Triglycerides Promote Lipid Homeostasis during Hypoxic Stress by Balancing Fatty Acid Saturation

Ackerman, Daniel; Tumanov, Sergey; Qiu, Bo; Michalopoulou, Evdokia; Spata, Michelle; Azzam, Andrew; Xie, Hong; Simon, M. Celeste; Kamphorst, Jurre J.

doi:10.1016/j.celrep.2018.08.015

Cited by 211 publications

(167 citation statements)

References 27 publications

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“…1h) for sequestering FA. Increased acylcarnitine accumulation following DGAT1 inhibition has been reported previously in other cell types 29,30 . However, in MEFs, accumulated acylcarnitines due to DGAT1 inhibition were reported to themselves cause mitochondrial dysfunction 29 .…”

supporting

confidence: 79%

Triacylglycerol synthesis enhances macrophage inflammatory function

Castoldi

Monteiro

Bakker

et al. 2020

Preprint

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Macrophages are integral to most tissues. Foam cells, macrophages with lipid droplets (LDs) which are stores of triacylglycerols (TGs) and cholesterol esters (CEs), are found in various disease states 1 . LDs can act as energy stores since TG lipolysis releases fatty acids (FAs) for mitochondrial oxidation (FAO), a process that relies on long-chain FA conversion into acylcarnitines by the enzyme Cpt1a 2 . However, in macrophages, proinflammatory signals result in diminished FAO and increased TG synthesis with LD development 3,4 . We explored the significance of LDs in cells that do not utilize FAO. We show that macrophages stimulated with lipopolysaccharide (LPS) plus interferon-g (IFNg) accumulate TGs in LDs, and long-chain acylcarnitines. In these cells, inhibition of TG synthesis results in diminished LD development, and increased long chain acylcarnitine levels, suggesting that FA fate is balanced between TG and acylcarnitine synthesis. Nevertheless, TG-synthesis is required for inflammatory macrophage function, since its inhibition negatively affects production of proinflammatory IL-1b, IL-6 and PGE2, and phagocytic capacity, and protects against LPS-induced shock in vivo. Failure to make PGE2 is critical for this phenotype, since exogenous PGE2 reverses the anti-inflammatory effects of TG-synthesis inhibition. These findings place LDs in a position of central functional importance in inflammatory macrophages. EJP and ELP are Founders of Rheos Medicines MethodsMice and in vivo experiments C57BL/6 mice (RRID: IMSR_JAX:000664) were from The Jackson Laboratory, and were maintained in specific pathogen-free conditions under protocols approved by the animal care committee of the Regierungspräsidium Freiburg, Germany, in compliance with all relevant ethical regulations. Animals were 6-8 weeks old when used. They were euthanized by carbon dioxide asphyxiation followed by cervical

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supporting

confidence: 79%

Triacylglycerol synthesis enhances macrophage inflammatory function

Castoldi

Monteiro

Bakker

et al. 2020

Preprint

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“…Therefore, HSPA6 may be involved in the regulation of sheep adipocytes. We also identified many target genes related to lipid deposition, such as ACAA2 [49], SCD [50], FADS2 [51] and PLA2G4E [52]. We further performed GO and KEGG enrichment analysis on these target genes.…”

Section: Discussionmentioning

confidence: 99%

Identification and co-expression analysis of long noncoding RNAs and mRNAs involved in the deposition of intramuscular fat in Aohan fine-wool sheep

Han

Liu

et al. 2020

Preprint

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Background: Intramuscular fat (IMF) content has become one of the most important indicators for measuring meat quality, and its level is affected by various genes. Long non-coding RNAs (lncRNAs) are widely expressed non-coding RNAs that play an important regulatory role in a variety of biological processes; however, research on lncRNAs involved in sheep intramuscular fat deposition is still in its infancy. Aohan fine-wool sheep (AFWS), China's representative meat-hair, dual-purpose sheep breed, provides a great model for studying the role of lncRNAs in the regulation of intramuscular fat deposition. We identified lncRNAs by RNA sequencing in sheep longissimus dorsi muscle(LDM) samples at two ages: 2 months (Mth-2) and 12 months .Results: We identified a total of 26,247 genes and 6,935 predicted novel lncRNAs in LDM samples of sheep. Among these, 606 mRNAs and 408 lncRNAs were differentially expressed. We then compared the structural characteristics of lncRNAs and mRNAs. We obtained targeted genes of differentially expressed lncRNAs and performed an enrichment analysis using Gene Ontology(GO) and the Kyoto Encyclopedia of Genes and Genomes(KEGG). We found these targeted mRNAs were primarily enriched in lipid metabolism, lipid transport, regulation of primary metabolic processes and developmental pathways, such as alpha-linolenic acid metabolism, biosynthesis of unsaturated fatty acids, phosphonate and phosphinate metabolism and cell proliferation. Based on the results of this enrichment analysis, we obtained candidate lncRNAs that potentially regulate lipid deposition and constructed a lncRNA-mRNA co-expression network. We speculated that these lncRNAs have important regulatory roles in intramuscular fat deposition. We randomly selected five mRNAs and five lncRNAs to verify the accuracy of sequencing results by qRT-PCR.Conclusions: Our study provided a list of the lncRNAs and mRNAs related to intramuscular lipid deposition in sheep and lay the foundation for future research on regulatory mechanisms. BackgroundWith improvements in living standards and changes in patterns of consumption, high-quality lamb meat is becoming increasingly popular. Currently, evaluations of the meat quality of livestock have revealed that the content of intramuscular fat (IMF) is lower in carcass fats, yet IMF has a critically 4 important influence on the edibility and flavor of muscle meat [1]. Indeed, the quantity of IMF has become one of the most critical parameters in meat quality indicators, as it is considered to be positively related to meat quality and texture [2,3]. When a certain amount of fat is deposited between the muscle bundles and muscle fibers, the marbled section of the meat has a high score, and the meat is fresh and juicy, which is often considered ideal [4, 5]. The selective deposition of fat can improve production efficiency and play a key role in improving meat quality. This practice is also a major focus and difficulty of modern livestock breeding [6]. Therefore, ensuring the appropriate deposition of IMF in le...

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“…Similar to other solid tumors, ccRCC is primarily driven by loss of key tumor suppressor such as von Hippel-Lindau (VHL) and activation of oncogenes (23)(24)(25). Closely associated with these genetic alterations, lipid metabolic processes are dramatically altered in the ccRCC tumor microenvironment (3,4,(26)(27)(28)(29)(30)(31)(32)(33). In fact, the "clear cell" subtype gets its name from cholesterol ester-rich lipid droplets that accumulate in tumor cells (32,33).…”

Section: Discussionmentioning

confidence: 99%

MBOAT7-Driven Phosphatidylinositol Remodeling Promotes the Progression of Clear Cell Renal Carcinoma

Neumann

Zhang

Silver

et al. 2019

Preprint

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The most common kidney cancer, clear cell Renal Cell Carcinoma (ccRCC) is closely associated with obesity. In fact, the "clear cell" variant of RCC is given this name due to large lipid droplets within the tumor cells. Although it is well appreciated that renal lipid metabolism is altered in ccRCC, the mechanisms driving this are not well understood. Leveraging a shotgun lipidomics approach we have identified a lipid signature for ccRCC that includes an increase in arachidonic acid-enriched phosphatidylinositols (AA-PI). In parallel, we found that ccRCC tumors have increased expression of the acyltransferase enzyme membrane bound O-acyltransferase domain containing 7 (MBOAT7) that contributes to AA-PI synthesis. In ccRCC patients, MBOAT7 expression increases with tumor grade, and increased MBOAT7 expression correlates with poor survival. Genetic deletion of MBOAT7 in ccRCC cells decreases proliferation and induces cell cycle arrest, and MBOAT7 -/cells fail to form tumors in vivo. RNAseq of MBOAT7 -/cells identified alterations in cell migration and extracellular matrix organization, which were functionally validated in migration assays. Our work highlights the accumulation of AA-PI in ccRCC and demonstrate a novel way to decrease the AA-PI pool in ccRCC by limiting MBOAT7. Our data reveal that metastatic ccRCC is associated with altered AA-PI metabolism, and identify MBOAT7 as a novel target in advanced ccRCC.

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Triglycerides Promote Lipid Homeostasis during Hypoxic Stress by Balancing Fatty Acid Saturation

Cited by 211 publications

References 27 publications

Triacylglycerol synthesis enhances macrophage inflammatory function

Triacylglycerol synthesis enhances macrophage inflammatory function

Identification and co-expression analysis of long noncoding RNAs and mRNAs involved in the deposition of intramuscular fat in Aohan fine-wool sheep

MBOAT7-Driven Phosphatidylinositol Remodeling Promotes the Progression of Clear Cell Renal Carcinoma

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