Subunit composition of the mammalian serine-palmitoyltransferase defines the spectrum of straight and methyl-branched long-chain bases

Lone, Museer A.; Hülsmeier, Andreas J.; Saied, Essa M.; Karsai, Gergely; Arenz, Christoph; Eckardstein, Arnold von; Hornemann, Thorsten

doi:10.1073/pnas.2002391117

Cited by 65 publications

(58 citation statements)

References 45 publications

(47 reference statements)

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“…This is consistent with an increase in BAT NEFA oxidation as a response to cold-induced thermogenesis [ 43 , 44 ]. The observation of significant cold-induced concentration changes in most odd-chain NEFA is also of interest given the evolving understanding of odd-chain lipid synthesis and metabolism in humans [ 45 , 46 ]. Previously thought to be strictly prokaryote-derived, it is now recognized that odd-chain fatty acids can be obtained through diet [ 47 ], produced by intestinal microbiota activity [ 48 ], endogenously synthesized from propionic acid, alpha–oxidation of hydroxylated fatty acids or produced from branched chain amino acids [ 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Plasma Docosahexaenoic Acid and Eicosapentaenoic Acid Concentrations Are Positively Associated with Brown Adipose Tissue Activity in Humans

et al. 2020

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Brown adipose tissue (BAT) activation is a possible therapeutic strategy to increase energy expenditure and improve metabolic homeostasis in obesity. Recent studies have revealed novel interactions between BAT and circulating lipid species—in particular, the non-esterified fatty acid (NEFA) and oxylipin lipid classes. This study aimed to identify individual lipid species that may be associated with cold-stimulated BAT activity in humans. A panel of 44 NEFA and 41 oxylipin species were measured using mass-spectrometry-based lipidomics in the plasma of fourteen healthy male participants before and after 90 min of mild cold exposure. Lipid measures were correlated with BAT activity measured via 18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT), along with norepinephrine (NE) concentration (a surrogate marker of sympathetic activity). The study identified a significant increase in total NEFA concentration following cold exposure that was positively associated with NE concentration change. Individually, 33 NEFA and 11 oxylipin species increased significantly in response to cold exposure. The concentration of the omega-3 NEFA, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) at baseline was significantly associated with BAT activity, and the cold-induced change in 18 NEFA species was significantly associated with BAT activity. No significant associations were identified between BAT activity and oxylipins.

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Section: Discussionmentioning

confidence: 99%

Plasma Docosahexaenoic Acid and Eicosapentaenoic Acid Concentrations Are Positively Associated with Brown Adipose Tissue Activity in Humans

et al. 2020

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“…In addition, Lone et al (2020) recently determined the properties and functions of each of the three subunits of SPT-SPTLC1, SPTLC2, and SPTLC3. Interestingly, they discovered a previously undescribed methyl-branched sphingoid base, exclusively produced by the SPTLC3 subunit in humans [22]. Considering that methyl-branched sphingoid bases had thus far only been known to exist in lower-level invertebrates [23], the authors hypothesized that humans may acquire methyl-branched sphingoid bases from their diet or gut microbiota [22].…”

Section: Sphingoid Bases and Simple Derivativesmentioning

confidence: 99%

A Comprehensive Review: Sphingolipid Metabolism and Implications of Disruption in Sphingolipid Homeostasis

Quinville

Deschenes

Ryckman

et al. 2021

IJMS

155

119

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Sphingolipids are a specialized group of lipids essential to the composition of the plasma membrane of many cell types; however, they are primarily localized within the nervous system. The amphipathic properties of sphingolipids enable their participation in a variety of intricate metabolic pathways. Sphingoid bases are the building blocks for all sphingolipid derivatives, comprising a complex class of lipids. The biosynthesis and catabolism of these lipids play an integral role in small- and large-scale body functions, including participation in membrane domains and signalling; cell proliferation, death, migration, and invasiveness; inflammation; and central nervous system development. Recently, sphingolipids have become the focus of several fields of research in the medical and biological sciences, as these bioactive lipids have been identified as potent signalling and messenger molecules. Sphingolipids are now being exploited as therapeutic targets for several pathologies. Here we present a comprehensive review of the structure and metabolism of sphingolipids and their many functional roles within the cell. In addition, we highlight the role of sphingolipids in several pathologies, including inflammatory disease, cystic fibrosis, cancer, Alzheimer’s and Parkinson’s disease, and lysosomal storage disorders.

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“…The elements involved in the most significant focal deletions were CDK11A (chr1p36.33; q=2.4×10-5; occurring in 6 samples), whose loss induces skin carcinogenesis [96]; the LCE cluster (chr1q21.3; q=2.4×10-6; occurring in 4 samples), including genes such as LCE2 and LCE3 , which play a role in maintaining skin barrier function and whose deletion has been associated with psoriasis [97]; and the HLA-D cluster ( HLA-DP , - DQ , and -DR , chr6p21.32; q=2×10-4; occurring in 3 samples), encoding components of major histocompatibility complex (MHC) class II molecules, whose increased expression has been associated with increased cancer immunogenicity and better prognosis in BCC, SCC and melanoma [98–104]. The skin/cancer-related genes in the most significant focally amplified regions worth mentioning are STIM2 (chr4p15.2; q=0.16; occurring in 2 samples) [105], KLRB1/CD161 (chr12p13.31; q=0.007; occurring in 2 samples) [106,107], and SPTLC3 (chr20p12.1 q=0.23; occurring in 2 samples) [108].…”

Section: Resultsmentioning

confidence: 99%

Profile of basal cell carcinoma mutations and copy number alterations - focus on gene-associated noncoding variants

Nawrocka

Galka-Marciniak

Urbanek-Trzeciak

et al. 2021

Preprint

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Basal cell carcinoma (BCC) of the skin is the most common cancer in humans, characterized by the highest mutation rate among cancers, and is mostly driven by mutations in genes involved in the hedgehog pathway. To date, almost all BCC genetic studies have focused exclusively on protein-coding sequences; therefore, the impact of noncoding variants on the BCC genome is unrecognized. In this study, with the use of whole-exome sequencing of 27 tumor/normal pairs of BCC samples, we performed an analysis of somatic mutations in both protein-coding sequences and gene-associated noncoding regions, including 5’UTRs, 3’UTRs, and exon-adjacent intron sequences. Separately, in each region, we performed hotspot identification, mutation enrichment analysis, and cancer driver identification with OncodriveFML. Additionally, we performed a whole-genome copy number alteration analysis with GISTIC2. Of the >80,000 identified mutations, ∼50% were localized in noncoding regions. The results of the analysis generally corroborated the previous findings regarding genes mutated in coding sequences, including PTCH1, TP53, and MYCN, but more importantly showed that mutations were also clustered in specific noncoding regions, including hotspots. Some of the genes specifically mutated in noncoding regions were identified as highly potent cancer drivers, of which BAD had a mutation hotspot in the 3’UTR, DHODH had a mutation hotspot in the Kozak sequence in the 5’UTR, and CHCHD2 frequently showed mutations in the 5’UTR. All of these genes are functionally implicated in cancer-related processes (e.g., apoptosis, mitochondrial metabolism, and de novo pyrimidine synthesis) or the pathogenesis of UV radiation-induced cancers. We also found that the identified BAD and CHCHD2 mutations frequently occur in melanoma but not in other cancers via The Cancer Genome Atlas analysis. Finally, we identified frequent deletion of chr9q, encompassing PTCH1, and unreported frequent copy number gain of chr9p, encompassing the genes encoding the immune checkpoint ligands PD-L1 and PD-L2. In conclusion, this study is the first systematic analysis of coding and noncoding mutations in BCC and provides a strong basis for further analyses of the variants in BCC and cancer in general.Author summaryThe study is the first systematic analysis of both coding and noncoding mutations in basal cell carcinoma (BCC), the most common and the most highly mutated human cancer. Noncoding mutations accounted for ∼50% (∼40K mutations) of all mutations detected by the standard WES approach. Among the genes frequently mutated in noncoding regions are: BAD with a hotspot in the 3’UTR, DHODH with a hotspot in the Kozak sequence, and CHCHD2 with mutations in 5’UTR, all genes functionally related to cell metabolism and apoptosis. Analysis of copy number alterations showed frequent chr9q deletion, encompassing PTCH1 (the key BCC tumor suppressor), and frequent copy number gain of chr9p, encompassing the genes of the immune checkpoint proteins PD-L1 and PD-L2.

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Subunit composition of the mammalian serine-palmitoyltransferase defines the spectrum of straight and methyl-branched long-chain bases

Cited by 65 publications

References 45 publications

Plasma Docosahexaenoic Acid and Eicosapentaenoic Acid Concentrations Are Positively Associated with Brown Adipose Tissue Activity in Humans

Plasma Docosahexaenoic Acid and Eicosapentaenoic Acid Concentrations Are Positively Associated with Brown Adipose Tissue Activity in Humans

A Comprehensive Review: Sphingolipid Metabolism and Implications of Disruption in Sphingolipid Homeostasis

Profile of basal cell carcinoma mutations and copy number alterations - focus on gene-associated noncoding variants

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