1.
The roles of lipids in SARS-CoV-2 viral replication and the host immune response.
Theken, KN, Tang, SY, Sengupta, S, FitzGerald, GA
Journal of lipid research. 2021;:100129
Abstract
The significant morbidity and mortality associated with severe acute respiratory syndrome coronavirus 2 infection has underscored the need for novel antiviral strategies. Lipids play essential roles in the viral life cycle. The lipid composition of cell membranes can influence viral entry by mediating fusion or affecting receptor conformation. Upon infection, viruses can reprogram cellular metabolism to remodel lipid membranes and fuel the production of new virions. Furthermore, several classes of lipid mediators, including eicosanoids and sphingolipids, can regulate the host immune response to viral infection. Here, we summarize the existing literature on the mechanisms through which these lipid mediators may regulate viral burden in COVID-19. Furthermore, we define the gaps in knowledge and identify the core areas in which lipids offer therapeutic promise for severe acute respiratory syndrome coronavirus 2.
2.
Folliculin - A tumor suppressor at the intersection of metabolic signaling and membrane traffic.
Dodding, MP
Small GTPases. 2017;(2):100-105
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Abstract
The Birt-Hoge-Dubé syndrome tumor suppressor Folliculin is a regulator of metabolism and has as a wide range of cellular and organismal phenotypes associated with its disruption. However, the molecular mechanisms which underlie its functions are poorly understood. Folliculin has been described to associate with lysosomes in response to nutrient depletion and form a key part of the signaling network that controls the activity of mTORC1. We recently reported that Folliculin can control the nutrient dependent cytoplasmic distribution of lysosomes by promoting the formation of a complex with the Golgi-associated small GTPase Rab34 and its effector RILP. We thus define a mechanistic connection between the lysosomal nutrient signaling network and the transport machinery that controls the distribution and dynamics of this organelle. Here we summarise the main conclusions from that study, attempt to integrate our findings with other recent studies on lysosome distribution/dynamics, and discuss the potential consequences of the dysregulation of this processes caused by Folliculin loss for Birt-Hoge-Dubé syndrome and normal cell function.
3.
Association of lipidome remodeling in the adipocyte membrane with acquired obesity in humans.
Pietiläinen, KH, Róg, T, Seppänen-Laakso, T, Virtue, S, Gopalacharyulu, P, Tang, J, Rodriguez-Cuenca, S, Maciejewski, A, Naukkarinen, J, Ruskeepää, AL, et al
PLoS biology. 2011;(6):e1000623
Abstract
Identification of early mechanisms that may lead from obesity towards complications such as metabolic syndrome is of great interest. Here we performed lipidomic analyses of adipose tissue in twin pairs discordant for obesity but still metabolically compensated. In parallel we studied more evolved states of obesity by investigating a separated set of individuals considered to be morbidly obese. Despite lower dietary polyunsaturated fatty acid intake, the obese twin individuals had increased proportions of palmitoleic and arachidonic acids in their adipose tissue, including increased levels of ethanolamine plasmalogens containing arachidonic acid. Information gathered from these experimental groups was used for molecular dynamics simulations of lipid bilayers combined with dependency network analysis of combined clinical, lipidomics, and gene expression data. The simulations suggested that the observed lipid remodeling maintains the biophysical properties of lipid membranes, at the price, however, of increasing their vulnerability to inflammation. Conversely, in morbidly obese subjects, the proportion of plasmalogens containing arachidonic acid in the adipose tissue was markedly decreased. We also show by in vitro Elovl6 knockdown that the lipid network regulating the observed remodeling may be amenable to genetic modulation. Together, our novel approach suggests a physiological mechanism by which adaptation of adipocyte membranes to adipose tissue expansion associates with positive energy balance, potentially leading to higher vulnerability to inflammation in acquired obesity. Further studies will be needed to determine the cause of this effect.
4.
Inactivity-mediated insulin resistance is associated with upregulated pro-inflammatory fatty acids in human cell membranes.
Mazzucco, S, Agostini, F, Biolo, G
Clinical nutrition (Edinburgh, Scotland). 2010;(3):386-90
Abstract
BACKGROUND & AIMS Low-grade systemic inflammation and pro-inflammatory pattern of cell membrane fatty acid composition characterize patients affected by type 2 diabetes and metabolic syndrome. We hypothesize that inactivity-induced insulin resistance could affect levels of pro-inflammatory fatty acids in cell membranes. METHODS Thirty healthy, male, young volunteers were investigated before and after 35-day experimental bed rest. Diet composition was adapted to previous dietary habits. Fatty acid composition of erythrocyte membranes was analyzed by gas-chromatography using flame ionization detector. RESULTS Following bed rest, the HOMA index of insulin resistance significantly increased by +51+/-11% (P<0.01). Bed rest was associated with increased n-6 polyunsaturated (+4.7+/-2.2%; P<0.01) and decreased monounsaturated (-4.8+/-1.5%; P<0.01) fatty acid content in erythrocyte membranes. Fractional content of arachidonic acid increased by +14+/-12% (P=0.01) following inactivity. Delta5 and Delta9 desaturase indexes, as estimated from product-to-precursor ratios, significantly diminished following bed rest from 9.6+/-0.4 to 8.4+/-0.3 (P<0.001) and from 0.72+/-0.02 to 0.69+/-0.01 (P<0.05), respectively. The n-3 fatty acids, alpha-linolenic and eicosapentaenoic, were decreased (P=0.05) following inactivity by 4.7+/-13.2% and 3.8+/-5.2%, respectively. CONCLUSIONS Inactivity-mediated insulin resistance was associated with altered Delta5 and Delta9 desaturase indexes and with pro-inflammatory fatty acid pattern in erythrocyte membranes. These abnormalities could contribute to the low-grade inflammation associated to inactivity.