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BBA - Molecular and Cell Biology of Lipids (v.1821, #7)

Editorial Board (pp. i).

DNA damage induces down-regulation of UDP-glucose ceramide glucosyltransferase, increases ceramide levels and triggers apoptosis in p53-deficient cancer cells by Teka-Ann S. Haynes; Valery Filippov; Maria Filippova; Jun Yang; Kangling Zhang; Penelope J. Duerksen-Hughes (pp. 943-953).

DNA damaging agents typically induce an apoptotic cascade in which p53 plays a central role. However, absence of a p53-mediated response does not necessarily abrogate programmed cell death, due to the existence of p53-independent apoptotic pathways, such as those mediated by the pro-apoptotic molecule ceramide. We compared ceramide levels before and after DNA damage in human osteosarcoma (U2OS) and colon cancer (HCT116) cells that were either expressing or deficient in p53. When treated with mitomycin C, p53-deficient cells, but not p53-expressing cells, showed a marked increase in ceramide levels. Microarray analysis of genes involved in ceramide metabolism identified acid ceramidase (ASAH1, up-regulated), ceramide glucosyltransferase (UGCG, down-regulated), and galactosylceramidase (GALC, up-regulated) as the three genes most affected. Experiments employing pharmacological and siRNA agents revealed that inhibition of UGCG is sufficient to increase ceramide levels and induce cell death. When inhibition of UGCG and treatment with mitomycin C were combined, p53-deficient, but not p53-expressing cells, showed a significant increase in cell death, suggesting that the regulation of sphingolipid metabolism could be used to sensitize cells to chemotherapeutic drugs.► DNA damaging agents induce both p53-dependent and -independent apoptotic cascades. ► In the absence of p53, DNA damage increases ceramide levels and down-regulates UGCG expression. ► The ability of UGCG to regulate ceramide was confirmed by over-expression and siRNA experiments. ► Inhibition of UGCG sensitizes cancer cells to treatment with a DNA damaging agent.

Keywords: Ceramide; Apoptosis; Ceramide glucosyltransferase; p53; HPV16 E6

Minimally modified low-density lipoprotein induces macrophage endoplasmic reticulum stress via toll-like receptor 4 by Shutong Yao; Nana Yang; Guohua Song; Hui Sang; Hua Tian; Cheng Miao; Ying Zhang; Shucun Qin (pp. 954-963).

Minimally modified low-density lipoprotein (mm-LDL) induces intimal foam cell formation, which is promoted by endoplasmic reticulum stress (ERS), a cross-point to link cellular processes with multiple risk factors that exist in all stages of atherosclerosis. However, it remains unclear whether mm-LDL-induced lipid accumulation in macrophages involves ERS and its underlying mechanisms. We showed that mm-LDL induced the accumulation of lipid droplets in RAW264.7 macrophages with increased free cholesterol in the endoplasmic reticulum, which was markedly attenuated by pretreatment with an antibody against toll-like receptor 4 (TLR4). Additionally, mm-LDL stimulated the transport of Cy3-labeled activating transcription factor 6 (ATF6), a key sensor to the unfolded protein response (UPR), from cytoplasm into nucleus. The expression of phosphorylated inositol-requiring enzyme 1 (p-IRE1), another sensor to the UPR, and its two downstream molecules, X box binding protein 1 and glucose-regulated protein 78 (GRP78), were significantly upregulated by mm-LDL. The alterations induced by mm-LDL were all significantly inhibited by antibodies against TLR4 or CD36. In addition, the upregulation of p-IRE1 and GRP78 and the nuclear translocation of ATF6 induced by mm-LDL were significantly attenuated by TLR4 siRNA. These results suggest that mm-LDL may induce free cholesterol accumulation in the endoplasmic reticulum and subsequently stimulate ERS and activate the UPR signaling pathway mediated by ATF6 and IRE1 in macrophages, a process that is potentially mediated by TLR4.►Mm-LDL induces lipid accumulation in macrophages with increased FC in ER. ►Mm-LDL stimulates ERS mediated by ATF6 and IRE1 in time and dose-dependent manner. ►TLR4 mediates the ERS response induced by mm-LDL.

Keywords: Abbreviations; AS; atherosclerosis; LDL; low-density lipoprotein; mm-LDL; minimally modified LDL; ERS; endoplasmic reticulum stress; ox-LDL; oxidative modified LDL; GRP78; glucose-regulated proteins 78; IRE1; inositol-requiring enzyme 1; ATF6; activating transcription factor 6; TLR4; toll-like receptor 4; XBP1; X-box-binding protein 1; TM; tunicamycin; ECL; enhanced chemiluminescence; CD36; membrane glycoprotein belonging to the class B scavenger receptor family; IOD; integrated optical density; FC; free cholesterol; UPR; unfolded protein responseEndoplasmic reticulum stress; Unfolded protein response; Macrophage; Minimally modified low-density lipoprotein; Toll-like receptor 4

Niemann–Pick C1-Like 1 and cholesterol uptake by Li-Juan Wang; Bao-Liang Song (pp. 964-972).

Niemann–Pick C1-Like 1 (NPC1L1) is a polytopic transmembrane protein responsible for dietary cholesterol and biliary cholesterol absorption. Consistent with its functions, NPC1L1 distributes on the brush border membrane of enterocytes and the canalicular membrane of hepatocytes in humans. As the molecular target of ezetimibe, a hypocholesterolemic drug, its physiological and pathological significance has been recognized and intensively studied for years. Recently, plenty of new findings reveal the molecular mechanism of NPC1L1's role in cholesterol uptake, which may provide new insights on our understanding of cholesterol absorption. In this review, we summarized recent progress in these studies and proposed a working model, hoping to provide new perspectives on the regulation of cholesterol transport and metabolism.► NPC1L1 mediates cholesterol absorption in small intestine and liver. ► NPC1L1 recycles between PM and ERC in response to cholesterol levels. ► The N-terminal domain of NPC1L1 binds cholesterol not phytosterols. ► NPC1L1 and flotillins form cholesterol enriched membrane microdomains. ► Cholesterol is taken up by the endocytosis of these membrane microdomains.

Keywords: Abbreviations; NPC1L1; Niemann–Pick C1-Like 1; LDL; low-density lipoprotein; PM; plasma membrane; ERC; endocytic recycling compartment; NTD; N-terminal domain; NFC; NPC1L1–Flotillin–CholesterolNPC1L1; Cholesterol absorption; Ezetimibe; NPC1; Flotillin; Lipid raft

Effects of CYP7B1-related steroids on androgen receptor activation in different cell lines by Johan Lundqvist; Maria Norlin (pp. 973-979).

The widely expressed steroid hydroxylase CYP7B1 is involved in metabolism of a number of steroids reported to influence estrogen and androgen signaling. Several studies by us and other investigators have linked this enzyme to effects on estrogen receptor activation. In a previous report we examined the effect of CYP7B1-mediated hormone metabolism for estrogen-mediated response in kidney-derived HEK293 cells. In the current study we used an androgen response element (ARE) reporter system to examine androgen-dependent response of some CYP7B1 substrates and CYP7B1-formed metabolites in several cell lines derived from different tissues. The results indicate significantly lower androgen receptor activation by CYP7B1-formed steroid metabolites than by the corresponding steroid substrates, suggesting that CYP7B1-mediated catalysis may decrease some androgenic responses. Thus, CYP7B1-dependent metabolism may be of importance not only for estrogenic signaling but also for androgenic. This finding, that CYP7B1 activity may be a regulator of androgenic signaling by converting AR ligands into less active metabolites, is also supported by real-time RT-PCR experiment where a CYP7B1 substrate, but not the corresponding product, was able to stimulate known androgen-sensitive genes. Furthermore, our data indicate that the effects of some steroids on hormone response element reporter systems are cell line-specific. For instance, despite transfection of the same reporter systems, 5-androstene-3β,17β-diol strongly activates an androgen-dependent response element in prostate cancer cells whereas it elicits only ER-dependent responses in kidney HEK293 cells. Potential roles of cell-specific metabolism or comodulator expression for the observed differences are discussed.► CYP7B1 substrates activate the androgen receptor (AR) in a cell line-specific way. ► Corresponding CYP7B1-formed products are less able to activate AR. ► CYP7B1 substrates but not CYP7B1-formed products stimulate androgen target genes. ► CYP7B1-mediated metabolism may decrease or abolish androgenic signalling.

Keywords: Abbreviations; 3β-Adiol; 5α-androstane-3β,17β-diol; Aene-diol; 5-androstene-3β,17β-diol; Aene-triol; 5-androstene-3β,7α,17β-triol; AR; androgen receptor; ARE; androgen response element; CYP; cytochrome P450; DHEA; dehydroepiandrosterone; DHT; dihydrotestosterone; ELISA; enzyme-linked immunosorbent assay; FKBP5; FK506 binding protein 5; 3β-HSD/KSI; 3β-hydroxysteroid dehydrogenase/ketosteroid isomerase; 17β-HSD; 17β-hydroxysteroid dehydrogenase; 4-MA; 17β-N,N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one; NCoR-1; nuclear receptor co-repressor 1; PSA; prostate-specific antigen; SMRT; nuclear receptor co-repressor 2; SRC-1; human steroid receptor coactivator; SRA; homo sapiens steroid receptor RNA activator; TLC; thin layer chromatographyAndrogen; CYP7B1; Hydroxylation; AR-mediated response; Steroid metabolism

Jacaric acid, a linolenic acid isomer with a conjugated triene system, has a strong antitumor effect in vitro and in vivo by Nahoko Shinohara; Tsuyoshi Tsuduki; Junya Ito; Taro Honma; Ryo Kijima; Soko Sugawara; Tatsuya Arai; Masao Yamasaki; Aya Ikezaki; Marino Yokoyama; Kazuo Nishiyama; Kiyotaka Nakagawa; Teruo Miyazawa; Ikuo Ikeda (pp. 980-988).

In this study, we compared the cytotoxic effects of natural conjugated linolenic acids (CLnAs) on human adenocarcinoma cells (DLD-1) in vitro, with the goal of finding CLnA isomers with strong cytotoxic effects. The antitumor effect of the CLnA with the strongest cytotoxic effect was then examined in mice. The results showed that all CLnA isomers have strong cytotoxic effects on DLD-1 cells, with jacaric acid (JA) having the strongest effect. Examination of the mechanism of cell death showed that CLnAs induce apoptosis in DLD-1 cells via lipid peroxidation. The intracellular levels of incorporated CLnAs were measured to examine the reason for differences in cytotoxic effects. These results showed that JA was taken into cells efficiently. Collectively, these results suggest that the cytotoxic effect of CLnAs is dependent on intracellular incorporation and induction of apoptosis via lipid peroxidation. JA also had a strong preventive antitumor effect in vivo in nude mice into which DLD-1 cells were transplanted. These results suggest that JA can be used as a dietary constituent for prevention of cancer.► Conjugated linolenic acid is a linolenic acid isomer with a conjugated triene system. ► Conjugated linolenic acid had a strong cytotoxic effect in tumor cells. ► Conjugated linolenic acid induced apoptosis via lipid peroxidation. ► Cytotoxic effects of fatty acids were dependent on intracellular incorporation. ► Jacaric acid had a strong preventive antitumor effect in vivo.

Keywords: Abbreviations; BHT; butylated hydroxytoluene; BSA; bovine serum albumin; α-CDA; α-calendic acid; β-CDA; β-calendic acid; CLA; conjugated linoleic acid; CLnA; conjugated linolenic acid; CPA; catalpic acid; α-ESA; α-eleostearic acid; β-ESA; β-eleostearic acid; JA; jacaric acid; LnA; linolenic acid; LOOH; lipid hydroperoxide; PA; punicic acid; TBARS; thiobarbituric acid reactive substances; α-Toc; α-tocopherolConjugated fatty acid; Conjugated linolenic acid; DLD-1; Jacaranda seed oil; Jacaric acid

Density gradient enrichment of Escherichia coli lpxL mutants by David A. Six; Bliss Lambert; Christian R.H. Raetz; William T. Doerrler (pp. 989-993).

We previously described enrichment of conditional Escherichia coli msbA mutants defective in lipopolysaccharide export using Ludox density gradients (Doerrler WT (2007) Appl Environ Microbiol 73; 7992–7996). Here, we use this approach to isolate and characterize temperature-sensitive lpxL mutants. LpxL is a late acyltransferase of the pathway of lipid A biosynthesis (The Raetz Pathway). Sequencing the lpxL gene from the mutants revealed the presence of both missense and nonsense mutations. The missense mutations include several in close proximity to the enzyme's active site or conserved residues (E137K, H132Y, G168D). These data demonstrate that Ludox gradients can be used to efficiently isolate conditional E. coli mutants with defects in lipopolysaccharide biosynthesis and provide insight into the enzymatic mechanism of LpxL.► We use Ludox density enrichment of E. coli mutants to isolate a new collection of LpxL mutants. ► LpxL is a lauroyltransferase involved in lipid A biosynthesis and is required for growth above 33°C. ► The mutants were found to harbor either missense or nonsense mutations in lpxL and produce underacylated lipid A. ► The missense mutations resulted in changes of putative catalytic or conserved amino acids.

Keywords: Abbreviations; LPS; lipopolysaccharide; TLC; thin layer chromatography; Amp; ampicillin; Kan; kanamycinLpxL; Acyltransferase; Lipopolysaccharide; Mutant

Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: Characterization of interaction of NSAIDs with phosphatidylcholine by Lenard M. Lichtenberger; Yong Zhou; Vasanthi Jayaraman; Janice R. Doyen; Roger G. O'Neil; Elizabeth J. Dial; David E. Volk; David G. Gorenstein; Mohan Babu Boggara; Ramanan Krishnamoorti (pp. 994-1002).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most widely consumed pharmaceuticals, yet both the mechanisms involved in their therapeutic actions and side-effects, notably gastrointestinal (GI) ulceration/bleeding, have not been clearly defined. In this study, we have used a number of biochemical, structural, computational and biological systems including; Fourier Transform InfraRed (FTIR). Nuclear Magnetic Resonance (NMR) and Surface Plasmon Resonance (SPR) spectroscopy, and cell culture using a specific fluorescent membrane probe, to demonstrate that NSAIDs have a strong affinity to form ionic and hydrophobic associations with zwitterionic phospholipids, and specifically phosphatidylcholine (PC), that are reversible and non-covalent in nature. We propose that the pH-dependent partition of these potent anti-inflammatory drugs into the phospholipid bilayer, and possibly extracellular mono/multilayers present on the luminal interface of the mucus gel layer, may result in profound changes in the hydrophobicity, fluidity, permeability, biomechanical properties and stability of these membranes and barriers. These changes may not only provide an explanation of how NSAIDs induce surface injury to the GI mucosa as a component in the pathogenic mechanism leading to peptic ulceration and bleeding, but potentially an explanation for a number of (COX-independent) biological actions of this family of pharmaceuticals. This insight also has proven useful in the design and development of a novel class of PC-associated NSAIDs that have reduced GI toxicity while maintaining their essential therapeutic efficacy to inhibit pain and inflammation.► NSAIDs attenuate GI barrier properties by associating with phospholipids. ► NSAID interaction with membrane phospholipids alters cell function. ► NSAIDs affect cell signaling by changing the membrane micro-environment. ► Reduction of GI injury by association of NSAIDs with phosphatidylcholine

Keywords: NSAIDs; Phospholipids; Ulcer; Membrane; Anti-inflammatory; Therapeutics

Impact of endothelial lipase on cellular lipid composition by Monika Riederer; Kofeler Harald Köfeler; Margarete Lechleitner; Michaela Tritscher; Saša Frank (pp. 1003-1011).

Using mass spectrometry (MS), we examined the impact of endothelial lipase (EL) overexpression on the cellular phospholipid (PL) and triglyceride (TG) content of human aortic endothelial cells (HAEC) and of mouse plasma and liver tissue. In HAEC incubated with the major EL substrate, HDL, adenovirus (Ad)-mediated EL overexpression resulted in the generation of various lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) species in cell culture supernatants. While the cellular phosphatidylethanolamine (PE) content remained unaltered, cellular phosphatidylcholine (PC)-, LPC- and TG-contents were significantly increased upon EL overexpression. Importantly, cellular lipid composition was not altered when EL was overexpressed in the absence of HDL. [¹⁴C]-LPC accumulated in EL overexpressing, but not LacZ-control cells, incubated with [¹⁴C]-PC labeled HDL, indicating EL-mediated LPC supply. Exogenously added [¹⁴C]-LPC accumulated in HAEC as well. Its conversion to [¹⁴C]-PC was sensitive to a lysophospholipid acyltransferase (LPLAT) inhibitor, thimerosal. Incorporation of [³H]-Choline into cellular PC was 56% lower in EL compared with LacZ cells, indicating decreased endogenous PC synthesis. In mice, adenovirus mediated EL overexpression decreased plasma PC, PE and LPC and increased liver LPC, LPE and TG content. Based on our results, we conclude that EL not only supplies cells with FFA as found previously, but also with HDL-derived LPC and LPE species resulting in increased cellular TG and PC content as well as decreased endogenous PC synthesis.► Endothelial lipase (EL) was overexpressed in human endothelial cells and in mice. ► EL generated various lysophosphatidyl-choline (LPC) and -ethanolamine (LPE) species. ► EL directly supplied cells with¹⁴C-HDL-derived¹⁴C-LPC. ► EL increased cellular LPC, phosphatidylcholine and triglyceride content. ►In mice, EL increased hepatic triglycerides, LPC and LPE.

Keywords: Abbreviations; EL; endothelial lipase; LPC; lysophosphatidylcholine; 16:0 LPC; palmitoyl-lysophosphatidylcholine; 18:2 LPC; linoleoyl-LPC; 20:4 LPC; arachidonoyl-LPC; 18:1 LPC; oleoyl-LPC; HAEC; human aortic endothelial cells; AA; arachidonic acid; PL; phospholipids; LysoPL; lysophospholipids; HDL; high-density lipoprotein; ATGL; adipose triglyceride lipase; DGAT; diacylglycerol acyltransferase; CT; CTP:phosphocholine cytidylyltransferase; ET; CTP:phosphoethanolamine cytidylyltransferase; LPLATs; lysophospholipid acyltransferases; BSA; bovine serum albumin; FCS; fetal calf serum; MS; mass spectrometryMass spectrometry; Endothelial cell; Lysophospholipid; HDL; Adenovirus

The structure of monoacylglycerol lipase from Bacillus sp. H257 reveals unexpected conservation of the cap architecture between bacterial and human enzymes by Srinivasan Rengachari; Gustavo A. Bezerra; Lina Riegler-Berket; Christian C. Gruber; Christian Sturm; Ulrike Taschler; Andras Boeszoermenyi; Ingrid Dreveny; Robert Zimmermann; Karl Gruber; Monika Oberer (pp. 1012-1021).

Monoacylglycerol lipases (MGLs) catalyse the hydrolysis of monoacylglycerol into free fatty acid and glycerol. MGLs have been identified throughout all genera of life and have adopted different substrate specificities depending on their physiological role. In humans, MGL plays an integral part in lipid metabolism affecting energy homeostasis, signalling processes and cancer cell progression. In bacteria, MGLs degrade short-chain monoacylglycerols which are otherwise toxic to the organism. We report the crystal structures of MGL from the bacterium Bacillus sp. H257 (bMGL) in its free form at 1.2Å and in complex with phenylmethylsulfonyl fluoride at 1.8Å resolution. In both structures, bMGL adopts an α/β hydrolase fold with a cap in an open conformation. Access to the active site residues, which were unambiguously identified from the protein structure, is facilitated by two different channels. The larger channel constitutes the highly hydrophobic substrate binding pocket with enough room to accommodate monoacylglycerol. The other channel is rather small and resembles the proposed glycerol exit hole in human MGL. Molecular dynamics simulation of bMGL yielded open and closed states of the entrance channel and the glycerol exit hole. Despite differences in the number of residues, secondary structure elements, and low sequence identity in the cap region, this first structure of a bacterial MGL reveals striking structural conservation of the overall cap architecture in comparison with human MGL. Thus it provides insight into the structural conservation of the cap amongst MGLs throughout evolution and provides a framework for rationalising substrate specificities in each organism.► First crystal structure of monoacylglycerol lipase from bacterial species. ► Small angle X-ray scattering shows that the protein is a monomer in solution. ► A large hydrophobic channel enables access of the substrate to the active site. ► Molecular dynamic simulations reveal open and closed states of the cap region. ► The cap architecture is conserved on a structural but not on a sequence level.

Keywords: Abbreviations; MGL; monoacylglycerol lipase; bMGL; monoacylglycerol lipase from; Bacillus; sp. H257; hMGL; human monoacylglycerol lipase; PMSF; phenylmethylsulfonyl fluoride; SAXS; small angle X-ray scattering; RMSD; root mean square deviation; SDS-PAGE; sodium dodecyl sulphate polyacrylamide gel electrophoresisMonoacylglycerol lipase; Open conformation; Evolutionary conservation; X-ray crystallography; Molecular dynamics simulation; Small-angle X-ray scattering

NGF blocks polyunsaturated fatty acids biosynthesis in n−3 fatty acid-supplemented PC12 cells by Ora Msika; Annette Brand; Michael A. Crawford; Ephraim Yavin (pp. 1022-1030).

Regulation of polyunsaturated fatty acid (PUFA) biosynthesis in proliferating and NGF-differentiated PC12 pheochromocytoma cells deficient in n−3 docosahexaenoic acid (DHA 22:6n−3) was studied. A dose- and time-dependent increase in eicosapentaenoic acid (EPA, 20:5n−3), docosapentaenoic acid (DPA, 22:5n−3) and DHA in phosphatidylethanolamine (PtdEtn) and phosphatidylserine (PtdSer) glycerophospholipids (GPL) via the elongation/desaturation pathway following alpha-linolenic acid (ALA, 18:3n−3) supplements was observed. That was accompanied by a marked reduction of eicosatrienoic acid (Mead acid 20:3n−9), an index of PUFA deficiency. EPA supplements were equally effective converted to 22:5n−3 and 22:6n−3. On the other hand, supplements of linoleic acid (LNA, 18:2n−6) were not effectively converted into higher n−6 PUFA intermediates nor did they impair elongation/desaturation of ALA. Co-supplements of DHA along with ALA did not interfere with 20:5n−3 biosynthesis but reduced further elongation to 22-hydrocarbon PUFA intermediates. A marked decrease in the newly synthesized 22:5n−3 and 22:6n−3 following ALA or EPA supplements was observed after nerve growth factor (NGF)-induced differentiation. NGF also inhibited the last step in 22:5n−6 formation from LNA. These results emphasize the importance of overcoming n−3 PUFA deficiency and raise the possibility that growth factor regulation of the last step in PUFA biosynthesis may constitute an important feature of neuronal phenotype acquisition.► PC12 cells are deficient in n−3 DHA due to lack of appropriate precursors. ► α-linolenic acid supplements overcome deficiency particularly in aminophospholipids. ► Linoleic acid does not affect α-linolenic acid intermediates biosynthesis. ► Nerve growth factor impairs denovo synthesis of n−3 and n−6 fatty acids metabolites.

Keywords: Abbreviations; ALA; α-linolenic acid (18:3n; −; 3); ARA; arachidonic acid (20:4n; −; 6); DHA; docosahexaenoic acid (22:6n; −; 3); DPA; docosapentaenoic acid (22:5n; −; 3); EPA; eicosapentaenoic acid (20:5n; −; 3); FA; fatty acid; FAME; fatty acid methyl ester; GC; gas chromatography; GPL; glycerophospholipids; LNA; linoleic acid (18:2n; −; 6); NGF; nerve growth factor; PtdEtn; phosphatidylethanolamine; PtdCho; phosphatidylcholine; PtdSer; phosphatidylserine; PUFA; polyunsaturated fatty acids; TLC; thin layer chromatographyDocosahexaenoic acid; Pheochromocytoma cell; Phospholipids; NGF; Lipid metabolism; Polyunsaturated fatty acid

A shift in sphingolipid composition from C24 to C16 increases susceptibility to apoptosis in HeLa cells by Takayuki Sassa; Shota Suto; Yuriko Okayasu; Akio Kihara (pp. 1031-1037).

Sphingolipids, major lipid components of the eukaryotic plasma membrane, have a variety of physiological functions and have been associated with many diseases. They have also been implicated in apoptosis. Sphingolipids are heterogeneous in their acyl chain length, with long-chain (C16) and very long-chain (C24) sphingolipids being predominant in most mammalian tissues. We demonstrate that knockdown of ELOVL1 or CERS2, which catalyze synthesis of C24 acyl-CoAs and C24 ceramide, respectively, drastically reduced C24 sphingolipid levels with a complementary increase in C16 sphingolipids. Under ELOVL1 or CERS2 knockdown conditions, cisplatin-induced apoptosis significantly increased. Enhanced sensitivity to cisplatin-induced apoptosis exhibited close correlation with increases in caspase-3/7 activity. No significant alterations in sphingolipid metabolism such as ceramide generation were apparent with the cisplatin-induced apoptosis, and inhibitors of ceramide generation had no effect on the apoptosis. Apoptosis induced by UV radiation or C6 ceramides also increased in ELOVL1 or CERS2 knockdown cells. Changes in the composition of sphingolipid chain length may affect susceptibility to stimuli-induced apoptosis by affecting the properties of cell membranes, such as lipid microdomain/raft formation.► A shift in sphingolipid composition from C24 to C16 affects apoptosis. ► Increased susceptibility to apoptosis following ELOVL1 or CERS2 knockdown ► Sphingolipid acyl chain length affects apoptosis.

Keywords: Abbreviations; CERS; ceramide synthase; FB; ₁; fumonisin B; ₁; VLCFA; very long-chain fatty acid; X-ALD; X-linked adrenoleukodystrophyCeramide; Sphingolipid; Very long-chain fatty acid; Apoptosis; Cisplatin; Caspase

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