A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism

Turner, Nigel; Lim, Xin Ying; Toop, Hamish D.; Osborne, Brenna; Brandon, Amanda E.; Taylor, Elysha N.; Fiveash, Corrine E; Govindaraju, Hemna; Teo, Jonathan D.; McEwen, Holly P.; Couttas, Timothy A.; Butler, Stephen; Das, Abhirup; Kowalski, Greg M.; Bruce, Clinton R.; Hoehn, Kyle L.; Fath, Thomas; Schmitz‐Peiffer, Carsten; Cooney, Gregory J.; Montgomery, Magdalene K; Morris, Jonathan C.; Don, Anthony S.

doi:10.1038/s41467-018-05613-7

Cited by 120 publications

(128 citation statements)

References 76 publications

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“…Treatment of mice with the inhibitor significantly reduced levels of C18-ceramide in skeletal muscle and prevented fat deposition in mice fed a high-fat diet. The decrease in fat deposition correlated with an increase in mitochondrial FAO, implicating C18-ceramide as a regulator of FAO (39). This finding is supported by a recent study demonstrating that targeted reduction of C18-ceramide in skeletal muscle by CerS1 KO significantly improves glucose metabolism and protects against insulin resistance (40).…”

Section: Obesity and Insulin Resistancesupporting

confidence: 67%

Advances in determining signaling mechanisms of ceramide and role in disease

Stith

Velazquez

Obeid

2019

Journal of Lipid Research

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Ceramide is a critical bioactive lipid involved in diverse cellular processes. It has been proposed to regulate cellular processes by influencing membrane properties and by directly interacting with effector proteins. Advances over the past decade have improved our understanding of ceramide as a bioactive lipid. Generation and characterization of ceramide-metabolizing enzyme KO mice, development of specific inhibitors and ceramide-specific antibodies, use of advanced microscopy and mass spectrometry, and design of synthetic ceramide derivatives have all provided insight into the signaling mechanisms of ceramide and its implications in disease. As a result, the role of ceramide in biological functions and disease are now better understood, with promise for development of therapeutic strategies to treat ceramide-regulated diseases.

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Section: Obesity and Insulin Resistancesupporting

confidence: 67%

Advances in determining signaling mechanisms of ceramide and role in disease

Stith

Velazquez

Obeid

2019

Journal of Lipid Research

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“…Notably, medium-chain ceramides (C18:0, C20:0, and C22:0) correlated more positively with BMI, HOMA-IR, and diabetes incidence than other ceramides, regardless of the nature of the sphingoid backbone. This may be due to alterations in the expression or activity of specific ceramide synthase genes, such as CERS1 and CERS4, which are known to generate these ceramide species preferentially (34,35). Furthermore, it is likely that this has functional significance because generation of these ceramides by CERS4 is associated with glucolipotoxicity in pancreatic β cells in vitro (34).…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

Large-scale lipidomics identifies associations between plasma sphingolipids and T2DM incidence

Chew¹,

Torta²,

Ji³

et al. 2019

JCI Insight

113

109

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BACKGROUND. Sphingolipids (SPs) are ubiquitous, structurally diverse molecules that include ceramides, sphingomyelins (SMs), and sphingosines. They are involved in various pathologies, including obesity and type 2 diabetes mellitus (T2DM). Therefore, it is likely that perturbations in plasma concentrations of SPs are associated with disease. Identifying these associations may reveal useful biomarkers or provide insight into disease processes. METHODS. We performed a lipidomics evaluation of molecularly distinct SPs in the plasma of 2302 ethnically Chinese Singaporeans using electrospray ionization mass spectrometry coupled with liquid chromatography. SP profiles were compared to clinical and biochemical characteristics, and subjects were evaluated with follow-up visits for 11 years. RESULTS. We found that ceramides correlated positively but hexosylceramides correlated negatively with BMI and homeostatic model assessment of insulin resistance (HOMA-IR). Furthermore, SPs with a d16:1 sphingoid backbone correlated more positively with BMI and HOMA-IR, while d18:2 SPs correlated less positively, relative to canonical d18:1 SPs. We also found that higher concentrations of 2 distinct SMs were associated with a higher risk of T2DM (HR 1.45 with 95% CI 1.18-1.78 for SM d16:1/18:0 and HR 1.40 with 95% CI 1.17-1.68 for SM d18:1/18:0). CONCLUSIONS. We identified significant associations between SPs and obesity/T2DM characteristics, specifically, those of hexosylceramides, d16:1 SPs, and d18:2 SPs. This suggests that the balance of SP metabolism, rather than ceramide accumulation, is associated with the pathology of obesity. We further identified 2 specific SPs that may represent prognostic biomarkers for T2DM.

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“…CERS1, 4, 5 and 6 have the highest expression in skeletal muscle thus their C-16:0 and C-18:0 ceramide products are the most abundant [34] in the tissue. Coincidentally, these species are also most commonly related to IR [35][36][37], specifically in human skeletal muscle [37][38][39][40][41].…”

Section: Source Of Substrate For Production And/or Accumulation Of Cementioning

confidence: 99%

Influence of Exercise Training on Skeletal Muscle Insulin Resistance in Aging: Spotlight on Muscle Ceramides

Reidy

Mahmassani

McKenzie

et al. 2020

IJMS

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Intramuscular lipid accumulation has been associated with insulin resistance (IR), aging, diabetes, dyslipidemia, and obesity. A substantial body of evidence has implicated ceramides, a sphingolipid intermediate, as potent antagonists of insulin action that drive insulin resistance. Indeed, genetic mouse studies that lower ceramides are potently insulin sensitizing. Surprisingly less is known about how physical activity (skeletal muscle contraction) regulates ceramides, especially in light that muscle contraction regulates insulin sensitivity. The purpose of this review is to critically evaluate studies (rodent and human) concerning the relationship between skeletal muscle ceramides and IR in response to increased physical activity. Our review of the literature indicates that chronic exercise reduces ceramide levels in individuals with obesity, diabetes, or hyperlipidemia. However, metabolically healthy individuals engaged in increased physical activity can improve insulin sensitivity independent of changes in skeletal muscle ceramide content. Herein we discuss these studies and provide context regarding the technical limitations (e.g., difficulty assessing the myriad ceramide species, the challenge of obtaining information on subcellular compartmentalization, and the paucity of flux measurements) and a lack of mechanistic studies that prevent a more sophisticated assessment of the ceramide pathway during increased contractile activity that lead to divergences in skeletal muscle insulin sensitivity.

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A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism

Cited by 120 publications

References 76 publications

Advances in determining signaling mechanisms of ceramide and role in disease

Advances in determining signaling mechanisms of ceramide and role in disease

Large-scale lipidomics identifies associations between plasma sphingolipids and T2DM incidence

Influence of Exercise Training on Skeletal Muscle Insulin Resistance in Aging: Spotlight on Muscle Ceramides

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