Journal of Genetics and Genomics

Lipid Is Moving to the Forefront of Bio-Medical Research

Guanghou Shui, Xun Huang

2014, 41(5): 229-230. doi: 10.1016/j.jgg.2014.05.001

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Diurnal Regulation of Lipid Metabolism and Applications of Circadian Lipidomics

Joshua J. Gooley, Eric Chern-Pin Chua

2014, 41(5): 231-250. doi: 10.1016/j.jgg.2014.04.001

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The circadian timing system plays a key role in orchestrating lipid metabolism. In concert with the solar cycle, the circadian system ensures that daily rhythms in lipid absorption, storage, and transport are temporally coordinated with rest-activity and feeding cycles. At the cellular level, genes involved in lipid synthesis and fatty acid oxidation are rhythmically activated and repressed by core clock proteins in a tissue-specific manner. Consequently, loss of clock gene function or misalignment of circadian rhythms with feeding cycles (e.g., in shift work) results in impaired lipid homeostasis. Herein, we review recent progress in circadian rhythms research using lipidomics, i.e., large-scale profiling of lipid metabolites, to characterize circadian-regulated lipid pathways in mammals. In mice, novel regulatory circuits involved in fatty acid metabolism have been identified in adipose tissue, liver, and muscle. Extensive diversity in circadian regulation of plasma lipids has also been revealed in humans using lipidomics and other metabolomics approaches. In future studies, lipidomics platforms will be increasingly used to better understand the effects of genetic variation, shift work, food intake, and drugs on circadian-regulated lipid pathways and metabolic health.

Gαq, Gγ1 and Plc21C Control Drosophila Body Fat Storage

Jens Baumbach, Yanjun Xu, Philip Hehlert, Ronald P. Kühnlein

2014, 41(5): 283-292. doi: 10.1016/j.jgg.2014.03.005

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Adaptive mobilization of body fat is essential for energy homeostasis in animals. In insects, the adipokinetic hormone (Akh) systemically controls body fat mobilization. Biochemical evidence supports that Akh signals via a G protein-coupled receptor (GPCR) called Akh receptor (AkhR) using cyclic-AMP (cAMP) and Ca²⁺ second messengers to induce storage lipid release from fat body cells. Recently, we provided genetic evidence that the intracellular calcium (iCa²⁺) level in fat storage cells controls adiposity in the fruit fly Drosophila melanogaster. However, little is known about the genes, which mediate Akh signalling downstream of the AkhR to regulate changes in iCa²⁺. Here, we used thermogenetics to provide in vivo evidence that the GPCR signal transducers G protein α q subunit (Gαq), G protein γ1 (Gγ1) and Phospholipase C at 21C (Plc21C) control cellular and organismal fat storage in Drosophila. Transgenic modulation of Gαq, Gγ1 and Plc21C affected the iCa²⁺ of fat body cells and the expression profile of the lipid metabolism effector genesmidway and brummer, which results in severely obese or lean flies. Moreover, functional impairment of Gαq, Gγ1 and Plc21C antagonised Akh-induced fat depletion. This study characterizes Gαq, Gγ1 and Plc21C as anti-obesity genes and supports the model that Akh employs the Gαq/Gγ1/Plc21C module of iCa²⁺ control to regulate lipid mobilization in adult Drosophila.

Recent Advances in Understanding Proteins Involved in Lipid Droplet Formation, Growth and Fusion

Jolene S.Y. Tan, Colin J.P. Seow, Vera J. Goh, David L. Silver

2014, 41(5): 251-259. doi: 10.1016/j.jgg.2014.03.003

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Lipid droplets (LDs) were once viewed as simple, inert lipid micelles. However, they are now known to be organelles with a rich proteome involved in a myriad of cellular processes. LDs are heterogeneous in nature with different sizes and compositions of phospholipids, neutral lipids and proteins. This review takes a focused look at the roles of proteins involved in the regulation of LD formation, expansion, and morphology. The related proteins are summarized such as the fat-specific protein (Fsp27), fat storage-inducing transmembrane (FIT) proteins, seipin and ADP-ribosylation factor 1-coat protein complex I (Arf-COPI). Finally, we present important challenges in LD biology for a deeper understanding of this dynamic organelle to be achieved.

The Involvement of Lipids in Alzheimer's Disease

Wei Ling Florence Lim, Ian James Martins, Ralph Nigel Martins

2014, 41(5): 261-274. doi: 10.1016/j.jgg.2014.04.003

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It has been estimated that Alzheimer's disease (AD), the most common form of dementia, will affect approximately 81 million individuals by 2040. To date, the actual cause and cascade of events in the progression of this disease have not been fully determined. Furthermore, there is currently no definitive blood test or simple diagnostic method for AD. Considerable efforts have been put into proteomic approaches to develop a diagnostic blood test, but to date these efforts have not been successful. More recently, there has been a stronger focus on lipidomic studies in the hope of increasing our understanding of the underlying mechanisms leading to AD and developing an AD blood test. It is well known that the strongest genetic risk factor for AD is the ε4 variant of apolipoprotein E (APOE). Evidence suggests that the ApoE protein, a major lipid transporter, plays a key role in the pathogenesis of AD, and its role in both normal and aberrant lipid metabolism warrants further extensive investigation. Here, we review ApoE-lipid interactions, as well as the roles that lipids may play in the pathogenesis of AD.

A Lipidomic Perspective on Intermediates in Cholesterol Synthesis as Indicators of Disease Status

Laura J. Sharpe, Vicky Burns, Andrew J. Brown

2014, 41(5): 275-282. doi: 10.1016/j.jgg.2014.03.001

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Lipidomics is increasingly becoming a viable method for researchers to routinely identify the various sterols present in samples, beyond just measuring cholesterol itself. In particular, the measurement of intermediates in cholesterol synthesis can shed new insights into not only the flux through the pathway, but also numerous disease states where levels of sterol intermediates are drastically altered. In this review, we indicate several intermediates that are relevant to disease, and discuss the challenges for analysing them, including the need for standardised methodology or universal controls across the lipidomics field.

Comprehensive Analysis of Lipid Composition in Crude Palm Oil Using Multiple Lipidomic Approaches

Wei Fun Cheong, Markus R. Wenk, Guanghou Shui

2014, 41(5): 293-304. doi: 10.1016/j.jgg.2014.04.002

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Palm oil is currently the leading edible oil consumed worldwide. Triacylglycerol (TAG) and diacylglycerol (DAG) are the dominant lipid classes in palm oil. Other lipid classes present in crude palm oil, such as phospholipids and galactolipids, are very low in abundance. These low-abundance lipids constitute key intermediates in lipid biosynthesis. In this study, we applied multiple lipidomic approaches, including high-sensitivity and high-specificity multiple reaction monitoring, to comprehensively quantify individual lipid species in crude palm oil. We also established a new liquid chromatography-coupled mass spectrometry method that allows direct quantification of low-abundance galactolipids in palm oil without the need for sample pretreatment. As crude palm oil contains large amounts of neutral lipids, our direct-detection method circumvents many of the challenges encountered with conventional lipid quantification methods. This approach allows direct measurement of lipids with no hassle during sample preparation and is more accurate and precise compared with other methods.

A Lipid Droplet-Associated GFP Reporter-Based Screen Identifies New Fat Storage Regulators in C. elegans

Zhenglong Liu, Xia Li, Qinlan Ge, Mei Ding, Xun Huang

2014, 41(5): 305-313. doi: 10.1016/j.jgg.2014.03.002

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Fat storage disorders including obesity are pandemic human health problems. As a genetically amenable model organism, Caenorhabditis elegans has often been used to explore the molecular mechanisms of fat storage regulation. Dye staining of fixed animals and stimulated Raman scattering (SRS) microscopy methods have been used successfully to study fat storage, but a genetic screening system that takes full advantage of C. elegans transparency to perform live imaging of fluorescent protein reporters has not yet been reported. Here, we investigated the tissue-specific expression of the GFP fusion of Perilipin 1 (PLIN1), a Drosophila lipid droplet-associated protein, in C. elegans. Our results indicate that PLIN1::GFP labels lipid droplets and can be used as a fat storage indicator in live worms. Through an RNAi screen, we further identified several previously uncharacterized new fat storage regulators.

2014 Vol. 41, No. 5