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Sphingolipids: the nexus between Gaucher disease and insulin resistance.

ABSTRACT: Sphingolipids constitute a diverse array of lipids in which fatty acids are linked through amide bonds to a long-chain base, and, structurally, they form the building blocks of eukaryotic membranes. Ceramide is the simplest and serves as a precursor for the synthesis of the three main types of complex sphingolipids; sphingomyelins, glycosphingolipids and gangliosides. Sphingolipids are no longer considered mere structural spectators, but bioactive molecules with functions beyond providing a mechanically stable and chemically resistant barrier to a diverse array of cellular processes. Although sphingolipids form a somewhat minor component of the total cellular lipid pool, their accumulation in certain cells forms the basis of many diseases. Human diseases caused by alterations in the metabolism of sphingolipids are conventionally inborn errors of degradation, the most common being Gaucher disease, in which the catabolism of glucosylceramide is defective and accumulates. Insulin resistance has been reported in patients with Gaucher disease and this article presents evidence that this is due to perturbations in the metabolism of sphingolipids. Ceramide and the more complex sphingolipids, the gangliosides, are constituents of specialised membrane microdomains termed lipid rafts. Lipid rafts play a role in facilitating and regulating lipid and protein interactions in cells, and their unique lipid composition enables them to carry out this role. The lipid composition of rafts is altered in cell models of Gaucher disease which may be responsible for impaired lipid and protein sorting observed in this disorder, and consequently pathology. Lipid rafts are also necessary for correct insulin signalling, and a perturbed lipid raft composition may impair insulin signalling. Unravelling common nodes of interaction between insulin resistance and Gaucher disease may lead to a better understanding of the biochemical mechanisms behind pathology.

SUBMITTER: Fuller M

PROVIDER: S-EPMC2964722 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Sphingolipids: the nexus between Gaucher disease and insulin resistance.

Fuller Maria M

Lipids in health and disease 20101011

Sphingolipids constitute a diverse array of lipids in which fatty acids are linked through amide bonds to a long-chain base, and, structurally, they form the building blocks of eukaryotic membranes. Ceramide is the simplest and serves as a precursor for the synthesis of the three main types of complex sphingolipids; sphingomyelins, glycosphingolipids and gangliosides. Sphingolipids are no longer considered mere structural spectators, but bioactive molecules with functions beyond providing a mech ...[more]

PMID: 20937139

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Project description:Insulin resistance is defined as a complex pathological condition of abnormal cellular and metabolic response to insulin. Obesity and consumption of high-fat diet lead to ectopic accumulation of bioactive lipids in insulin-sensitive tissues. Intracellular lipid accumulation is regarded as one of the major factors in the induction of insulin resistance and type 2 diabetes (T2D). A significant number of studies have described the involvement of ceramides and other sphingolipids in the inhibition of insulin-signaling pathway in both skeletal muscles and the liver. Adverse effects of sphingolipid accumulation have recently been linked to the activation of protein kinase Cζ (PKCζ) and protein phosphatase 2A (PP2A), which, in turn, negatively affect phosphorylation of serine/threonine kinase Akt [also known as protein kinase B (PKB)], leading to decreased glucose uptake in skeletal muscles as well as increased gluconeogenesis and glycogenolysis in the liver. Sphingolipids, in addition to their direct impact on the insulin signaling pathway, may be responsible for other negative aspects of diabetes, namely mitochondrial dysfunction and deficiency. Mitochondrial health, which is characterized by appropriate mitochondrial quantity, oxidative capacity, controlled oxidative stress, undisturbed respiratory chain function, adenosine triphosphate (ATP) production and mitochondrial proliferation through fission and fusion, is impaired in the skeletal muscles and liver of T2D subjects. Recent findings suggest that impaired mitochondrial function may play a key role in the development of insulin resistance. Mitochondria stay in contact with the endoplasmic reticulum (ER), Golgi membranes and mitochondria-associated membranes (MAM) that are the main places of sphingolipid synthesis. Moreover, mitochondria are capable of synthesizing ceramide though ceramide synthase (CerS) activity. Recently, ceramides have been demonstrated to negatively affect mitochondrial respiratory chain function and fission/fusion activity, which is also a hallmark of T2D. Despite a significant correlation between sphingolipids, mitochondrial dysfunction, insulin resistance and T2D, this subject has not received much attention compared to the direct effect of sphingolipids on the insulin signaling pathway. In this review, we focus on the current state of scientific knowledge regarding the involvement of sphingolipids in the induction of insulin resistance by inhibiting mitochondrial function.

Project description:Purpose: In order to describe how non- genetic factors may contribute to emergence of additional neurodegenerative disorders in mice with neuronal Gaucher Disease (nGD), full transcript mRNA sequencing was implemented with half brain in order to study differential gene expression between experimental groups: (Untreated) Control, CBE (Conduritol β epoxide ), SVNI (Sindbis virus), and CBE + SVNI Methods: Full transcript mRNA sequencing was implemented with half brain in order to study differential gene expression between experimental groups (biologilal triplicates in each group). We mapped 20 million sequence reads per sample to the mouse genome (GRCm38) and identified 16,903 transcripts. . All subjects were 28 days old. Half of the bisected brains were flash-frozen in liquid nitrogen and stored in -80C conditions until use. RNA was isolated using a RNeasy mini kit (Qiagen, Hilden, Germany). Extraction of RNA was performed at the Israeli Institute for Biological Research and the RNA was then transferred to the Weizmann Institute of Science for further analysis. Quality was examined with the Agilent 2200 TapeStation system (Agilent Technologies); RIN values of each sample were determined satisfactory for use in sequencing. Expression of mRNA was quantified using DESeq following normalization of library size with Pipeline. Gene lists were created by criteria based on an absolute linear fold change ≥ 2.0, *p ≤ 0.05. Enriched pathways in the resulting gene lists were analyzed with Ingenuity Pathway Analysis (IPA). Results: Our study represents the first full RNA transcriptome analysis of brains from of CBE-treated mice, with biological triplicates generated by RNA-seq technology. The CBE and CBE+SVNI conditions boast remarkably similar genetic profiles with no differentially expressed genes changed between them (fold change ≥ 2.0, *p ≤ 0.05). In CBE, SVNI, and CBE + SVNI conditions respectively, 501, 1724, and 554 genes were significantly upregulated compared to the control, while 5, 333, and 40 genes were significantly downregulated respectively (Fig. 2B). Surprisingly, 476 upregulated genes in the CBE condition were shared with SVNI, while only 25 genes were uniquely upregulated. No downregulated genes were shared between the two conditions (Fig. 2C). Here, we conclude that CBE and CBE+SVNI demonstrate nearly identical mRNA profiles while SVNI boasted highly differential genes compared to all other conditions. Conclusion: Half brain mRNA profiles of 28-day old untreated (Control), CBE-treated, SVNI-treated, and SVNI + CBE-treated mice were generated by deep sequencing, in triplicate, using Illumina Hiseq.

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Sphingolipids: the nexus between Gaucher disease and insulin resistance.

Publications

Sphingolipids: the nexus between Gaucher disease and insulin resistance.

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