Sphingolipids and Metabolic Disease

Cowart, L. Ashley

doi:10.1007/978-1-4614-0650-1

Advances in Experimental Medicine and Biology

2011

DOI: 10.1007/978-1-4614-0650-1

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Sphingolipids and Metabolic Disease

L. Ashley Cowart¹

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Cited by 11 publications

(1 citation statement)

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“…To date, many studies on sphingolipids have been conducted on the yeast Saccharomyces cerevisiae, in which sphingolipids comprise approximately 30% of the total plasmalemma (Patton & Lester, 1991). In the mammalian human body, various disorders can occur due to abnormal expressions resulted from either more or less sphingolipids such as very harmful neurological disorders, fatty material coalescence and Fabry's disease, all are well-known sphingolipid-related diseases (Brice & Cowart, 2011;Kolter & Sandhoff, 2006).…”

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confidence: 99%

A sphingolipid synthesis‐related protein OrmA in Aspergillus fumigatus is responsible for azole susceptibility and virulence

Zhai

Song

Gao

et al. 2019

Cellular Microbiology

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Previous studies identified that the budding yeast Saccharomyces cerevisiae have two sphingolipid synthesis‐related proteins, Orm1p and Orm2p, that negatively regulate the activities of SPT, which is a key rate‐limiting enzyme in sphingolipid synthesis. However, little is known about whether sphingolipids in the cell membrane, which are closely related to ergosterols, could affect the efficacy of azole drugs, which target to the ergosterol biosynthesis. In this study, through genome‐wide homologue search analysis, we found that the Aspergillus fumigatus genome only contains one Orm homologue, referred to as OrmA for which the protein expression could be induced by azole antifungals in a dose‐dependent manner. Deletion of ormA caused hypersensitivity to azoles, and adding the sphingolipid synthesis inhibitor myriocin rescued the azole susceptibility induced by lack of ormA. In contrast, overexpression of OrmA resulted in azole resistance, indicating that OrmA is a positive azole‐response regulator. Further mechanism analysis verified that OrmA is related to drug susceptibility by affecting endoplasmic reticulum stress responses in an unfolded protein response pathway‐HacA‐dependent manner. Lack of ormA led to an abnormal profile of sphingolipid ceramide components accompanied by hypersensitivity to low temperatures. Furthermore, deletion of OrmA significantly reduced virulence in an immunosuppressed mouse model. The findings in this study collectively suggest that the sphingolipid metabolism pathway in A. fumigatus plays a critical role in azole susceptibility and fungal virulence.

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mentioning

confidence: 99%

A sphingolipid synthesis‐related protein OrmA in Aspergillus fumigatus is responsible for azole susceptibility and virulence

Zhai

Song

Gao

et al. 2019

Cellular Microbiology

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Plasma Ceramides and Sphingomyelins and Sudden Cardiac Death in the Cardiovascular Health Study

Bockus,

Jensen,

Fretts

et al. 2023

JAMA Netw Open

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ImportanceSphingolipids, including ceramides and sphingomyelins, may influence the pathophysiology and risk of sudden cardiac death (SCD) through multiple biological activities. Whether the length of the fatty acid acylated to plasma sphingolipid species is associated with SCD risk is not known.ObjectiveTo determine whether the saturated fatty acid length of plasma ceramides and sphingomyelins influences the association with SCD risk.Design, Setting, and ParticipantsIn this cohort study, multivariable Cox proportional hazards regression models were used to examine the association of sphingolipid species with SCD risk. The study population included 4612 participants in the Cardiovascular Health Study followed up prospectively for a median of 10.2 (IQR, 5.5-11.6) years. Baseline data were collected from January 1992 to December 1995 during annual examinations. Data were analyzed from February 11, 2020, to September 9, 2023.ExposuresEight plasma sphingolipid species (4 ceramides and 4 sphingomyelins) with saturated fatty acids of 16, 20, 22, and 24 carbons.Main Outcome and MeasureAssociation of plasma ceramides and sphingomyelins with saturated fatty acids of different lengths with SCD risk.ResultsAmong the 4612 CHS participants included in the analysis (mean [SD] age, 77 [5] years; 2724 [59.1%] women; 6 [0.1%] American Indian; 4 [0.1%] Asian; 718 [15.6%] Black; 3869 [83.9%] White, and 15 [0.3%] Other), 215 SCD cases were identified. In adjusted Cox proportional hazards regression analyses, plasma ceramides and sphingomyelins with palmitic acid (Cer-16 and SM-16) were associated with higher SCD risk per higher SD of log sphingolipid levels (hazard ratio [HR] for Cer-16, 1.34 [95% CI, 1.12-1.59]; HR for SM-16, 1.37 [95% CI, 1.12-1.67]). Associations did not differ by baseline age, sex, race, or body mass index. No significant association of SCD with sphingolipids with very-long-chain saturated fatty acids was observed after correction for multiple testing (HR for ceramide with arachidic acid, 1.06 [95% CI, 0.90-1.24]; HR for ceramide with behenic acid, 0.92 [95% CI, 0.77-1.10]; HR for ceramide with lignoceric acid, 0.92 [95% CI, 0.77-1.09]; HR for sphingomyelin with arachidic acid, 0.83 [95% CI, 0.71-0.98]; HR for sphingomyelin with behenic acid, 0.84 [95% CI, 0.70-1.00]; HR for sphingomyelin with lignoceric acid, 0.86 [95% CI, 0.72-1.03]).Conclusions and RelevanceThe findings of this large, population-based cohort study of SCD identified that higher plasma levels of Cer-16 and SM-16 were associated with higher risk of SCD. Future studies are needed to examine the underlying mechanism of these associations.

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Metabolomic profiling in liver of adiponectin-knockout mice uncovers lysophospholipid metabolism as an important target of adiponectin action

Liu

Sen

Wannaiampikul

et al. 2015

Biochemical Journal

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Adiponectin mediates anti-diabetic effects via increasing hepatic insulin sensitivity and direct metabolic effects. In the present study, we conducted a comprehensive and unbiased metabolomic profiling of liver tissue from AdKO (adiponectin-knockout) mice, with and without adiponectin supplementation, fed on an HFD (high-fat diet) to derive insight into the mechanisms and consequences of insulin resistance. Hepatic lipid accumulation and insulin resistance induced by the HFD were reduced by adiponectin. The HFD significantly altered levels of 147 metabolites, and bioinformatic analysis indicated that one of the most striking changes was the profile of increased lysophospholipids. These changes were largely corrected by adiponectin, at least in part via direct regulation of PLA2 (phospholipase A2) as palmitate-induced PLA2 activation was attenuated by adiponectin in primary hepatocytes. Notable decreases in several glycerolipids after the HFD were reversed by adiponectin, which also corrected elevations in several diacyglycerol and ceramide species. Our data also indicate that stimulation of ω-oxidation of fatty acids by the HFD is enhanced by adiponectin. In conclusion, this metabolomic profiling approach in AdKO mice identified important targets of adiponectin action, including PLA2, to regulate lysophospholipid metabolism and ω-oxidation of fatty acids.

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Sphingolipids and Metabolic Disease

Cited by 11 publications

References 136 publications

A sphingolipid synthesis‐related protein OrmA in Aspergillus fumigatus is responsible for azole susceptibility and virulence

A sphingolipid synthesis‐related protein OrmA in Aspergillus fumigatus is responsible for azole susceptibility and virulence

Plasma Ceramides and Sphingomyelins and Sudden Cardiac Death in the Cardiovascular Health Study

Metabolomic profiling in liver of adiponectin-knockout mice uncovers lysophospholipid metabolism as an important target of adiponectin action

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