The Complex Tail of Circulating Sphingolipids in Atherosclerosis and Cardiovascular Disease

Zelnik Iris D.,김지윤,Futerman Anthony H. 한국지질동맥경화학회 2021 지질·동맥경화학회지 Vol.10 No.3

Sphingolipids (SLs) are critical players in a number of cellular processes and have recently been implicated in a large number of human diseases, including atherosclerosis and cardiovascular disease (CVD). SLs are generated intracellularly in a stepwise manner, starting with the generation of the sphingoid long chain base (LCB), followed by N-acylation of the LCB to form ceramide, which can be subsequently metabolized to sphingomyelin and glycosphingolipids. Fatty acids, which are taken up by cells prior to their activation to fatty acyl-CoAs, are used in 2 of these enzymatic steps, including by ceramide synthases, which use fatty acyl-CoAs of different chain lengths to generate ceramides with different N-acyl chain lengths. Recently, alterations in plasma ceramides with specific N-acyl chain lengths and degrees of saturation have emerged as novel biomarkers for the prediction of atherosclerosis and overall cardiovascular risk in the general population. We briefly review the sources of plasma SLs in atherosclerosis, the roles of SLs in CVD, and the possible use of the “ceramide score” as a prognostic marker for CVD.

Ceramide synthases as potential targets for therapeutic intervention in human diseases

Park, Joo-Won,Park, Woo-Jae,Futerman, Anthony H. Elsevier 2014 Biochimica et biophysica acta, Molecular and cell Vol.1841 No.5

<P>Ceramide is located at a key hub in the sphingolipid metabolic pathway and also acts as an important cellular signaling molecule. Ceramide contains one acyl chain which is attached to a sphingoid long chain base via an amide bond, with the acyl chain varying in length and degree of saturation. The identification of a family of six mammalian ceramide synthases (CerS) that synthesize ceramide with distinct acyl chains, has led to significant advances in our understanding of ceramide biology, including further delineation of the role of ceramide in various pathophysiologies in both mice and humans. Since ceramides, and the complex sphingolipids generated from ceramide, are implicated in disease, the CerS might potentially be novel targets for therapeutic intervention in the diseases in which the ceramide acyl chain length is altered. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology. (C) 2013 Elsevier B.V. All rights reserved.</P>

Ablation of very long acyl chain sphingolipids causes hepatic insulin resistance in mice due to altered detergent‐resistant membranes

Park, Joo‐,Won,Park, Woo‐,Jae,Kuperman, Yael,Boura‐,Halfon, Sigalit,Pewzner‐,Jung, Yael,Futerman, Anthony H. Wiley Subscription Services, Inc., A Wiley Company 2013 Hepatology Vol.57 No.2

<P><B>Abstract</B></P><P>Sphingolipids are important structural components of cell membranes and act as critical regulators of cell function by modulating intracellular signaling pathways. Specific sphingolipids, such as ceramide, glucosylceramide, and ganglioside GM3, have been implicated in various aspects of insulin resistance, because they have been shown to modify several steps in the insulin signaling pathway, such as phosphorylation of either protein kinase B (Akt) or of the insulin receptor. We now explore the role of the ceramide acyl chain length in insulin signaling by using a ceramide synthase 2 (CerS2) null mouse, which is unable to synthesize very long acyl chain (C22‐C24) ceramides. CerS2 null mice exhibited glucose intolerance despite normal insulin secretion from the pancreas. Both insulin receptor and Akt phosphorylation were abrogated in liver, but not in adipose tissue or in skeletal muscle. The lack of insulin receptor phosphorylation in liver correlated with its inability to translocate into detergent‐resistant membranes (DRMs). Moreover, DRMs in CerS2 null mice displayed properties significantly different from those in wild‐type mice, suggesting that the altered sphingolipid acyl chain length directly affects insulin receptor translocation and subsequent signaling. <I>Conclusion:</I> We conclude that the sphingolipid acyl chain composition of liver regulates insulin signaling by modifying insulin receptor translocation into membrane microdomains. (H<SMALL>EPATOLOGY</SMALL> 2013)</P>

Hepatic triglyceride accumulation via endoplasmic reticulum stress-induced SREBP-1 activation is regulated by ceramide synthases

Ye-Ryung Kim,이은지,Kyong-Oh Shin,김민희,Yael Pewzner-Jung,Yong-Moon Lee,박주원,Anthony H. Futerman,Woo-Jae Park 생화학분자생물학회 2019 Experimental and molecular medicine Vol.51 No.-

The endoplasmic reticulum (ER) is not only important for protein synthesis and folding but is also crucial for lipid synthesis and metabolism. In the current study, we demonstrate an important role of ceramide synthases (CerS) in ER stress and NAFLD progression. Ceramide is important in sphingolipid metabolism, and its acyl chain length is determined by a family of six CerS in mammals. CerS2 generates C22-C24 ceramides, and CerS5 or CerS6 produces C16 ceramide. To gain insight into the role of CerS in NAFLD, we used a high-fat diet (HFD)-induced NAFLD mouse model. Decreased levels of CerS2 and increased levels of CerS6 were observed in the steatotic livers of mice fed a HFD. In vitro experiments with Hep3B cells indicated the protective role of CerS2 and the detrimental role of CerS6 in the ER stress response induced by palmitate treatment. In particular, CerS6 overexpression increased sterol regulatory elementbinding protein-1 (SREBP-1) cleavage with decreased levels of INSIG-1, leading to increased lipogenesis. Blocking ER stress abrogated the detrimental effects of CerS6 on palmitate-induced SREBP-1 cleavage. In accordance with the protective role of CerS2 in the palmitate-induced ER stress response, CerS2 knockdown enhanced ER stress and SREBP1 cleavage, and CerS2 heterozygote livers exhibited a stronger ER stress response and higher triglyceride levels following HFD. Finally, treatment with a low dose of bortezomib increased hepatic CerS2 expression and protected the development of NAFLD following HFD. These results indicate that CerS and its derivatives impact hepatic ER stress and lipogenesis differently and might be therapeutic targets for NAFLD.

Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle via KC _a 1.1 upregulation

Choi, Shinkyu,Kim, Ji Aee,Kim, Tae Hun,Li, Hai‐,yan,Shin, Kyong‐,Oh,Lee, Yong‐,Moon,Oh, Seikwan,Pewzner‐,Jung, Yael,Futerman, Anthony H.,Suh, Suk Hyo BLACKWELL PUBLISHING 2015 AGING CELL Vol.14 No.6

<P><B>Summary</B></P><P>KC<SUB>a</SUB>1.1 regulates smooth muscle contractility by modulating membrane potential, and age‐associated changes in KC<SUB>a</SUB>1.1 expression may contribute to the development of motility disorders of the gastrointestinal tract. Sphingolipids (SLs) are important structural components of cellular membranes whose altered composition may affect KC<SUB>a</SUB>1.1 expression. Thus, in this study, we examined whether altered SL composition due to aging may affect the contractility of gastric smooth muscle (GSM). We studied changes in ceramide synthases (CerS) and SL levels in the GSM of mice of varying ages and compared them with those in young CerS2‐null mice. The levels of C16‐ and C18‐ceramides, sphinganine, sphingosine, and sphingosine 1‐phosphate were increased, and levels of C22, C24:1 and C24 ceramides were decreased in the GSM of both aged wild‐type and young CerS2‐null mice. The altered SL composition upregulated KC<SUB>a</SUB>1.1 and increased KC<SUB>a</SUB>1.1 currents, while no change was observed in KC<SUB>a</SUB>1.1 channel activity. The upregulation of KC<SUB>a</SUB>1.1 impaired intracellular Ca2+ mobilization and decreased phosphorylated myosin light chain levels, causing GSM contractile dysfunction. Additionally, phosphoinositide 3‐kinase, protein kinase C<SUB>ζ</SUB>, c‐Jun N‐terminal kinases, and nuclear factor kappa‐B were found to be involved in KC<SUB>a</SUB>1.1 upregulation. Our findings suggest that age‐associated changes in SL composition or CerS2 ablation upregulate KC<SUB>a</SUB>1.1 via the phosphoinositide 3‐kinase/protein kinase C<SUB>ζ</SUB>/c‐Jun N‐terminal kinases/nuclear factor kappa‐B‐mediated pathway and impair Ca2+ mobilization, which thereby induces the contractile dysfunction of GSM. CerS2‐null mice exhibited similar effects to aged wild‐type mice; therefore, CerS2‐null mouse models may be utilized for investigating the pathogenesis of aging‐associated motility disorders.</P>

Ablation of Ceramide Synthase 2 Causes Chronic Oxidative Stress Due to Disruption of the Mitochondrial Respiratory Chain

Zigdon, Hila,Kogot-Levin, Aviram,Park, Joo-Won,Goldschmidt, Ruth,Kelly, Samuel,Merrill Jr., Alfred H.,Scherz, Avigdor,Pewzner-Jung, Yael,Saada, Ann,Futerman, Anthony H. American Society for Biochemistry and Molecular Bi 2013 The Journal of biological chemistry Vol.288 No.7

K _Ca 3.1 upregulation preserves endothelium‐dependent vasorelaxation during aging and oxidative stress

Choi, Shinkyu,Kim, Ji Aee,Li, Hai‐,yan,Shin, Kyong‐,Oh,Oh, Goo Taeg,Lee, Yong‐,Moon,Oh, Seikwan,Pewzner‐,Jung, Yael,Futerman, Anthony H.,Suh, Suk Hyo BLACKWELL PUBLISHING 2016 AGING CELL Vol.15 No.5

<P><B>Summary</B></P><P>Endothelial oxidative stress develops with aging and reactive oxygen species impair endothelium‐dependent relaxation (EDR) by decreasing nitric oxide (NO) availability. Endothelial K<SUB>Ca</SUB>3.1, which contributes to EDR, is upregulated by H<SUB>2</SUB>O<SUB>2</SUB>. We investigated whether K<SUB>Ca</SUB>3.1 upregulation compensates for diminished EDR to NO during aging‐related oxidative stress. Previous studies identified that the levels of ceramide synthase 5 (CerS5), sphingosine, and sphingosine 1‐phosphate were increased in aged wild‐type and CerS2 mice. In primary mouse aortic endothelial cells (MAECs) from aged wild‐type and CerS2 null mice, superoxide dismutase (SOD) was upregulated, and catalase and glutathione peroxidase 1 (GPX1) were downregulated, when compared to MAECs from young and age‐matched wild‐type mice. Increased H<SUB>2</SUB>O<SUB>2</SUB> levels induced Fyn and extracellular signal‐regulated kinases (ERKs) phosphorylation and K<SUB>Ca</SUB>3.1 upregulation. Catalase/GPX1 double knockout (catalase<SUP>−/−</SUP>/GPX1<SUP>−/−</SUP>) upregulated K<SUB>Ca</SUB>3.1 in MAECs. NO production was decreased in aged wild‐type, CerS2 null, and catalase<SUP>−/−</SUP>/GPX1<SUP>−/−</SUP>MAECs. However, K<SUB>Ca</SUB>3.1 activation‐induced, NG‐nitro‐<SMALL>L</SMALL>‐arginine‐, and indomethacin‐resistant EDR was increased without a change in acetylcholine‐induced EDR in aortic rings from aged wild‐type, CerS2 null, and catalase<SUP>−/−</SUP>/GPX1<SUP>−/−</SUP> mice. CerS5 transfection or exogenous application of sphingosine or sphingosine 1‐phosphate induced similar changes in levels of the antioxidant enzymes and upregulated K<SUB>Ca</SUB>3.1. Our findings suggest that, during aging‐related oxidative stress, SOD upregulation and downregulation of catalase and GPX1, which occur upon altering the sphingolipid composition or acyl chain length, generate H<SUB>2</SUB>O<SUB>2</SUB> and thereby upregulate K<SUB>Ca</SUB>3.1 expression and function via a H<SUB>2</SUB>O<SUB>2</SUB>/Fyn‐mediated pathway. Altogether, enhanced K<SUB>Ca</SUB>3.1 activity may compensate for decreased NO signaling during vascular aging.</P>