Li Ying
Email Address
gmsliyin@nus.edu.sg
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Publication Ablation of dihydroceramide desaturase 1, a therapeutic target for the treatment of metabolic diseases, simultaneously stimulates anabolic and catabolic signaling(American Society for Microbiology, 2013) Siddique M.M.; Li Y.; Wang L.; Ching J.; Mal M.; Ilkayeva O.; Wu, Y.J.; Bay B.-H.; Summers S.A.; ANATOMY; DUKE-NUS MEDICAL SCHOOLThe lipotoxicity hypothesis posits that obesity predisposes individuals to metabolic diseases because the oversupply of lipids to tissues not suited for fat storage leads to the accumulation of fat-derived molecules that impair tissue function. Means of combating this have been to stimulate anabolic processes to promote lipid storage or to promote catabolic ones to drive fat degradation. Herein, we demonstrate that ablating dihydroceramide desaturase 1 (Des1), an enzyme that produces ceramides, leads to the simultaneous activation of both anabolic and catabolic signaling pathways. In cells lacking Des1, the most common sphingolipids were replaced with dihydro forms lacking the double bond inserted by Des1. These cells exhibited a remarkably strong activation of the antiapoptotic and anabolic signaling pathway regulated by Akt/protein kinase B (PKB), were resistant to apoptosis, and were considerably larger than their wild-type counterparts. Paradoxically, Des1-/- cells exhibited high levels of autophagy. Mechanistic studies revealed that this resulted from impaired ATP synthesis due in part to decreased expression and activity of several complexes of the electron transport chain, particularly complex IV, leading to activation of AMP-activated protein kinase and its induction of the autophagosome. Thus, Des1 ablation enhanced starvation responses but dissociated them from the anabolic, prosurvival, and antiautophagic Akt/PKB pathways. ? 2013, American Society for Microbiology.Publication Molecular pathways reflecting poor intrauterine growth are found in Wharton's jelly-derived mesenchymal stem cells(Oxford University Press, 2014) Sukarieh R.; Joseph R.; Leow S.C.; Li Y.; Löffler M.; Aris I.M.; Tan J.H.; Teh A.L.; Chen L.; Holbrook J.D.; Ng K.; Lee Y.S.; Chong Y.S.; Summers S.A.; Gluckman P.D.; Stünkel W.; DEPARTMENT OF COMPUTER SCIENCE; DUKE-NUS MEDICAL SCHOOL; PAEDIATRICS; BIOCHEMISTRY; OBSTETRICS & GYNAECOLOGYStudy Question: Are molecular pathways reflecting the biology of small for gestational age (SGA) neonates preserved in umbilical cordderived mesenchymal stem cells (MSCs)? Summary Answer: MSCs from SGA newborns were found to express an altered EGR-1-dependent gene network involved in the regulation of cell proliferation and oxidative stress. What is Known Already: Individuals with suboptimal intrauterine development are at greater risk of metabolic diseases such as type II diabetes, obesity and cardiovascular disease. Study Design, Size, Duration: Umbilical cords (n = 283) from the GUSTO (growing up in Singapore towards healthy outcomes) birth cohort study, and primary MSC isolates established from SGA and matched control cases (n = 6 per group), were subjected to gene expression analysis and candidate genes were studied for functional validation. Participants/Materials, Setting, Methods: Umbilical cord specimens were derived from babies born at the National University Hospital (NUH) in Singapore. Local ethical approvalwas obtained.MSCisolates were established in Wharton's jelly and molecular analysis was conducted by gene expression microarrays andRT-PCR. Cells fromSGAand control groups were compared in the presence and absence of insulin and candidate gene function was studied via siRNA-mediated gene knockdown and over-expression experiments in MSCs. Main Results and the Role of Chance: Using repeated measureANOVAs, proliferation rates of MSCs isolated from SGA neonates were found to be significantly increased (P < 0.01). In the absence of insulin, EGR-1 levels were found to be significantly reduced in the group of SGA-derived MSCs, whereas EGR-1 expression was found to be up-regulated in the same group in the presence of insulin (P < 0.01). EGR-1 was found to induce expression of COX-2 in the SGA group (P < 0.01) and both, EGR-1 and COX-2 stimulated glucose uptake in MSCs (P < 0.01). EGR-1 andCOX-2 levels were associated in whole umbilical cords (n = 283, P < 0.01) and EGR-1 positively correlated with abdominal circumference and birthweight (n = 91, P < 0.01 and n = 91, P < 0.01). Limitations, Reasons for Caution: Cell models may not entirely reflect the physiology of the host and patient follow-up studies will be necessary for further clinical validation. Wider Implications of the Findings: Our study suggests that Wharton's jelly-derived MSCs are useful in identifying pathways specific for fetal growth restriction. Study Funding/Competing Interest(s): This work is supported by the Translational Clinical Research (TCR) Flagship Program on Developmental Pathways to Metabolic Disease funded by the National Research Foundation (NRF) and administered by the National Medical Research Council (NMRC), Singapore- NMRC/TCR/004-NUS/2008'. SICS Investigators are supported through the Agency for Science Technology and Research (A?STAR) funding. No potential conflicts of interest relevant to this article were reported. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.Publication Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice(John Wiley and Sons Ltd., 2014) Sinha R.A.; Farah B.L.; Singh B.K.; Siddique M.M.; Li Y.; Wu Y.; Ilkayeva O.R.; Gooding J.; Ching J.; Zhou J.; Martinez L.; Xie S.; Bay B.-H.; Summers S.A.; Newgard C.B.; Yen P.M.; ANATOMY; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); DUKE-NUS MEDICAL SCHOOLCaffeine is one of the world's most consumed drugs. Recently, several studies showed that its consumption is associated with lower risk for nonalcoholic fatty liver disease (NAFLD), an obesity-related condition that recently has become the major cause of liver disease worldwide. Although caffeine is known to stimulate hepatic fat oxidation, its mechanism of action on lipid metabolism is still not clear. Here, we show that caffeine surprisingly is a potent stimulator of hepatic autophagic flux. Using genetic, pharmacological, and metabolomic approaches, we demonstrate that caffeine reduces intrahepatic lipid content and stimulates ?-oxidation in hepatic cells and liver by an autophagy-lysosomal pathway. Furthermore, caffeine-induced autophagy involved down-regulation of mammalian target of rapamycin signaling and alteration in hepatic amino acids and sphingolipid levels. In mice fed a high-fat diet, caffeine markedly reduces hepatosteatosis and concomitantly increases autophagy and lipid uptake in lysosomes. Conclusion: These results provide novel insight into caffeine's lipolytic actions through autophagy in mammalian liver and its potential beneficial effects in NAFLD. ? 2014 by the American Association for the Study of Liver Diseases.