Segregation of sphingolipids and sterols during formation of secretory vesicles at the trans-Golgi network

The trans-Golgi network (TGN) is the major sorting station in the secretory pathway of all eukaryotic cells. How the TGN sorts proteins and lipids to generate the enrichment of sphingolipids and sterols at the plasma membrane is poorly understood. To address this fundamental question in membrane trafficking, we devised an immunoisolation procedure for specific recovery of post-Golgi secretory vesicles transporting a transmembrane raft protein from the TGN to the cell surface in the yeast Saccharomyces cerevisiae. Using a novel quantitative shotgun lipidomics approach, we could demonstrate that TGN sorting selectively enriched ergosterol and sphingolipid species in the immunoisolated secretory vesicles. This finding, for the first time, indicates that the TGN exhibits the capacity to sort membrane lipids. Furthermore, the observation that the immunoisolated vesicles exhibited a higher membrane order than the late Golgi membrane, as measured by C-Laurdan spectrophotometry, strongly suggests that lipid rafts play a role in the TGN-sorting machinery

Discovery of a potent thiazolidine free fatty acid receptor 2 agonist with favorable pharmacokinetic properties

Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metabolism, appetite, fat accumulation and inflammatory responses, and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, we were able to rapidly synthesize and screen analogues modified at both the 2- and 3-positions on the thiazolidine core. Herein, we report SAR exploration of thiazolidine FFA2 agonists and the identification of 31 (TUG-1375), a compound with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clogP) relative to the pyrrolidine lead structure. The compound has high solubility, high chemical, microsomal and hepatocyte stability, favorable pharmacokinetic properties, and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes

Lipidomics needs more standardization

Modern mass spectrometric technologies provide quantitative readouts for a wide variety of lipid specimens. However, many studies do not report absolute lipid concentrations and differ vastly in methodologies, workflows, and data presentation. Therefore, we appeal to researchers to engage with the Lipidomics Standards Initiative to develop common standards for minimum acceptable data quality and reporting for lipidomics data to take lipidomics research to the next level

Update on LIPID MAPS classification, nomenclature, and shorthand notation for MS-derived lipid structures

A comprehensive and standardized system to report lipid structures analyzed by mass spectrometry is essentialfor the communication and storage of lipidomics data. Herein, an update on both the LIPID MAPSclassification system and shorthand notation of lipid structures is presented for lipid categories Fatty Acyls(FA), Glycerolipids (GL), Glycerophospholipids (GP), Sphingolipids (SP), and Sterols (ST). With its majorchanges, i.e. annotation of ring double bond equivalents and number of oxygens, the updated shorthandnotation facilitates reporting of newly delineated oxygenated lipid species as well. For standardized reportingin lipidomics, the hierarchical architecture of shorthand notation reflects the diverse structural resolutionpowers provided by mass spectrometric assays. Moreover, shorthand notation is expanded beyond mammalianphyla to lipids from plant and yeast phyla. Finally, annotation of atoms is included for the use of stableisotope-labelled compounds in metabolic labelling experiments or as internal standards

Membranes by the Numbers

Many of the most important processes in cells take place on and across membranes. With the rise of an impressive array of powerful quantitative methods for characterizing these membranes, it is an opportune time to reflect on the structure and function of membranes from the point of view of biological numeracy. To that end, in this article, I review the quantitative parameters that characterize the mechanical, electrical and transport properties of membranes and carry out a number of corresponding order of magnitude estimates that help us understand the values of those parameters.Comment: 27 pages, 12 figure