CRISPR screens for lipid regulators reveal a role for ER-bound SNX13 in lysosomal cholesterol export

We report here two genome-wide CRISPR screens performed to identify genes that, when knocked out, alter levels of lysosomal cholesterol or bis(monoacylglycero)phosphate. In addition, these screens were also performed under conditions of NPC1 inhibition to identify modifiers of NPC1 function in lysosomal cholesterol export. The screens confirm tight coregulation of cholesterol and bis(monoacylglycero)phosphate in cells and reveal an unexpected role for the ER-localized SNX13 protein as a negative regulator of lysosomal cholesterol export and contributor to ER–lysosome membrane contact sites. In the absence of NPC1 function, SNX13 knockdown redistributes lysosomal cholesterol and is accompanied by triacylglycerol-rich lipid droplet accumulation and increased lysosomal bis(monoacylglycero)phosphate. These experiments provide unexpected insight into the regulation of lysosomal lipids and modification of these processes by novel gene products.

What Is the Impact of Microplastics and Lipid Regulators on Marine Meiofauna? Case Study of Polyvinyl Chloride, Atorvastatin, and Simvastatin

A microcosm experiment was carried out to provide a deeper insight into the toxic mechanisms exerted by two lipid regulator agents, as well as their interactions with the polyvinyl chloride microplastic on marine meiofauna. Two concentrations of Atorvastatin “A” and of Simvastatin “S”, (i.e., 0.6 mg.kg−1 and 6 mg.kg−1), as well as a single dosage of polyvinyl chloride microplastics “P” at 20 mg.kg−1, separately and their combined mixtures (“AP” and “SP”) were used on coastline dwelling marine meiofauna, with a main focus on nematodes. The results showed a significant reduction in meiofauna abundance in treatments compared to control. SIMPER analysis highlighted a significant decrease in the abundance of epigrowth feeders (2A), which possess conical (co) tails, and indistinct (id) amphideal foveas compared to control microcosms, reflected mainly in the decrease in abundance of the species Prochromadorella longicaudata. Furthermore, the contamination with microplastic affected only the omnivores-carnivores guild. Another finding of the current experiment is that the mixtures of microplastic with drugs lead to synergic interactions that increased their toxic effects on marine nematode communities.

Assessment of Human Pharmaceuticals in Drinking Water Catchments, Tap and Drinking Fountain Waters

The occurrence of pharmaceuticals in water catchments and drinking waters raises potential risks to public health. Therefore, after addressing the major aquatic contamination pathway, the wastewater treatment plants (WWTPs), and, subsequently, surface waters, 18 human pharmaceuticals from 6 therapeutic groups (antibiotics, lipid regulators, selective serotonin reuptake inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs) and hormones) were analyzed in drinking water catchments, tap and drinking fountain waters. This was performed by solid phase extraction (SPE) and liquid chromatography coupled with tandem mass detection (LC-MS/MS). The 97 samples analyzed were collected from 31 different sites in the center of Portugal. All samples presented concentrations below the method detection limits (MDLs) that ranged between 1.13 to 5.45 ng L−1. The achieved results contributed to a better knowledge on the Portuguese and European context of drinking water, since there is a knowledge gap regarding this matrix. Comparing our data with other studies, published worldwide, we can observe that median concentrations of pharmaceuticals were reported in the low ng L−1 levels, values close to our MDLs. Consequently, it is unlikely that, in light of the current knowledge, the presence of pharmaceuticals in drinking water presents a threat to human health.

Daily Variation of Lipid Regulators and Personal Care Products in a River Impacted by Domestic Effluents in Southern Brazil

In urban areas, wastewater treatment plants (WWTPs) play a major role in the water quality of rivers. The removal efficiency of emerging contaminants by WWTPs is strongly correlated with the type of treatment and the hydraulic retention time (HRT) of the process, which can vary according to the volumetric influent flow of wastewater and occasional peak flows. This paper aims, for the first time, to assess the daily variation of lipid regulators and personal care products in an urban river impacted by domestic effluents. Samples were collected upstream and downstream of a WWTP. The concentrations downstream of the effluent discharge were higher than upstream, but they varied significantly during the day. Concentration peaks upstream of the WWTP were detected at 07:00, 15:00 and 21:00, while downstream of the effluent discharge, concentration peaks occurred between 13:00 and 19:00 and between 21:00 and 23:00. The highest downstream concentrations of triclosan and methylparaben (420 ng L−1 and 460 ng L−1) were 6.8 and 5.4 times higher than the lowest concentrations detected, respectively. These results show that in WWTP-impacted rivers, the time of the sampling has a great influence on the final results and conclusions of a monitoring study.

CRISPR screens for lipid regulators reveal a role for ER-bound SNX13 in lysosomal cholesterol export

We report here two genome-wide CRISPR screens carried out to identify genes that when knocked out, alter levels of lysosomal cholesterol or bis(monoacylglycero)phosphate. In addition, these screens were also carried out under conditions of NPC1 inhibition to identify modifiers of NPC1 function in lysosomal cholesterol export. The screens confirm tight co-regulation of cholesterol and bis(monoacylglycero)phosphate levels in cells, and reveal an unexpected role for the ER-localized, SNX13 protein as a negative regulator of lysosomal cholesterol export. In the absence of NPC1 function, SNX13 knockout decreases lysosomal cholesterol, and is accompanied by triacylglycerol-rich lipid droplet accumulation and increased lysosomal bis(monoacylglycero)phosphate. These experiments provide unexpected insight into the regulation of lysosomal lipids and modification of these processes by novel gene products.

Roles of endogenous ether lipids and associated PUFAs in the regulation of ion channels and their relevance for disease

Ether lipids (ELs) are lipids characterized by the presence of either an ether linkage (alkyl lipids) or a vinyl ether linkage [i.e., plasmalogens (Pls)] at the sn1 position of the glycerol backbone, and they are enriched in PUFAs at the sn2 position. In this review, we highlight that ELs have various biological functions, act as a reservoir for second messengers (such as PUFAs) and have roles in many diseases. Some of the biological effects of ELs may be associated with their ability to regulate ion channels that control excitation-contraction/secretion/mobility coupling and therefore cell physiology. These channels are embedded in lipid membranes, and lipids can regulate their activities directly or indirectly as second messengers or by incorporating into membranes. Interestingly, ELs and EL-derived PUFAs have been reported to play a key role in several pathologies, including neurological disorders, cardiovascular diseases, and cancers. Investigations leading to a better understanding of their mechanisms of action in pathologies have opened a new field in cancer research. In summary, newly identified lipid regulators of ion channels, such as ELs and PUFAs, may represent valuable targets to improve disease diagnosis and advance the development of new therapeutic strategies for managing a range of diseases and conditions.

Selected Pharmaceuticals in Different Aquatic Compartments: Part I—Source, Fate and Occurrence

Potential risks associated with releases of human pharmaceuticals into the environment have become an increasingly important issue in environmental health. This concern has been driven by the widespread detection of pharmaceuticals in all aquatic compartments. Therefore, 22 pharmaceuticals, 6 metabolites and transformation products, belonging to 7 therapeutic groups, were selected to perform a systematic review on their source, fate and occurrence in different aquatic compartments, important issues to tackle the Water Framework Directive (WFD). The results obtained evidence that concentrations of pharmaceuticals are present, in decreasing order, in wastewater influents (WWIs), wastewater effluents (WWEs) and surface waters, with values up to 14 mg L−1 for ibuprofen in WWIs. The therapeutic groups which presented higher detection frequencies and concentrations were anti-inflammatories, antiepileptics, antibiotics and lipid regulators. These results present a broad and specialized background, enabling a complete overview on the occurrence of pharmaceuticals in the aquatic compartments.