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Lipidomics in longevity and healthy aging.

The role of classical lipids in aging diseases and human longevity has been widely acknowledged. Triglyceride and cholesterol concentrations … sease and health. For example, low density lipoproteins are the main carriers of sphingomyelins and ceramides, while high density lipoproteins are mostly loaded with ether phosphocholines, partly explaining their opposing roles in atherogenesis. Moreover, the identification of specific lipid species in aging diseases and longevity would aid to clarify how t …

Complete failure of insulin-transmitted signaling, but not obesity-induced insulin resistance, impairs respiratory chain function in muscle.

The role of mitochondrial dysfunction in the development of insulin resistance and type 2 diabetes remains controversial. In order to specif … emained unchanged even though intramyocellular diacylglycerols (DAGs), triacylglycerols (TAGs), and ceramides accumulated. In contrast, in muscle-specific InsR knockout (MIRKO) and streptozotocin (STZ)-treated hypoinsulinemic, hyperglycemic mice, levels of mitochondrial respiratory chain complexes and mitochondrial function were markedly reduced. In STZ, bu …

Abnormal gangliosides are localized in lipid rafts in Sanfilippo (MPS3a) mouse brain.

Allogenic stem cell transplantation can reduce lysosomal storage of heparan sulfate-derived oligosaccharides by up to 27 % in Sanfilippo MPS … l mouse brain. HPLC/MS/MS analysis revealed the expected enrichment of normal complex gangliosides, ceramides, galatosylceramides and sphingomyelin enrichment in this LR fraction. The abnormal HS-derived oligosaccharide storage material was in the Triton X100-soluble at 4 °C fractions (8-12),whereas both GM3 and sialo[GalNAc]lactosylceramide (GM2) were foun …

Intramyocellular lipid kinetics and insulin resistance.

More than fifteen years ago it was discovered that intramyocellular triglyceride (imcTG) content in skeletal muscle is abnormally high in co … ress glucose utilization. Meanwhile, it releases abundant fatty acid products (e.g. diacylglycerol, ceramides) that impair insulin actions via signal transduction, thereby causing MIR. Thus, intramyocellular fatty acids and their products released from imcTG appear to function as a link to MIR. Accordingly, a forward mechanism is proposed that explains the …

Polar lipids in human meibomian gland secretions.

PURPOSE: To determine the polar lipid composition of human meibomian gland secretions and their relationship to the preocular tear film. ME … her unidentified phospholipids were also present. Also present in secretions were the sphingolipids ceramides and cerebrosides. Fatty acids present were 12-18 carbon chain length. All fatty acids were normal (not branched) saturated fatty acids except in sphingolipids, where hydroxy fatty acids were also present. Unsaturated normal fatty acids were present …

A novel function for transglutaminase 1: attachment of long-chain omega-hydroxyceramides to involucrin by ester bond formation.

Transglutaminases (TGases) are defined as enzymes capable of forming isopeptide bonds by transfer of an amine onto glutaminyl residues of a protein. Here we show that the membrane-bound form of the TGase 1 enzyme can also form ester bonds between specific glutaminyl residues of human involucrin and a synthetic analog of epidermal specific omega-hydroxyceramides. The formation of a approximately 5-nm-thick lipid envelope on the surface of epidermal keratinocytes is an important component of normal barrier function. The lipid envelope consists of omega-hydroxyceramides covalently linked by ester…

Specificity of purified monoacylglycerol lipase, palmitoyl-CoA hydrolase, palmitoyl-carnitine hydrolase, and nonspecific carboxylesterase from rat liver microsomes.

The comparative substrate specificities of five purified serine hydrolases from rat liver microsomes have been investigated, especially their action upon natural lipoids. All enzymes had high carboxylesterase activities with simple aliphatic and aromatic esters and thioesters. The broad pH optima were in the range of pH 6-10. Synthetic amides were less potent substrates. The hydrolytic activities towards palmitoyl-CoA and monoacyl glycerols were generally high, whereas phospholipids and palmitoyl carnitine were cleaved at moderate rates. Acetyl-CoA, acetyl carnitine, and ceramides were not cle…

Deletion of the T1D risk gene Ormdl3 in β-cells does not impact disease progression.

Orosomucoid-like (ORMDL) proteins are a component of the serine palmitoyltransferase complex and a negative regulator of ceramide synthesis. Among these ORMDL3 in addition to its role in lipid homeostasis, plays a key role in inflammation, endoplasmic reticulum stress, and immune regulation. Single nucleotide polymorphisms in the 17q12-q21 locus, which harbors ORMDL3, have been associated with multiple autoimmune diseases, including type 1 diabetes (T1D). T1D results from dysregulation of both β-cells and immune cells; yet the role of ORMDL3 in disease pathogenesis remains unclear. Here, we de

Discovery of N-Ethyl Sulfonamide Derivatives as Potent Intestinal-Restricted Farnesoid X Receptor Antagonists for the Treatment of Metabolic Disorders.

Farnesoid X receptor (FXR) plays a critical role in regulating bile acid and lipid metabolism, and intestinal FXR antagonism contributes to significant metabolic improvements. Herein, we report the discovery of a series of FXR antagonists featuring an N-ethyl sulfonamide scaffold. Through systematic structural optimization and structure-activity relationship studies, 101 derivatives were synthesized, among which F44-S101 was identified as a potent and selective intestine-restricted FXR antagonist with an IC50 value of 0.48 μM. In Triton-induced hyperlipidemic mice, F44-S101 significantly reduc

Downregulation of AKT-mediated p27Kip1 phosphorylation with shift to sphingomyelin synthesis in CLN3 disease.

CLN3 disease is a fatal childhood neurodegenerative disorder without drug-modifying therapies. Wild-type CLN3 gene is anti-apoptotic. Previous work proves that CLN3 disease pathogenesis is associated with reduced cell viability/apoptotic cell death and increase in ceramide, in cells and brains of patients and in Cln3 Δex7/8 mouse brain. AKT, a serine/threonine protein kinase, is at the core of a complex signaling pathway regulating apoptosis and cell proliferation and is neuroprotective. AKT fulfils this function via cyclin-dependent kinase inhibitor p27Kip1 phosphorylation at residue T198 res

Diabetic encephalopathy: metabolic reprogramming as a potential driver of accelerated brain aging and cognitive decline.

Diabetic encephalopathy (DE) is a serious neurological complication of diabetes and is expressed as progressive decline in cognitive function, emotional disorders, and changes in brain structure. This review brings together the relevant evidence and demonstrates that metabolic reprogramming, the adaptive reconfiguration of the core metabolic pathway in response to hyperglycemia, is a potential driver of accelerated brain aging in DE. The main pathological characteristics are: abnormal brain insulin signaling, resulting in a decrease in neuronal glucose intake and a decrease in mitochondrial ox

Dysregulation of sphingolipid metabolism in pain.

Pain is a clinical condition that is currently of great concern and is often caused by tissue or nerve damage or occurs as a concomitant symptom of a variety of diseases such as cancer. Severe pain seriously affects the functional status of the body. However, existing pain management programs are not fully satisfactory. Therefore, there is a need to delve deeper into the pathological mechanisms underlying pain generation and to find new targets for drug therapy. Sphingolipids (SLs), as a major component of the bilayer structure of eukaryotic cell membranes, also have powerful signal transducti

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… Sphingomyelins are hydrolyzed by sphingomyelinases (SMase) to produce ceramides and free phosphocholine, and glycosphingolipids are also broken down to ceramides by their specific hydrolyzing enzymes, galactosylceramides and glucose ceramides, which are further broken down to ceramides by galactolactonase … that ceramide is an upstream signaling mediator of neuroimmune activation, and that inhibition of ceramide synthesis blocks morphine resistance to injury, a process that is achieved by intervening in nitrogen oxidative stress through peroxynitrite synthesis Ceramide | Ceramide also induces oxidative …

Primary versus Secondary Elevations in Fundus Autofluorescence.

The method of quantitative fundus autofluorescence (qAF) can be used to assess the levels of bisretinoids in retinal pigment epithelium (RPE) cells so as to aid the interpretation and management of a variety of retinal conditions. In this review, we focused on seven retinal diseases to highlight the possible pathways to increased fundus autofluorescence. ABCA4- and RDH12-associated diseases benefit from known mechanisms whereby gene malfunctioning leads to elevated bisretinoid levels in RPE cells. On the other hand, peripherin2/RDS-associated disease (PRPH2/RDS), retinitis pigmentosa (RP), cen

The Pathogenic Sphingolipid Psychosine is Secreted in Extracellular Vesicles in the Brain of a Mouse Model of Krabbe Disease.

Psychosine exerts most of its toxic effects by altering membrane dynamics with increased shedding of extracellular vesicles (EVs). In this study, we discovered that a fraction of psychosine produced in the brain of the Twitcher mouse, a model for Krabbe disease, is associated with secreted EVs. We evaluated the effects of attenuating EV secretion in the Twitcher brain by depleting ceramide production with an inhibitor of neutral sphingomyelinase 2, GW4869. Twitcher mice treated with GW4869 had decreased overall EV levels, reduced EV-associated psychosine and unexpectedly, correlated with incre

Antidepressive-like Behavior-Related Metabolomic Signatures of Sigma-1 Receptor Knockout Mice.

Sigma-1 receptor (Sig1R) has been proposed as a therapeutic target for neurological, neurodegenerative, and psychiatric disorders, including depression and anxiety. Identifying metabolites that are affected by Sig1R absence and cross-referencing them with specific mood-related behaviors would be helpful for the development of new therapies for Sig1R-associated disorders. Here, we examined metabolic profiles in the blood and brains of male CD-1 background Sig1R knockout (KO) mice in adulthood and old age and correlated them with the assessment of depression- and anxiety-related behaviors. The m

Mitophagy in tumorigenesis and metastasis.

Cells use mitophagy to remove dysfunctional or excess mitochondria, frequently in response to imposed stresses, such as hypoxia and nutrient deprivation. Mitochondrial cargo receptors (MCR) induced by these stresses target mitochondria to autophagosomes through interaction with members of the LC3/GABARAP family. There are a growing number of these MCRs, including BNIP3, BNIP3L, FUNDC1, Bcl2-L-13, FKBP8, Prohibitin-2, and others, in addition to mitochondrial protein targets of PINK1/Parkin phospho-ubiquitination. There is also an emerging link between mitochondrial lipid signaling and mitophagy

Metabolome-Driven Regulation of Adenovirus-Induced Cell Death.

A viral infection that involves virus invasion, protein synthesis, and virion assembly is typically accompanied by sharp fluctuations in the intracellular levels of metabolites. Under certain conditions, dramatic metabolic shifts can result in various types of cell death. Here, we review different types of adenovirus-induced cell death associated with changes in metabolic profiles of the infected cells. As evidenced by experimental data, in most cases changes in the metabolome precede cell death rather than represent its consequence. In our previous study, the induction of autophagic cell deat

The role of Sphingolipids in myelination and myelin stability and their involvement in childhood and adult demyelinating disorders.

Multiple sclerosis (MS) represents the most common demyelinating disease affecting the central nervous system (CNS) in adults as well as in children. Furthermore, in children, in addition to acquired diseases such as MS, genetically inherited diseases significantly contribute to the incidence of demyelinating disorders. Some genetic defects lead to sphingolipid alterations that are able to elicit neurological symptoms. Sphingolipids are essential for brain development, and their aberrant functionality may thus contribute to demyelinating diseases such as MS. In particular, sphingolipidoses cau

Therapeutic implications and role of serum sphingolipids on psoriasis severity after narrow band ultraviolet B treatment: A cross sectional controlled study.

Sphingolipids (SLs), are structural components of the skin that contribute to the regulation of the proliferation and differentiation of keratinocytes as well as regulation of the skin epidermal barrier. A prospective cross sectional comparative controlled study was designed to evaluate the serum level of sphingosine 1 phosphate (S1P) and ceramide (CER) before and after narrow band ultraviolet B (NBUVB) in psoriatic patients. The study included 32 patients presented with psoriasis and 32 healthy age and sex matched control volunteers. (S1P and CER) levels were measured before and after NBUVB s

ZAG Regulates the Skin Barrier and Immunity in Atopic Dermatitis.

Adipokines modulate immune responses and lipid metabolism in allergic disease; however, little is known about their role in the skin barrier and atopic dermatitis (AD). We identified ZAG, an adipokine that regulates lipid mobilization, as a biomarker for AD. ZAG levels were consistently decreased in sera, T cells, and skin in human AD patients compared with healthy controls. ZAG was primarily detected in the stratum corneum along with FLG and LOR. Knockdown of ZAG with short hairpin RNA resulted in decreased FLG and increased TSLP. Topical ZAG treatment in AD mice recovered ZAG expression in t