Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in
            <i>CIDEC</i>

Rubio-Cabezas, Óscar; Puri, Vishwajeet; Murano, Incoronata; Saudek, Vladimı́r; Semple, Robert K.; Dash, Satya; Hyden, C. S.; Bottomley, William; Vigouroux, Corinne; Magré, Jocelyne; Raymond-Barker, Philippa; Murgatroyd, Peter R.; Chawla, Anil; Skepper, Jeremy N.; Chatterjee, Krishna; Suliman, Sara; Patch, Ann Marie; Agarwal, Anil K.; Garg, Abhimanyu; Barroso, Inês; Cinti, Saverio; Czech, Michael P.; Argente, Jesús; O’Rahilly, Stephen; Savage, David B.

doi:10.1002/emmm.200900037

Cited by 237 publications

(192 citation statements)

References 23 publications

(41 reference statements)

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“…In addition, there is a close correlation between insulin resistance and hyperlipidemia in metabolic diseases (53). Intriguingly, it has been reported that a human patient lacking FSP27 showed partial lipodystrophy and insulin resistance (86). Accordingly, our data showed that PKA-mediated lipolysis was suppressed by insulin, and PKA activation was not accompanied by changes in Fsp27-mediated lipid droplet fusion (supplemental Fig.…”

Section: Discussionsupporting

confidence: 64%

Protein Kinase A Subunit Balance Regulates Lipid Metabolism in Caenorhabditis elegans and Mammalian Adipocytes

Lee

Han

Kong

et al. 2016

Journal of Biological Chemistry

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Protein kinase A (PKA) is a cyclic AMP (cAMP)-dependent protein kinase composed of catalytic and regulatory subunits and involved in various physiological phenomena, including lipid metabolism. Here we demonstrated that the stoichiometric balance between catalytic and regulatory subunits is crucial for maintaining basal PKA activity and lipid homeostasis. To uncover the potential roles of each PKA subunit, Caenorhabditis elegans was used to investigate the effects of PKA subunit deficiency. In worms, suppression of PKA via RNAi resulted in severe phenotypes, including shortened life span, decreased egg laying, reduced locomotion, and altered lipid distribution. Similarly, in mammalian adipocytes, suppression of PKA regulatory subunits RI␣ and RII␤ via siRNAs potently stimulated PKA activity, leading to potentiated lipolysis without increasing cAMP levels. Nevertheless, insulin exerted anti-lipolytic effects and restored lipid droplet integrity by antagonizing PKA action. Together, these data implicate the importance of subunit stoichiometry as another regulatory mechanism of PKA activity and lipid metabolism.Protein kinase A (PKA) is a cyclic AMP (cAMP)-dependent serine/threonine kinase that mediates various cellular responses, including lipolysis. Since its discovery in the 1950s (1-4), the cAMP-PKA system has become one of the best understood signaling pathways in terms of biochemical properties. PKA is composed of catalytic subunits and cAMP-binding regulatory subunits (5). In the absence of cAMP stimulation, PKA forms an inactive tetramer composed of four subunits with two regulatory and two catalytic subunits. Upon nutritional deprivation or hormonal stimulation, activated adenylyl cyclase produces cAMP from ATP. Then, the regulatory subunit of PKA binds cAMP, causing a conformational change that decreases its affinity for catalytic subunits by ϳ10 4 -fold and leads to the release of active catalytic subunits to phosphorylate target proteins (6, 7).PKA has a wide range of substrates that regulate a number of physiological processes. To date, several hundred PKA target proteins have been identified, and yet new PKA substrates are continually being reported (8, 9). In mammalian adipocytes, numerous studies over the last 40 years have revealed that the cAMP-PKA axis forms a critical node in the regulation of lipolysis. For instance, major components of lipolytic pathways, including hormone-sensitive lipase (Hsl) 2 and perilipin 1 (Plin1), are direct targets of PKA (10, 11). Recently, adipose triglyceride lipase (Atgl) was also reported to be a target of PKA (12, 13). Upon receiving activation signals from molecules such as catecholamine and glucagon, activated PKA phosphorylates Plin1 and HSL to promote the recruitment of HSL to lipid droplets (14, 15). In addition, phosphorylated Plin1 releases comparative gene identification-58 (CGI-58; Abhd5), a coactivator of Atgl, to mediate lipolysis upon PKA activation (16 -20). On the contrary, insulin can activate phosphodiesterase 3B (Pde3b) and reduce cAMP levels (1...

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Section: Discussionsupporting

confidence: 64%

Protein Kinase A Subunit Balance Regulates Lipid Metabolism in Caenorhabditis elegans and Mammalian Adipocytes

Lee

Han

Kong

et al. 2016

Journal of Biological Chemistry

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“…We have recently reported the fact that loss-of-function mutations in two of these LD coat proteins are associated with smaller LDs and lipodystrophy (19,20). We have now also shown that siRNA-mediated PCYT1A knockdown impairs adipogenesis in cultured adipocytes.…”

Section: Resultsmentioning

confidence: 87%

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease

Payne

Lim

Girousse

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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124

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Significance The characterization of rare monogenic human disorders can and has yielded unique biological insights. Our phenotypic description and functional characterization of human loss-of-function mutations in PCYT1A is both clinically important for patients and their families afflicted with this rare but serious metabolic disease and biologically helpful in advancing understanding of the physiological consequences of impaired PCYT1A activity in humans.

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“…Another study using molecular-replacement phasing method also showed that the homodimerization of FSP27 CIDE-N domain was mediated by R46, R55 and K56 (basic patch) from one FSP27 molecule and by E87, D88 and E93 (acidic patch) from the second molecule [20]. Assuming that the mechanisms by which FSP27-CT forms a homodimer are similar, the positively-charged residues (K181, K183, R184 and K187) in one FSP27-CT molecule may be as important as the interaction of residues with the cluster of negatively-charged amino acids (D215, E218, E219, E220) of the adjacent molecule for promoting the homodimerization of the FSP27-CT. A patient carrying a homozygous nonsense mutation in CIDE-C (the human homologue of FSP27), which is predicted to truncate the protein at amino acid 186, showed small and multilocular LDs in white adipocytes [21]. This implies that the mutant FSP27 in the patient has no function with respect to expanding LD size despite the intact CIDE-N domain.…”

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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Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC

Cited by 237 publications

References 23 publications

Protein Kinase A Subunit Balance Regulates Lipid Metabolism in Caenorhabditis elegans and Mammalian Adipocytes

Protein Kinase A Subunit Balance Regulates Lipid Metabolism in Caenorhabditis elegans and Mammalian Adipocytes

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease

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

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