Myocardium of type 2 diabetic and obese patients is characterized by alterations in sphingolipid metabolic enzymes but not by accumulation of ceramide

Baranowski, Marcin; Błachnio-Zabielska, Agnieszka; Hirnle, Tomasz; Harasiuk, Dorota; Matlak, K.; Knapp,; Górski, Jan

doi:10.1194/jlr.m900002-jlr200

Cited by 47 publications

(34 citation statements)

References 35 publications

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“…Lactosylceramide was reported to enhance ROS production in isolated mitochondria respiring on succinate ( 28 ), which is consistent with inhibition of the respiratory chain at the level of complex III or complex IV ( 90 ). In our studies, the lactosylceramide suppressed the state 3 respiration supported by A similar phenomenon was reported by Gorski and colleagues for the myocardium of type 2 diabetic patients where, despite of an increase in apoptotic markers, ceramide level was unchanged compared with controls ( 79,80 ). At the same time, activation of the enzymes involved in both ceramide formation (neutral SMase, SPT) and ceramide utilization (ceramidases, sphingosine kinase 1) occurred in concert, suggesting an elevated rate of ceramide turnover.…”

Section: Lactosylceramide Suppresses Mitochondrial Respiration and Desupporting

confidence: 91%

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Novgorodov

Riley

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.orgCompelling epidemiological and clinical data indicate that diabetes mellitus increases the risk for cardiac dysfunction and heart failure independently of other risk factors, such as coronary disease and hypertension. Lipotoxicity is an important contributor to cardiac dysfunction in both type 1 ( 1, 2 ) and type 2 ( 3-6 ) diabetes, which are characterized by excessive accumulation of triacylglycerols, long-chain acyl-CoAs, diacylglycerols, and ceramides in myocardium. Correlation of the increased ceramide level with development of diabetic cardiomyopathy has attracted special attention in recent years because of the well-documented ability of this sphingolipid to regulate a number of cell processes, including cell proliferation, growth arrest, differentiation and apoptosis, and the mediation of responses to stress stimuli .Ceramide is a hub of sphingolipid metabolism ( 7,8 ). The balance between ceramide-producing pathways and pathways that consume it dictates ceramide level in the cell. The de novo ceramide biosynthesis pathway, one of the major ceramide producing pathways, localizes in the endoplasmic reticulum (ER) and starts with the condensation of serine and palmitoyl-CoA producing 3-ketosphingonine, which, in turn, is rapidly converted to dihydrosphingosine. Subsequent acylation of dihydrosphingosine by a set of (dihydro)ceramide synthases (CerSs) gives rise to dihydroceramide. Finally, the removal of two hydrogens from the fatty acid chain of dihydroceramide by desaturase leads to the formation of ceramide. Other possible contributors to elevated ceramide level are: hydrolysis of SM catalyzed by SMases, Abstract Sphingolipids have been implicated as key mediators of cell-stress responses and effectors of mitochondrial function. To investigate potential mechanisms underlying mitochondrial dysfunction, an important contributor to diabetic cardiomyopathy, we examined alterations of cardiac sphingolipid metabolism in a mouse with streptozotocininduced type 1 diabetes. Diabetes increased expression of desaturase 1, (dihydro)ceramide synthase (CerS)2, serine palmitoyl transferase 1, and the rate of ceramide formation by mitochondria-resident CerSs, indicating an activation of ceramide biosynthesis. However, the lack of an increase in mitochondrial ceramide suggests concomitant upregulation of ceramide-metabolizing pathways. Elevated levels of lactosylceramide, one of the initial products in the formation of glycosphingolipids were accompanied with decreased respiration and calcium retention capacity (CRC) in mitochondria from diabetic heart tissue. In baseline mitochondria, lactosylceramide potently suppressed state 3 respiration and decreased CRC, suggesting lactosylceramide as the primary sphingolipid responsible for mitochondrial defects in diabetic hearts. Moreover, knocking down the neutral ceramidase (NCDase) resulted in an increase in lactosylceramide level, suggesting a crosstalk between glucosylceramide synthase-and NCDase-mediated ceramide utiliz...

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Section: Lactosylceramide Suppresses Mitochondrial Respiration and Desupporting

confidence: 91%

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Novgorodov

Riley

et al. 2016

Journal of Lipid Research

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“…Metabolic stressors such as hyperglycemia (12,22,44,51) and dyslipidemia (8,26,34) have repeatedly been shown to cause increased mitochondrial-derived oxidative stress and cell death. Mechanisms by which these metabolic stressors cause alterations in the biochemistry of cardiac mitochondria remain a focus of intense research and are likely a collective result of a multifaceted degenerative process comprised of oxidative mitochondrial DNA damage (20), posttranslational modification of mitochondrial enzymes (10, 13), alterations in mitochondrial membrane architecture (55), and compromised antioxidant defenses (23,27).…”

Section: Discussionmentioning

confidence: 99%

Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways

Anderson

Rodríguez

Anderson

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

126

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“…There are also differences for the expression of sphingosine kinase isoforms. It is noteworthy that SphK1 is dominant subtype in the human myocardium, whereas the rodent heart expresses predominantly SphK2 [22]. Besides de novo synthesis, ceramide can also be produced by the action of sphingomyelinases (SMases) (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…However, it is well known that acid ceramidase activity in the rat heart is definitely lower than the activity of alkaline or neutral ceramidase isoforms of this enzyme. Therefore, this isoform probably does not play significant role in the generation of myocardial ceramide pool [22]. Finally, sphingosine can be phosphorylated by sphingosine kinase to form sphingosine-1-phosphate (S1P).…”

Section: Introductionmentioning

confidence: 99%

Hyperthyroidism Evokes Myocardial Ceramide Accumulation

Mikłosz

Łukaszuk

Chabowski

et al. 2015

Cell Physiol Biochem

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Background: Thyroid hormones (THs) are key regulators of cardiac physiology as well as modulators of different cellular signals including the sphingomyelin/ceramide pathway. The objective of this study was to examine the effect of hyperthyroidism on the metabolism of sphingolipids in the muscle heart. Methods: Male Wistar rats were treated for 10 days with triiodothyronine (T₃) at a dose of 50µg/100g of body weight. Animals were then anaesthetized and samples of the left ventricle were excised. Results: We have demonstrated that prolonged, in vivo, T₃ treatment increased the content of sphinganine (SFA), sphingosine (SFO), ceramide (CER) and sphingomyelin (SM), but decreased the level of sphingosine-1-phosphate (S1P) in cardiac muscle. Accordingly, the changes in sphingolipids content were accompanied by a lesser activity of neutral sphingomyelinase and without significant changes in ceramidases activity. Hyperthyroidism also induced activation of AMP-activated protein kinase (AMPK) with subsequently increased expression of mitochondrial proteins: cytochrome c oxidase IV (COX IV), β-hydroxyacyl-CoA dehydrogenase (β-HAD), carnityne palmitoyltransferase I (CPT I) and nuclear peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α). Conclusions: We conclude that prolonged T₃ treatment increases sphingolipids metabolism which is reflected by higher concentration of SFA and CER in heart muscle. Furthermore, hyperthyroidism-induced increase in heart sphingomyelin (SM) concentration might be one of the mechanisms underlying maintenance of CER at relatively low level by its conversion to SM together with decreased S1P content.

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Myocardium of type 2 diabetic and obese patients is characterized by alterations in sphingolipid metabolic enzymes but not by accumulation of ceramide

Cited by 47 publications

References 35 publications

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways

Hyperthyroidism Evokes Myocardial Ceramide Accumulation

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