scholarly journals Alterations in cellular lipid metabolism produce neutral lipid accumulation following exposure to the organochlorine compound trans-nonachlor in rat primary hepatocytes

2018 ◽  
Author(s):  
George Eli Howell ◽  
Erin McDevitt ◽  
Lucie Henein ◽  
Charlee Mulligan ◽  
Darian Young
Keyword(s):  
Lipid Metabolism ◽  
Neutral Lipid ◽  
Lipid Accumulation ◽  
Organochlorine Compound ◽  
Cellular Lipid ◽  
Primary Hepatocytes ◽  
Rat Primary Hepatocytes

scholarly journals Identification of novel genes involved in neutral lipid storage by quantitative trait loci analysis of Saccharomyces cerevisiae

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Klavdija Pačnik ◽  
Mojca Ogrizović ◽  
Matthias Diepold ◽  
Tobias Eisenberg ◽  
Mia Žganjar ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Lipid Metabolism ◽  
Quantitative Trait Loci ◽  
Neutral Lipid ◽  
Lipid Content ◽  
Quantitative Trait ◽  
Lipid Accumulation ◽  
Lipid Storage ◽  
Neutral Lipid Content ◽  
Trait Loci

Abstract Background The accumulation of intracellular fat depots is a polygenic trait. Therefore, the extent of lipid storage in the individuals of a species covers a broad range and is determined by many genetic factors. Quantitative trait loci analysis can be used to identify those genetic differences between two strains of the same species that are responsible for the differences in a given phenotype. We used this method and complementary approaches to identify genes in the yeast Saccharomyces cerevisiae that are involved in neutral lipid storage. Results We selected two yeast strains, the laboratory strain BY4741 and the wine yeast AWRI1631, with a more than two-fold difference in neutral lipid content. After crossing, sporulation and germination, we used fluorescence activated cell sorting to isolate a subpopulation of cells with the highest neutral lipid content from the pool of segregants. Whole genome sequencing of this subpopulation and of the unsorted pool of segregants implicated several loci that are involved in lipid accumulation. Three of the identified genes, PIG1, PHO23 and RML2, were investigated in more detail. Deletions of these genes and the exchange of the alleles between the two parental strains confirmed that the encoded proteins contribute to neutral lipid storage in S. cerevisiae and that PIG1, PHO23 and RML2 are the major causative genes. Backcrossing of one of the segregants with the parental strains for seven generations revealed additional regions in the genomes of both strains with potential causative genes for the high lipid accumulation phenotype. Conclusions We identified several genes that contribute to the phenotype of lipid accumulation in an allele-specific manner. Surprisingly, no allelic variations of genes with known functions in lipid metabolism were found, indicating that the level of storage lipid accumulation is determined by many cellular processes that are not directly related to lipid metabolism.

scholarly journals CVB3 Nonstructural 2A Protein Modulates SREBP1a Signaling via the MEK/ERK Pathway

2018 ◽  
Vol 92 (24) ◽  
Author(s):  
Lei Wang ◽  
Wei Xie ◽  
Le Zhang ◽  
Defeng Li ◽  
Hua Yu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Lipid Metabolism ◽  
Signaling Pathway ◽  
Virus Replication ◽  
Lipid Accumulation ◽  
Viral Myocarditis ◽  
Coxsackievirus B3 ◽  
Erk Pathway ◽  
Cellular Lipid ◽  
Cvb3 Infection

ABSTRACT Coxsackievirus B3 (CVB3) is the predominant pathogen of viral myocarditis. In our previous study, we found that CVB3 caused abnormal lipid accumulation in host cells. However, the underlying mechanisms by which CVB3 disrupts and exploits the host lipid metabolism are not well understood. Sterol regulatory element binding protein 1 (SREBP1) is the major transcriptional factor in lipogenic genes expression. In this study, we demonstrated that CVB3 infection and nonstructural 2A protein upregulated and activated SREBP1a at the transcriptional level. Deletion analysis of SREBP1a promoter revealed that two regions, –1821/–1490 and –312/+217, in this promoter were both required for its activation by 2A. These promoter regions possessed several binding motifs for transcription factor SP1. Next, we used SP1-specific small interfering RNAs (siRNAs) to confirm that SP1 might be the essential factor in SREBP1a upregulation by 2A. Furthermore, we showed that MEK/ERK pathway was involved in the activation of SREBP1a by 2A and that blocking this signaling pathway with the specific inhibitor U0126 attenuated SREBP1a activation and lipid accumulation by 2A. Finally, we showed that inhibition of SREBP1 with siRNAs attenuated lipid accumulation induced by CVB3 infection and reduced virus replication. Moreover, inhibition of the MEK/ERK pathway also led to reduction of SREBP1a activation, lipid accumulation, and virus replication during CVB3 infection. Taken together, these data demonstrate that CVB3 nonstructural 2A protein activates SREBP1a at the transcription level through a mechanism involving MEK/ERK signaling pathway and SP1 transcription factor, which promotes cellular lipid accumulation and benefits virus replication.IMPORTANCE Coxsackievirus B3 (CVB3) infection is the leading cause of viral myocarditis, but effective vaccines and antiviral therapies against CVB3 infection are still lacking. It is important to understand the precise interactions between host and virus for the rational design of effective therapies. During infection, CVB3 disrupts and exploits host lipid metabolism to promote excessive lipid accumulation, which benefits virus replication. SREBP1 is the master regulator of cellular lipid metabolism. Here, we report that one of the viral nonstructural proteins, 2A, upregulates and activates SREBP1a. Furthermore, we find that inhibition of SREBP1 decreases CVB3 virus replication. These results reveal the regulation of SREBP1a expression by 2A and the roles of SREBP1 in lipid accumulation and viral replication during CVB3 infection. Our findings provide a new insight into CVB3 host interactions and inform a potential novel therapeutic target for this important pathogen.

scholarly journals Differential modulation of hepatic very low-density lipoprotein secretion by triacylglycerol-rich lipoproteins derived from different oleic-acid rich dietary oils

2007 ◽  
Vol 99 (1) ◽  
pp. 29-36 ◽  
Author(s):  
Javier S. Perona ◽  
Michael Avella ◽  
Kathleen M. Botham ◽  
Valentina Ruiz-Gutierrez
Keyword(s):  
Oleic Acid ◽  
Lipid Accumulation ◽  
Virgin Olive Oil ◽  
Minor Component ◽  
Minor Components ◽  
Primary Hepatocytes ◽  
High Oleic ◽  
Dietary Oils ◽  
Vldl Secretion ◽  
Rat Primary Hepatocytes

Minor components from dietary oils can modulate the atherogenic response of the TAG-rich lipoproteins (TRL) in which they are transported. In the present study we investigated the influence of TRL isolated from man after the intake of oleic acid-rich oils with different minor component compositions on VLDL secretion by rat primary hepatocytes. TRL were isolated from nine men after the intake of meals enriched with high-oleic sunflower oil (HOSO) or virgin olive oil (VOO) or VOO enriched with minor components (EVO). TRL were incubated with rat primary hepatocytes and the lipid accumulation was analysed in the cells and the secreted VLDL. The expression of genes for proteins related to hepatic lipid metabolism and VLDL production was also measured. Incubation of hepatocytes with TRL derived from HOSO as compared to VOO led to lower intracellular lipid accumulation and VLDL production despite higher mRNA expression for diacylglycerol-acyltransferase, microsomal TAG transfer protein, apoB and PPARα. When TRL derived from EVO were used there were no changes in VLDL secretion. These results suggest that incorporation of minor components from dietary high-oleic oils into TRL modulates the effect of these atherogenic particles on VLDL secretion.

scholarly journals How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease?

2021 ◽  
Vol 15 (1) ◽  
pp. 21-35
Author(s):  
Yana Geng ◽  
Klaas Nico Faber ◽  
Vincent E. de Meijer ◽  
Hans Blokzijl ◽  
Han Moshage
Keyword(s):  
Lipid Metabolism ◽  
Liver Disease ◽  
Fatty Liver ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Lipid Uptake ◽  
Cellular Mechanisms ◽  
Alcoholic Fatty Liver ◽  
Lipid Species ◽  
Alcoholic Fatty Liver Disease

Abstract Background Non-alcoholic fatty liver disease (NAFLD), characterized as excess lipid accumulation in the liver which is not due to alcohol use, has emerged as one of the major health problems around the world. The dysregulated lipid metabolism creates a lipotoxic environment which promotes the development of NAFLD, especially the progression from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH). Purposeand Aim This review focuses on the mechanisms of lipid accumulation in the liver, with an emphasis on the metabolic fate of free fatty acids (FFAs) in NAFLD and presents an update on the relevant cellular processes/mechanisms that are involved in lipotoxicity. The changes in the levels of various lipid species that result from the imbalance between lipolysis/lipid uptake/lipogenesis and lipid oxidation/secretion can cause organellar dysfunction, e.g. ER stress, mitochondrial dysfunction, lysosomal dysfunction, JNK activation, secretion of extracellular vesicles (EVs) and aggravate (or be exacerbated by) hypoxia which ultimately lead to cell death. The aim of this review is to provide an overview of how abnormal lipid metabolism leads to lipotoxicity and the cellular mechanisms of lipotoxicity in the context of NAFLD.

scholarly journals The Role of Lipids, Lipid Metabolism and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair after CNS Injury and Disease

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1078
Author(s):  
Debasish Roy ◽  
Andrea Tedeschi
Keyword(s):  
Nervous System ◽  
Lipid Metabolism ◽  
Lipid Accumulation ◽  
Axon Regeneration ◽  
Axon Growth ◽  
The Body ◽  
Cns Repair ◽  
Cord Injury ◽  
Cns Trauma

Axons in the adult mammalian nervous system can extend over formidable distances, up to one meter or more in humans. During development, axonal and dendritic growth requires continuous addition of new membrane. Of the three major kinds of membrane lipids, phospholipids are the most abundant in all cell membranes, including neurons. Not only immature axons, but also severed axons in the adult require large amounts of lipids for axon regeneration to occur. Lipids also serve as energy storage, signaling molecules and they contribute to tissue physiology, as demonstrated by a variety of metabolic disorders in which harmful amounts of lipids accumulate in various tissues through the body. Detrimental changes in lipid metabolism and excess accumulation of lipids contribute to a lack of axon regeneration, poor neurological outcome and complications after a variety of central nervous system (CNS) trauma including brain and spinal cord injury. Recent evidence indicates that rewiring lipid metabolism can be manipulated for therapeutic gain, as it favors conditions for axon regeneration and CNS repair. Here, we review the role of lipids, lipid metabolism and ectopic lipid accumulation in axon growth, regeneration and CNS repair. In addition, we outline molecular and pharmacological strategies to fine-tune lipid composition and energy metabolism in neurons and non-neuronal cells that can be exploited to improve neurological recovery after CNS trauma and disease.

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