Systematic mapping of genetic interactions for de novo fatty acid synthesis identifies C12orf49 as a regulator of lipid metabolism

We determined the effects of leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) on lipid metabolism in intact rats. Administration of LIF and CNTF increased serum triglycerides in a dose-dependent manner with peak values at 2 h. The effects of LIF and CNTF on serum cholesterol were very small, and serum glucose was unaffected. Both LIF and CNTF stimulated hepatic triglyceride secretion, hepatic de novo fatty acid synthesis, and lipolysis. Pretreatment with phenylisopropyl adenosine, which inhibits lipolysis, partially inhibited LIF- and CNTF-induced hypertriglyceridemia. Interleukin-4, which inhibits cytokine-induced hepatic fatty acid synthesis, also partially inhibited LIF- and CNTF-induced hypertriglyceridemia. These results indicate that both lipolysis and de novo fatty acid synthesis play a role in providing fatty acids for the increase in hepatic triglyceride secretion. Neither indomethacin nor adrenergic receptor antagonists affected the hypertriglyceridemia. The combination of LIF plus CNTF showed no additive effects consistent with the action of both cytokines through the gp130 transduction system. Thus LIF and CNTF have similar effects on lipid metabolism; they join a growing list of cytokines that stimulate hepatic triglyceride secretion and may mediate the changes in lipid metabolism that accompany the acute phase response.

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Systematic mapping of genetic interactions for de novo fatty acid synthesis

10.1101/834721 ◽

2019 ◽

Author(s):

Michael Aregger ◽

Keith A. Lawson ◽

Maximillian Billmann ◽

Michael Costanzo ◽

Amy H. Y. Tong ◽

...

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Synthesis ◽

De Novo ◽

Strong Dependence ◽

Acid Synthesis ◽

Protein Glycosylation ◽

Genetic Interactions ◽

Lipid Uptake ◽

Functional Relationships

ABSTRACTThe de novo synthesis of fatty acids has emerged as a therapeutic target for various diseases including cancer. While several translational efforts have focused on direct perturbation of de novo fatty acid synthesis, only modest responses have been associated with mono-therapies. Since cancer cells are intrinsically buffered to combat metabolic stress, cells may adapt to loss of de novo fatty acid biosynthesis. To explore cellular response to defects in fatty acid synthesis, we used pooled genome-wide CRISPR screens to systematically map genetic interactions (GIs) in human HAP1 cells carrying a loss-of-function mutation in FASN, which catalyzes the formation of long-chain fatty acids. FASN mutant cells showed a strong dependence on lipid uptake that was reflected by negative GIs with genes involved in the LDL receptor pathway, vesicle trafficking, and protein glycosylation. Further support for these functional relationships was derived from additional GI screens in query cell lines deficient for other genes involved in lipid metabolism, including LDLR, SREBF1, SREBF2, ACACA. Our GI profiles identified a potential role for a previously uncharacterized gene LUR1 (C12orf49) in exogenous lipid uptake regulation. Overall, our data highlights the genetic determinants underlying the cellular adaptation associated with loss of de novo fatty acid synthesis and demonstrate the power of systematic GI mapping for uncovering metabolic buffering mechanisms in human cells.

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Taurine-Mediated IDOL Contributes to Resolution of Streptococcus uberis Infection

Infection and Immunity ◽

10.1128/iai.00788-20 ◽

2021 ◽

Vol 89 (5) ◽

Author(s):

Zhixin Wan ◽

Riguo Lan ◽

Yilin Zhou ◽

Yuanyuan Xu ◽

Zhenglei Wang ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Synthesis ◽

De Novo ◽

Bacterial Load ◽

Critical Role ◽

Acid Synthesis ◽

Content Type ◽

Streptococcus Uberis

ABSTRACT Metabolic alterations occur in pathogenic infections, but the role of lipid metabolism in the progression of bacterial mastitis is unclear. Cross talk between lipid droplets (LDs) and invading bacteria occurs, and targeting of de novo lipogenesis inhibits pathogen reproduction. In this study, we investigate the role(s) of lipid metabolism in mammary cells during Streptococcus uberis infection. Our results indicate that S. uberis induces the synthesis of fatty acids and production of LDs. Importantly, taurine reduces fatty acid synthesis, the abundance of LDs and the in vitro bacterial load of S. uberis. These changes are mediated, at least partly, by the E3 ubiquitin ligase IDOL, which is associated with the degradation of low-density lipoprotein receptors (LDLRs). We have identified a critical role for IDOL-mediated fatty acid synthesis in bacterial infection, and we suggest that taurine may be an effective prophylactic or therapeutic strategy for preventing S. uberis mastitis.

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Conjugated Linoleic Acid (t-10, c-12) Reduces Fatty Acid Synthesis de Novo, but not Expression of Genes for Lipid Metabolism in Bovine Adipose Tissue ex Vivo

Lipids ◽

10.1007/s11745-013-3869-0 ◽

2013 ◽

Vol 49 (1) ◽

pp. 15-24 ◽

Cited By ~ 14

Author(s):

Seong Ho Choi ◽

David T. Silvey ◽

Bradley J. Johnson ◽

Matthew E. Doumit ◽

Ki Yong Chung ◽

...

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Lipid Metabolism ◽

Linoleic Acid ◽

Conjugated Linoleic Acid ◽

Fatty Acid Synthesis ◽

De Novo ◽

Ex Vivo ◽

Acid Synthesis ◽

Expression Of Genes

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Targeted induction of de novo Fatty acid synthesis enhances MDV replication in a COX-2/PGE2α dependent mechanism through EP2 and EP4 receptors engagement

10.1101/323840 ◽

2018 ◽

Cited By ~ 1

Author(s):

Nitish Boodhoo ◽

Nitin Kamble ◽

Benedikt B. Kaufer ◽

Shahriar Behboudi

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Virus Replication ◽

Fatty Acid Synthesis ◽

De Novo ◽

Acid Synthesis ◽

Acid Oxidation ◽

Particle Assembly ◽

Infected Cells ◽

Cox 2

AbstractMany viruses alter de novo Fatty Acid (FA) synthesis pathway, which can increase availability of energy for replication and provide specific cellular substrates for particle assembly. Marek’s disease virus (MDV) is a herpesvirus that causes deadly lymphoma and has been linked to alterations of lipid metabolism in MDV-infected chickens. However, the role of lipid metabolism in MDV replication is largely unknown. We demonstrate here that infection of primary chicken embryonic fibroblast with MDV activates de novo lipogenesis, which is required for virus replication. In contrast, activation of Fatty Acid Oxidation (FAO) reduced MDV titer, while inhibition of FAO moderately increased virus replication. Thus optimized virus replication occurs if synthetized fatty acids are not used for generation of energy in the infected cells, and they are likely converted to lipid compounds, which are important for virus replication. We showed that infection with MDV activates COX-2/PGE2α pathway and increases the biosynthesis of PGE2α, a lipid mediator generated from arachidonic acid. Inhibition of COX-2 or PGE2α receptors, namely EP2 and EP4 receptors, reduced MDV titer, indicating that COX-2/PGE2α pathway are involved in virus replication. Our data show that the FA synthesis pathway inhibitors reduce COX-2 expression level and PGE2α synthesis in MDV infected cells, arguing that there is a direct link between virus-induced fatty acid synthesis and activation of COX-2/PGE2α pathway. This notion was confirmed by the results showing that PGE2α can restore MDV replication in the presence of the FA synthesis pathway inhibitors. Taken together, our data demonstrate that MDV uses FA synthesis pathway to enhance PGE2α synthesis and promote MDV replication through EP2 and EP4 receptors engagement.

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Synthesis of fatty acids in the perfused mouse liver

Biochemical Journal ◽

10.1042/bj1420611 ◽

1974 ◽

Vol 142 (3) ◽

pp. 611-618 ◽

Cited By ~ 57

Author(s):

D. Michael W. Salmon ◽

Neil L. Bowen ◽

Douglas A. Hems

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Synthesis ◽

De Novo ◽

Saturated Fatty Acids ◽

Carbon Sources ◽

Acid Synthesis ◽

Hepatic Glycogen ◽

Total Rate ◽

Glucose Carbon

1. Fatty acid synthesis de novo was measured in the perfused liver of fed mice. 2. The total rate, measured by the incorporation into fatty acid of3H from3H2O (1–7μmol of fatty acid/h per g of fresh liver), resembled the rate found in the liver of intact mice. 3. Perfusions with l-[U-14C]lactic acid and [U-14C]glucose showed that circulating glucose at concentrations less than about 17mm was not a major carbon source for newly synthesized fatty acid, whereas lactate (10mm) markedly stimulated fatty acid synthesis, and contributed extensive carbon to lipogenesis. 4. The identification of 50% of the carbon converted into newly synthesized fatty acid lends further credibility to the use of3H2O to measure hepatic fatty acid synthesis. 5. The total rate of fatty acid synthesis, and the contribution of glucose carbon to lipogenesis, were directly proportional to the initial hepatic glycogen concentration. 6. The proportion of total newly synthesized lipid that was released into the perfusion medium was 12–16%. 7. The major products of lipogenesis were saturated fatty acids in triglyceride and phospholipid. 8. The rate of cholesterol synthesis, also measured with3H2O, expressed as acetyl residues consumed, was about one-fourth of the basal rate of fatty acid synthesis. 9. These results are discussed in terms of the carbon sources of hepatic newly synthesized fatty acids, and the effect of glucose, glycogen and lactate in stimulating lipogenesis, independently of their role as precursors.

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