Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Novgorodov, Sergei A.; Riley, Christopher L.; Yu, Jin; Keffler, Jarryd A.; Clarke, Christopher J.; Laer, An O. Van; Baicu, Catalin F.; Zile, Michael R.; Gudz, Tatyana I.

doi:10.1194/jlr.m060061

Cited by 45 publications

(40 citation statements)

References 97 publications

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“…In fact, several reports indicate that CerS5 and CerS2 directly interact and that these interactions may augment catalytic activity (2,3,48). Moreover, these enzymes and their respective ceramide products have been identified in mitochondria (1,4,49). Our previous studies demonstrated that loss of function of CerS5 led to cell hypertrophy (2), which we did not observe in CerS2 knockdown in this study (data not shown), suggesting that each of these enzymes directly regulates distinct cell processes.…”

Section: Discussioncontrasting

confidence: 43%

Lipotoxic very‐long‐chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes

et al. 2018

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Accumulating data support a role for bioactive lipids as mediators of lipotixicity in cardiomyocytes. One class of these, the ceramides, constitutes a family of molecules that differ in structure and are synthesized by distinct enzymes, ceramide synthase (CerS)1-CerS6. Data support that specific ceramides and the enzymes that catalyze their formation play distinct roles in cell function. In a mouse model of diabetic cardiomyopathy, sphingolipid profiling revealed increases in not only the CerS5-derived ceramides but also in very long chain (VLC) ceramides derived from CerS2. Overexpression of CerS2 elevated VLC ceramides caused insulin resistance, oxidative stress, mitochondrial dysfunction, and mitophagy. Palmitate induced CerS2 and oxidative stress, mitophagy, and apoptosis, which were prevented by depletion of CerS2. Neither overexpression nor knockdown of CerS5 had any function in these processes, suggesting a chain-length dependent impact of ceramides on mitochondrial function. This concept was also supported by the observation that synthetic mitochondria-targeted ceramides led to mitophagy in a manner proportional to N-acyl chain length. Finally, blocking mitophagy exacerbated cell death. Taken together, our results support a model by which CerS2 and VLC ceramides have a distinct role in lipotoxicity, leading to mitochondrial damage, which results in subsequent adaptive mitophagy. Our data reveal a novel lipotoxic pathway through CerS2.-Law, B. A., Liao, X., Moore, K. S., Southard, A., Roddy, P., Ji, R., Szulc, Z., Bielawska, A., Schulze, P. C., Cowart, L. A. Lipotoxic very-long-chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes.

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Section: Discussioncontrasting

confidence: 43%

Lipotoxic very‐long‐chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes

et al. 2018

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“…Moreover, modulation of lipid metabolism can restore the mitochondrial dysfunction seen in T1D. This is exemplified by Novgorodov and colleagues who increased lactosylceramide via knockdown of neutral ceramidase (Novgorodov et al 2016). As mentioned previously, Han and coworkers postulated that early changes in cardiolipin species play a causal role in the mitochondrial dysfunction seen in T1D, which results in an inability of mitochondria to deal with the excess lipid burden in this setting ).…”

Section: Cardiac Lipid Accumulation and Mitochondrial Functionmentioning

confidence: 85%

“…↑ Increased (Nielsen et al 2002, Ueno et al 2008, Pulinilkunnil et al 2013, Kuramoto et al 2014, Yan et al 2015, Novgorodov et al 2016 ↑ Increased (Bugger et al 2008, Basu et al 2009, Pulinilkunnil et al 2013 Glucose oxidation ↓ Decreased (Pulinilkunnil et al 2013) ↓ Decreased (Bugger et al 2008, Basu et al 2009) Fatty acid oxidation ↑ Increased (Pulinilkunnil et al 2013) ↑ Increased (Bugger et al 2008, Basu et al 2009) Pathways modulated Inflammation ↑ Increased (Westermann et al 2009) ↑ Increased (Wang et al 2013) ↑ Increased (Chavali et al 2014) Mitochondrial function Dysfunction/abnormal (Pulinilkunnil et al 2013, Xu et al 2013, Novgorodov et al 2016 Dysfunction/abnormal (Shen et al 2004, Ye et al 2004, Xie et al 2011, Vadvalkar et al 2013, Xu et al 2013 Dysfunction/abnormal (Bugger et al 2008(Bugger et al , 2009 (Continued) R233 Review r h ritchie and others Lipid metabolism and diabetic cardiomyopathy impaired folding of proinsulin leading to endoplasmic reticulum (ER) stress in pancreatic islets such that Akita mice exhibit progressive loss of beta-cells, which correlates with diabetes development. Hyperglycaemia is evident from 3 to 4 weeks of age.…”

Section: ) Cardiac Lipidsmentioning

confidence: 99%

“…Interestingly, plasma levels of fibroblast growth factor (FGF)-21, known for its role in regulating energy homeostasis, were markedly reduced with the induction of diabetes. Given their role in the modulation of mitochondrial function, which has been shown to be an important mediator of diabetic cardiomyopathy, Novgorodov specifically investigated the effect of cardiac sphingolipid metabolism in mice administered with 50 mg/kg STZ for 5 days (Novgorodov et al 2016). Diabetic mice exhibited increased expression of desaturase 1, dihydroceramide synthase 2, serine palmitoyl transferase and the rate of ceramide formation by mitochondrial ceramide synthase, indicative of an upregulation of ceramide biosynthesis; however, no changes in ceramide levels were observed, suggesting a compensatory upregulation of ceramide metabolising pathways (Novgorodov et al 2016).…”

Section: Streptozotocin-diabetic Mousementioning

confidence: 99%

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Lipid metabolism and its implications for type 1 diabetes-associated cardiomyopathy

Ritchie

Zerenturk

Prakoso

et al. 2017

Journal of Molecular Endocrinology

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Diabetic cardiomyopathy was first defined over four decades ago. It was observed in small post-mortem studies of diabetic patients who suffered from concomitant heart failure despite the absence of hypertension, coronary disease or other likely causal factors, as well as in large population studies such as the Framingham Heart Study. Subsequent studies continue to demonstrate an increased incidence of heart failure in the setting of diabetes independent of established risk factors, suggesting direct effects of diabetes on the myocardium. Impairments in glucose metabolism and handling receive the majority of the blame. The role of concomitant impairments in lipid handling, particularly at the level of the myocardium, has however received much less attention. Cardiac lipid accumulation commonly occurs in the setting of type 2 diabetes and has been suggested to play a direct causal role in the development of cardiomyopathy and heart failure in a process termed as cardiac lipotoxicity. Excess lipids promote numerous pathological processes linked to the development of cardiomyopathy, including mitochondrial dysfunction and inflammation. Although somewhat underappreciated, cardiac lipotoxicity also occurs in the setting of type 1 diabetes. This phenomenon is, however, largely understudied in comparison to hyperglycaemia, which has been widely studied in this context. The current review addresses the changes in lipid metabolism occurring in the type 1 diabetic heart and how they are implicated in disease progression. Furthermore, the pathological pathways linked to cardiac lipotoxicity are discussed. Finally, we consider novel approaches for modulating lipid metabolism as a cardioprotective mechanism against cardiomyopathy and heart failure.

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“…In support, palmitoleic acid has a demonstrated ability to reduce inflammation and to improve insulin sensitivity (Chan et al, 2015;Dimopoulos et al, 2006). While the significance of changes in circulating lactosyl ceramides is less clear, recent evidence indicates that elevated lactosylcermide concentrations appear to be involved with mitochondrial respiration rates and calcium retention in diabetic mice (Novgorodov et al, 2016). Furthermore, Iwabuchi et al (2008) reported that lactoysl-ceramides are believed to be involved in lipid raft formation of neutrophils (Iwabuchi et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Flaxseed Oil or n‐7 Fatty Acid‐Enhanced Fish Oil Supplementation Alters Fatty Acid Composition, Plasma Insulin and Serum Ceramide Concentrations, and Gene Expression in Lambs

Duckett

Garcia

Rico

et al. 2019

Lipids

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The objective of this study was to examine the effects of flaxseed (FLAX) oil or 16‐carbon n‐7 fatty acid ‐enhanced fish oil (Provinal; POA) supplementation on serum, liver and skeletal muscle fatty acid concentrations, serum ceramide and plasma insulin concentrations, and gene expression. Lambs [n = 18; 42 ± 5.6 kg body weight (BW); 7 months] were individually fed one of the three treatments: (1) control (CON), no oil supplement, (2) FLAX; at 0.1% of BW, or (3) POA at 0.1% of BW for 60 days. Daily feed intake and weight gain were decreased by 21% and 34%, respectively, for POA than FLAX. Liver and skeletal muscle concentrations of palmitoleic acid were greater by 396% and 87%, respectively, for POA than FLAX; whereas, liver and skeletal muscle α‐linolenic acid concentrations were greater by 199% and 118%, respectively, for FLAX. Supplementation with POA also had greater serum and tissue concentrations of eicosapentaenoic and docosahexaenoic acids. Serum glucose and plasma insulin concentrations were elevated with FLAX supplementation at the end of the study. Supplementation with POA altered serum ceramide concentrations compared to CON or FLAX. Oil supplementation, both FLAX and POA, downregulated expression of unesterified fatty acid receptors (FFAR) 1 and FFAR4 in the liver; however, oil supplementation upregulated expression of FFAR1 in muscle. Interleukin‐6 (IL6) and tumor necrosis factor‐α (TNFA) expression were downregulated with oil supplementation in the liver; however, FLAX upregulated TNFA in muscle. These results show that oil supplementation can enhance uptake and deposition of unique fatty acids that alter ceramide concentrations and gene expression in tissues.

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Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Cited by 45 publications

References 97 publications

Lipotoxic very‐long‐chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes

Lipotoxic very‐long‐chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes

Lipid metabolism and its implications for type 1 diabetes-associated cardiomyopathy

Flaxseed Oil or n‐7 Fatty Acid‐Enhanced Fish Oil Supplementation Alters Fatty Acid Composition, Plasma Insulin and Serum Ceramide Concentrations, and Gene Expression in Lambs

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