Sphingolipids and Lipoproteins in Health and Metabolic Disorders

Iqbal, Jahangir; Walsh, Meghan T.; Hammad, Samar M.; Hussain, M. Mahmood

doi:10.1016/j.tem.2017.03.005

Cited by 187 publications

(176 citation statements)

References 86 publications

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“…It is becoming clear that plasma sphingolipids could be markers for several metabolic disorders such as insulin resistance, progression of NAFLD to NASH, atherosclerosis, and coronary artery disease (6)(7)(8)(9)(10)(11)(12)(13). However, very little is known about the mechanisms that control plasma sphingolipids.…”

Section: Discussionmentioning

confidence: 99%

“…A published study showed significantly reduced sphinogsine-1P levels in the plasma of older Tangier subjects with very low levels of HDL and apoAI (99% and 97% reduction, respectively) (43). It is known that sphinogsine-1P transport to plasma involves apoM and spinster 2 and resides mainly on HDL 3 (6,(44)(45)(46). Longitudinal, prospective studies in larger cohorts are needed to determine plasma apoM, sphingoid bases, and their phosphate levels in Tangier subjects.…”

Section: Sphingoid Bases and Their Phosphatesmentioning

confidence: 99%

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ATP binding cassette family A protein 1 determines hexosylceramide and sphingomyelin levels in human and mouse plasma

Iqbal

Walsh

Hammad

et al. 2018

Journal of Lipid Research

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Low density apoB-containing lipoproteins (B-lps) andHDLs carry the bulk of lipids in the blood circulation. These lipoproteins carry triacylglycerols, phospholipids, cholesterol, and sphingolipids (1-5). The major sphingolipids in the plasma are SM, ceramide (Cer), hexosylceramide (HxCer), and lactosylceramide (LactCer). Sphingolipids consist of a common 18-carbon amino-alcohol backbone, sphingosine. These molecules are structurally diverse and regulate significant physiologic functions associated with several metabolic diseases such as insulin resistance, progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH), atherosclerosis, and coronary artery disease (6-13). Earlier, we showed that microsomal triglyceride transfer protein (MTP) is a critical determinant of plasma Cer levels and partially contributes to plasma SM by investigating sphingolipid concentrations in the plasma of MTP-deficient abetalipoproteinemia subjects as well as in liver-and intestine-specific MTP-deficient mice (14). MTP deficiency in humans and mice was associated with 80% reductions in plasma Cer levels and 40% reduction in plasma SM levels. Mechanistic studies showed that MTP does not play a role in sphingolipid biosynthesis but is important for sphingolipid secretion. Furthermore, the data Abstract Sphingolipids, including ceramide, SM, and hexosylceramide (HxCer), are carried in the plasma by lipoproteins. They are possible markers of metabolic diseases, but little is known about their control. We previously showed that microsomal triglyceride transfer protein (MTP) is critical to determine plasma ceramide and SM, but not HxCer, levels. In human plasma and mouse models, we examined possible HxCer-modulating pathways, including the role of ABCA1 in determining sphingolipid plasma concentrations. Compared with control samples, plasma from patients with Tangier disease (deficient in ABCA1) had significantly lower HxCer (69%) and SM (40%) levels. Similarly, mice deficient in hepatic and intestinal ABCA1 had significantly reduced HxCer (79%) and SM (85%) levels. Tissue-specific ablation studies revealed that hepatic ABCA1 determines plasma HxCer and SM levels; that ablation of MTP and ABCA1 in the liver and intestine reduces plasma HxCer, SM, and ceramide levels; and that hepatic and intestinal MTP contribute to plasma ceramide levels, whereas only hepatic MTP modulates plasma SM levels. These results identify the contribution of ABCA1 to plasma SM and HxCer levels and suggest that MTP and ABCA1 are critical determinants of plasma sphingolipid levels.-Iqbal, J., M. T. Walsh, S. M. Hammad, M. Cuchel, D. J. Rader, and M. M. Hussain. ATP binding cassette family A protein 1 determines hexosylceramide and sphingomyelin levels in human and mouse plasma.

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Section: Discussionmentioning

confidence: 99%

Section: Sphingoid Bases and Their Phosphatesmentioning

confidence: 99%

ATP binding cassette family A protein 1 determines hexosylceramide and sphingomyelin levels in human and mouse plasma

Iqbal

Walsh

Hammad

et al. 2018

Journal of Lipid Research

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“…Ståhlman et al found that small HDL-particles predominated in dyslipidemic subjects, with and without diabetes, compared to respective normolipidemic controls, and were distinguished as the primary carrier of ceramides, which is known for promoting inflammation and insulin resistance [16]. In healthy individuals, LDL particles are typically the major carriers of ceramide compared to VLDL and HDL particles [33,42]. In the current study, when lipoprotein particles were incubated in vitro with different ceramide species, C16 ceramide had the highest level of incorporation into all lipoproteins (LDL, HDL2, HDL3) ( Figure 2).…”

Section: Ceramide Enrichment Of Lipoprotein Particlesmentioning

confidence: 99%

Transcriptomics Reveal Altered Metabolic and Signaling Pathways in Podocytes Exposed to C16 Ceramide-Enriched Lipoproteins

Hammad

Twal

Arif

et al. 2020

Genes

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Sphingolipids are bioactive lipids associated with cellular membranes and plasma lipoproteins, and their synthesis and degradation are tightly regulated. We have previously determined that low plasma concentrations of certain ceramide species predict the development of nephropathy in diabetes patients with normal albumin excretion rates at baseline. Herein, we tested the hypothesis that altering the sphingolipid content of circulating lipoproteins can alter the metabolic and signaling pathways in podocytes, whose dysfunction leads to an impairment of glomerular filtration. Cultured human podocytes were treated with lipoproteins from healthy subjects enriched in vitro with C16 ceramide, or D-erythro 2-hydroxy C16 ceramide, a ceramide naturally found in skin. The RNA-Seq data demonstrated differential expression of genes regulating sphingolipid metabolism, sphingolipid signaling, and mTOR signaling pathways. A multiplex analysis of mTOR signaling pathway intermediates showed that the majority (eight) of the pathway phosphorylated proteins measured (eleven) were significantly downregulated in response to C16 ceramide-enriched HDL2 compared to HDL2 alone and hydroxy ceramide-enriched HDL2. In contrast, C16 ceramide-enriched HDL3 upregulated the phosphorylation of four intermediates in the mTOR pathway. These findings highlight a possible role for lipoprotein-associated sphingolipids in regulating metabolic and signaling pathways in podocytes and could lead to novel therapeutic targets in glomerular kidney diseases.

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“…С возрастом снижается продукция липидов кожи, но соотношение не меняется [12]. При различных метаболических нарушениях концентрация липидов кожи, а также церамидов крови может служить прогностическим и диагностическим маркерами сердечно-сосудистых заболеваний, ожирения, сахарного диабета, инсулинорезистентности и неалкогольной жировой болезни печени [13][14][15][16].…”

Section: характеристика липидного состава при заболеванияхunclassified

Role of lipids in skin barrier properties

Svirshchevskaya¹,

Matushevskaya²

2019

Klin. dermatol. venerol.

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Sphingolipids and Lipoproteins in Health and Metabolic Disorders

Cited by 187 publications

References 86 publications

ATP binding cassette family A protein 1 determines hexosylceramide and sphingomyelin levels in human and mouse plasma

ATP binding cassette family A protein 1 determines hexosylceramide and sphingomyelin levels in human and mouse plasma

Transcriptomics Reveal Altered Metabolic and Signaling Pathways in Podocytes Exposed to C16 Ceramide-Enriched Lipoproteins

Role of lipids in skin barrier properties

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