Stearoyl-CoA Desaturase-Mediated Monounsaturated Fatty Acid Availability Supports Humoral Immunity

Zhou, Xian; Zhu, Xingxing; Li, Chaofan; Li, Yanfeng; Ye, Zhenqing; Shapiro, Virginia Smith; Copland, John A.; Hitosugi, Taro; Bernlohr, David A.; Sun, Jie; Zeng, Hu

doi:10.1016/j.celrep.2020.108601

Cited by 39 publications

(39 citation statements)

References 58 publications

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“…Consistent with this, careful titrations allowed identification of a mechanism in which mTORC1 inhibition reduced translation of Aicda mRNA into AID protein in B cells via mTORC1 phosphorylation of eIF4 binding protein (4EBP-1) and eukaryotic (translation) initiation factor (eIF)4E [ 94 ]. A recent work on B cells reported that stearoyl-CoA desaturase, a component of biosynthetic pathways that catalyzes desaturation to generate monounsaturated fatty acids (MUFAs), was downstream of mTORC1 [ 143 ]. Supply of MUFAs was essential for B cells during rapid proliferation, but uptake and utilization of these macromolecules from the interstitial spaces appeared to suffice in the absence of synthesis within the B cells.…”

Section: Blasting Off From the Resting Statementioning

confidence: 99%

Supplying the trip to antibody production—nutrients, signaling, and the programming of cellular metabolism in the mature B lineage

et al. 2021

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The COVID pandemic has refreshed and expanded recognition of the vital role that sustained antibody (Ab) secretion plays in our immune defenses against microbes and of the importance of vaccines that elicit Ab protection against infection. With this backdrop, it is especially timely to review aspects of the molecular programming that govern how the cells that secrete Abs arise, persist, and meet the challenge of secreting vast amounts of these glycoproteins. Whereas plasmablasts and plasma cells (PCs) are the primary sources of secreted Abs, the process leading to the existence of these cell types starts with naive B lymphocytes that proliferate and differentiate toward several potential fates. At each step, cells reside in specific microenvironments in which they not only receive signals from cytokines and other cell surface receptors but also draw on the interstitium for nutrients. Nutrients in turn influence flux through intermediary metabolism and sensor enzymes that regulate gene transcription, translation, and metabolism. This review will focus on nutrient supply and how sensor mechanisms influence distinct cellular stages that lead to PCs and their adaptations as factories dedicated to Ab secretion. Salient findings of this group and others, sometimes exhibiting differences, will be summarized with regard to the journey to a distinctive metabolic program in PCs.

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Section: Blasting Off From the Resting Statementioning

confidence: 99%

Supplying the trip to antibody production—nutrients, signaling, and the programming of cellular metabolism in the mature B lineage

et al. 2021

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“…We believe targeting SCD5 is a good strategy to inhibit SCD activity more effectively in the brain and not elsewhere in the body. This is important because of the connection between SCD and MUFAs to proper immune function and other potential negative side effects of broad SCD inhibition ( Meingassner et al, 2013 ; Zhou et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

SCD Inhibition Protects from α-Synuclein-Induced Neurotoxicity But Is Toxic to Early Neuron Cultures

Nicholatos

Groot

Dhokai

et al. 2021

eNeuro

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Here, we report the independent discovery and validation of stearoyl-CoA desaturase (SCD) as a modulator of α-synuclein (αSyn)-induced pathology and toxicity in cell-based Parkinson’s disease (PD) models. We identified SCD as top altered gene from transcriptional profiling in primary neurons exogenously expressing αSyn with the amplified familial PD mutation 3K. Thus, we sought to further explore SCD as a therapeutic target in neurodegeneration. We report that SCD inhibitors are toxic to early human and rat neuron cultures while displaying minimal toxicity to late cultures. The fatty acid product of SCD, oleic acid (OLA), fully rescues this toxicity in early cultures, suggesting on-target toxicity. Furthermore, SCD inhibition rescues αSyn 3K-induced toxicity in late primary neurons. We also confirm that SCD inhibitors reduce formation of αSyn accumulations, while OLA increases these accumulations in an αSyn 3K neuroblastoma model. However, we identify a caveat with this model where αSyn 3K levels can be suppressed by high SCD inhibitor concentrations, obscuring true effect size. Further, we show that both SCD1 or SCD5 knock-down reduce αSyn 3K accumulations and toxicity, making both a putative drug target. Overall, we confirm key findings of published data on SCD inhibition and its benefits in αSyn accumulation and stress models. The differential neurotoxicity induced by SCD inhibition based on neuron culture age must be accounted for when researching SCD in neuron models and has potential clinical implications. Lastly, our gene profiling studies also revealed novel putative genes connected to αSyn neurotoxicity that are worth further study.

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“…Stearoyl-CoA desaturase 1 (SCD1) is the rate-limiting enzyme catalyzing the synthesis of MUFAs . Previous studies performed with SCD1 tissue-specific and global knockout mice have shown the essential function of SCD1 in beige fat biogenesis, glucose uptake, and lipid metabolism. , MUFAs generated by SCD1 provide energy in B cells and prevent excessive autophagy and endoplasmic reticulum (ER) stress, indicating the critical function of SCD1 in humoral immunity . Deficiency of SCD1 expression in mice promoted beige adipogenesis, which made this gene a direct target for obesity treatment .…”

Section: Introductionmentioning

confidence: 99%

“…6,7 MUFAs generated by SCD1 provide energy in B cells and prevent excessive autophagy and endoplasmic reticulum (ER) stress, indicating the critical function of SCD1 in humoral immunity. 8 Deficiency of SCD1 expression in mice promoted beige adipogenesis, which made this gene a direct target for obesity treatment. 6 In ruminants, inhibition of SCD1 expression led to decreased synthesis of fatty acids, specifically in bovine adipocytes.…”

Section: ■ Introductionmentioning

confidence: 99%

Knockout of Stearoyl-CoA Desaturase 1 Decreased Milk Fat and Unsaturated Fatty Acid Contents of the Goat Model Generated by CRISPR/Cas9

Tian

Niu

Luo

et al. 2022

J. Agric. Food Chem.

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Goat milk contains a rich source of nutrients, especially unsaturated fatty acids. However, the regulatory mechanism of milk fat and fatty acid synthesis remains unclear. Stearoyl-CoA desaturase 1 (SCD1) is the key enzyme catalyzing monounsaturated fatty acid synthesis and is essential for milk lipid metabolism. To explore milk lipid synthesis mechanism in vivo, SCD1-knockout goats were generated through CRISPR/Cas9 technology for the first time. SCD1 deficiency did not influence goat growth or serum biochemistry. Plasma phosphatidylcholines increased by lipidomics after SCD1 knockout in goats. Whole-blood RNA-seq indicated alterations in biosynthesis of unsaturated fatty acid synthesis, cAMP, ATPase activity, and Wnt signaling pathways. In SCD1-knockout goats, milk fat percentage and unsaturated fatty acid levels were reduced but other milk components were unchanged. Milk lipidomics revealed decreased triacylglycerols and diacylglycerols levels, and the differential abundance of lipids were enriched in glycerolipid, glycerophospholipids, and thermogenesis metabolism pathways. In milk fat globules, the expression levels of genes related to fatty acid and TAG synthesis including SREBP1 were reduced. ATP content and AMPK activity were promoted, and p-p70S6K protein level was suppressed in SCD1-knockout goat mammary epithelial cells, suggesting that SCD1 affected milk lipid metabolism by influencing AMPK-mTORC1/p70S6K-SREBP1 pathway. The integrative analysis of gene expression levels and lipidomics of milk revealed a crucial role of SCD1 in glycerolipids and glycerophospholipids metabolism pathways. Our observations indicated that SCD1 regulated the synthesis of milk fat and unsaturated fatty acid in goat by affecting lipid metabolism gene expression and lipid metabolic pathways. These findings would be essential for improving goat milk nutritional value which is beneficial to human health.

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Stearoyl-CoA Desaturase-Mediated Monounsaturated Fatty Acid Availability Supports Humoral Immunity

Cited by 39 publications

References 58 publications

Supplying the trip to antibody production—nutrients, signaling, and the programming of cellular metabolism in the mature B lineage

Supplying the trip to antibody production—nutrients, signaling, and the programming of cellular metabolism in the mature B lineage

SCD Inhibition Protects from α-Synuclein-Induced Neurotoxicity But Is Toxic to Early Neuron Cultures

Knockout of Stearoyl-CoA Desaturase 1 Decreased Milk Fat and Unsaturated Fatty Acid Contents of the Goat Model Generated by CRISPR/Cas9

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