces LD enlargement despite these organisms lacking CIDE homologues and therefore are unlikely to present functional interactors [19].…”

Section: Ld-ld Fusionmentioning

confidence: 99%

Lipid droplet growth: regulation of a dynamic organelle

Barneda

Christian

2017

Current Opinion in Cell Biology

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Intracellular lipid droplets (LDs) are remarkably dynamic and complex organelles that enact regulated storage and release of lipids to fulfil their fundamental roles in energy metabolism, membrane synthesis and provision of lipid-derived signaling molecules.Although small LDs are observed in all types of eukaryotic cells, it is adipocytes that present the widest range of sizes up to the massive unilocular droplet of a white adipocyte. Our knowledge of the proteins and associated processes that control LD dynamics is improving. The dynamic expression of LD-associated proteins is vital for controlling LD biology and is most apparent during adipocyte differentiation. Recent findings on the molecular mechanisms of lipid droplet enlargement reveal the importance of distinct functional groups of proteins and phospholipids.Highlights (max 5 points 85 characters each) Lipid droplet fusion involves major changes in the LD membrane components.Phosphatidic Acid is a key regulator of LD dynamics.Adipocyte differentiation invokes profound regulation of lipid droplet proteins.Transitions between white and BRITE adipocytes require lipid droplet remodelling.

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“…One is growth of LD itself and the other is fusion of the LDs. FSP27 is proposed to promote LD growth by the latter mechanism by which it is focally enriched at the contact site between LDs and assumed to mediate the fusion of contacted LDs through their dimerization [17,18]. However, the clarification of molecular mechanism responsible for this process is still not sufficient.…”

Section: Discussionmentioning

confidence: 99%

Negatively‐charged residues in the polar carboxy‐terminal region in FSP27 are indispensable for expanding lipid droplets

et al. 2016

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FSP27 has an important role in large lipid droplet (LD) formation because it exchanges lipids at the contact site between LDs. In the present study, we clarify that the amino-terminal domain of FSP27 (amino acids 1-130) is dispensable for LD enlargement, although it accelerates LD growth. LD expansion depends on the carboxy-terminal domain of FSP27 (amino acids 131-239). Especially, the negative charge of the acidic residues (D215, E218, E219 and E220) in the polar carboxy-terminal region (amino acids 202-239) is essential for the enlargement of LD. We propose that the carboxy-terminal domain of FSP27 has a crucial role in LD expansion, whereas the aminoterminal domain only has a supportive role.Keywords: adipocyte; fat specific protein of 27 kDa; lipid droplet; lipid droplet enlargement; negatively-charged amino acid; structure and function Obesity increases dramatically [1]. It develops as a consequence of nutritional excess and insufficient exercise and is characterized by excessive triacylglycerol (TAG) storage in the form of lipid droplets (LD) in adipose tissue. This results in adipose tissue inflammation and the deregulation of adipokines, both of which induce systemic insulin resistance [2,3]. At the same time, a hallmark of obesity is TAG accumulation in the liver and skeletal muscle, which is also important for inducing insulin resistance in these tissues [4]. These findings highlight the significance of lipid accumulation in insulin-sensitive organs in the development of insulin resistance and type 2 diabetes.LDs comprise a central core of neutral lipids containing TAG and cholesterol ester that is surrounded by a phospholipid monolayer [5,6]. This monolayer of LD is decorated with a variety of proteins that contribute to the formation of the droplet, the synthesis and hydrolysis of its lipids, and the movement of these lipids to specific intracellular and secretory pathways [6,7]. The ability to store TAG in LDs is evolutionarily conserved in yeast, plants, invertebrates and vertebrates [8]. In mammals, excess energy is primarily stored as TAG in LDs of adipose tissue. In particular, white adipocytes comprise specifically differentiated cells for storing TAG as a large unilocular LD that occupies a majority of the cell volume. The LD size can be in the 100 lm range [9]. TAG storage in LDs serves a vital role as a major store of energy supply. In the case of energy demand, such as starvation and exercise, TAG reserves are hydrolyzed by lipolysis to supply free fatty acid to various tissues. LDs are also detected in non-adipose cells; however, non-adipocyte LDs are usually much smaller than adipocyte LDs.Abbreviations CIDE, cell death-inducing DFFA-like effector; FSP27, fat specific protein of 27 kDa; LD, lipid droplet; TAG, triacylglycerol. 750FEBS Letters 590 (2016) 750-759 ª

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Perilipin1 promotes unilocular lipid droplet formation through the activation of Fsp27 in adipocytes

Cited by 218 publications

References 56 publications

Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C

Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C

Lipid droplet growth: regulation of a dynamic organelle

Negatively‐charged residues in the polar carboxy‐terminal region in FSP27 are indispensable for expanding lipid droplets

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