Dihydroceramides: Their emerging physiological roles and functions in cancer and metabolic diseases

2020 ◽  
Author(s):  
Floriane Lachkar ◽  
Pascal Ferre ◽  
Fabienne Foufelle ◽  
Alexandra Papaioannou
Keyword(s):  
Stress Responses ◽  
Metabolic Diseases ◽  
De Novo ◽  
Metabolic Intermediates ◽  
New Class ◽  
Survival Pathways ◽  
Long Time ◽  
Cellular Stress Responses

Dihydroceramides are a type of sphingolipids that for a long time were regarded as biologically inactive. They are metabolic intermediates of the de novo sphingolipid synthesis pathway, and are converted into ceramides with the addition of a double bond. Ceramides are abundant in tissues and have well-established biological functions. On the contrary, dihydroceramides are less prevalent and despite their hitherto characterization as inert lipids, studies of the last decade begun to unravel their implication in various biological processes distinct from those involving ceramides. These processes include cellular stress responses and autophagy, cell growth, pro-death or pro-survival pathways, hypoxia and immune responses. In addition, their plasma concentration has been related to metabolic diseases and shown as a long-term predictor of type 2 diabetes onset. They are thus important players and potential biomarkers in pathologies ranging from diabetes to cancer and neurodegenerative diseases. The purpose of this mini-review is to highlight the emergence of dihydroceramides as a new class of bioactive sphingolipids by reporting recent advances on their biological characterization and pathological implications, focusing on cancer and metabolic diseases.

Emerging roles of endoplasmic reticulum-resident selenoproteins in the regulation of cellular stress responses and the implications for metabolic disease

2018 ◽  
Vol 475 (6) ◽  
pp. 1037-1057 ◽  
Author(s):  
Alex B. Addinsall ◽  
Craig R. Wright ◽  
Sof Andrikopoulos ◽  
Chris van der Poel ◽  
Nicole Stupka
Keyword(s):  
Metabolic Disease ◽  
Endoplasmic Reticulum ◽  
Stress Responses ◽  
Cellular Stress ◽  
Metabolic Stress ◽  
Metabolic Dysfunction ◽  
Iodothyronine Deiodinase ◽  
Inflammatory Stress ◽  
Cellular Stress Responses

Chronic metabolic stress leads to cellular dysfunction, characterized by excessive reactive oxygen species, endoplasmic reticulum (ER) stress and inflammation, which has been implicated in the pathogenesis of obesity, type 2 diabetes and cardiovascular disease. The ER is gaining recognition as a key organelle in integrating cellular stress responses. ER homeostasis is tightly regulated by a complex antioxidant system, which includes the seven ER-resident selenoproteins — 15 kDa selenoprotein, type 2 iodothyronine deiodinase and selenoproteins S, N, K, M and T. Here, the findings from biochemical, cell-based and mouse studies investigating the function of ER-resident selenoproteins are reviewed. Human experimental and genetic studies are drawn upon to highlight the relevance of these selenoproteins to the pathogenesis of metabolic disease. ER-resident selenoproteins have discrete roles in the regulation of oxidative, ER and inflammatory stress responses, as well as intracellular calcium homeostasis. To date, only two of these ER-resident selenoproteins, selenoproteins S and N have been implicated in human disease. Nonetheless, the potential of all seven ER-resident selenoproteins to ameliorate metabolic dysfunction warrants further investigation.

scholarly journals Anabolic androgenic steroids exert a selective remodeling of the plasma lipidome that mirrors the decrease of the de novo lipogenesis in the liver

Metabolomics ◽  
2020 ◽  
Vol 16 (1) ◽  
Author(s):  
David Balgoma ◽  
Sofia Zelleroth ◽  
Alfhild Grönbladh ◽  
Mathias Hallberg ◽  
Curt Pettersson ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Metabolic Diseases ◽  
De Novo ◽  
High Resolution Mass Spectrometry ◽  
De Novo Lipogenesis ◽  
Anabolic Androgenic Steroids ◽  
Lipid Profiling ◽  
Testosterone Undecanoate ◽  
Androgenic Steroids

Abstract Introduction The abuse of anabolic androgenic steroids (AASs) is a source of public concern because of their adverse effects. Supratherapeutic doses of AASs are known to be hepatotoxic and regulate the lipoproteins in plasma by modifying the metabolism of lipids in the liver, which is associated with metabolic diseases. However, the effect of AASs on the profile of lipids in plasma is unknown. Objectives To describe the changes in the plasma lipidome exerted by AASs and to discuss these changes in the light of previous research about AASs and de novo lipogenesis in the liver. Methods We treated male Wistar rats with supratherapeutic doses of nandrolone decanoate and testosterone undecanoate. Subsequently, we isolated the blood plasma and performed lipidomics analysis by liquid chromatography-high resolution mass spectrometry. Results Lipid profiling revealed a decrease of sphingolipids and glycerolipids with palmitic, palmitoleic, stearic, and oleic acids. In addition, lipid profiling revealed an increase in free fatty acids and glycerophospholipids with odd-numbered chain fatty acids and/or arachidonic acid. Conclusion The lipid profile presented herein reports the imprint of AASs on the plasma lipidome, which mirrors the downregulation of de novo lipogenesis in the liver. In a broader perspective, this profile will help to understand the influence of androgens on the lipid metabolism in future studies of diseases with dysregulated lipogenesis (e.g. type 2 diabetes, fatty liver disease, and hepatocellular carcinoma).

Overestimation of Risk and Increased Fear of Long-term Complications of Diabetes in People with Type 1 and 2 Diabetes

2019 ◽  
Vol 127 (10) ◽  
pp. 645-652 ◽  
Author(s):  
Florian Arend ◽  
Ulrich A. Müller ◽  
Andreas Schmitt ◽  
Margarete Voigt ◽  
Nadine Kuniss
Keyword(s):  
Diabetes Complications ◽  
Metabolic Diseases ◽  
Population Based ◽  
Diabetes Type ◽  
Complications Of Diabetes ◽  
Personal Risk ◽  
Disease Management Programmes

AbstrAct Objective The quality report of the disease management programmes of North Rhine Westphalia 2016 showed prevalences for long-term complications (neuropathy, nephropathy, retinopathy) of less than 30% for people with diabetes type 1 (DM1) and type 2 (DM2). The aim of this study was to assess risk expectations and fear regarding long-term complications of diabetes in people with DM1 and DM2. Methods We assessed risk expectations and fear regarding diabetes complications in people with DM1 (n=110) and DM2 (n=143 without insulin, n=249 with insulin) visiting an University outpatient department of metabolic diseases. Fear of long-term complications was measured with the “Fear of Complications Questionnaire (FCQ)” (range 0–45 points, scores ≥30 suggest elevated fear). Participants were asked to estimate general and personal risks of long-term complications 10 years after developing diabetes in %. Results Elevated fear of complications (FCQ scores ≥30) was observed in 34.5, 25.9, and 43.0% of those with DM1, DM2 without insulin and DM2 with insulin, respectively. Participants estimated a mean general risk of diabetes-related complications after 10 years amounting to 45.9±15.8% (DM1), 49.7±15.4% (DM2 without insulin), and 52.5±16.4% (DM2 with insulin) and personal risk with 52.5±24.4% (DM1), 45.8±22.7% (DM2 without insulin), and 54.1±23.4% (DM2 with insulin), respectively. Higher risk expectations were associated with higher fear of complications (p<0.001). Conclusion Risk estimations regarding long-term complications were exaggerated in people with DM1 and DM2. About one third of the participants reported elevated fear of complications. Participants’ risk expectations and fear regarding diabetes complications appear excessive compared to population-based prevalence rates.

scholarly journals Proteome plasticity in response to persistent environmental change

2021 ◽  
Author(s):  
Matthew Domnauer ◽  
Fan Zheng ◽  
Liying Li ◽  
Yanxiao Zhang ◽  
Catherine E. Chang ◽  
...  
Keyword(s):  
Environmental Change ◽  
Temperature Change ◽  
Stress Responses ◽  
Variable Component ◽  
Temperature Sensitive ◽  
Cellular Functions ◽  
Alternative Conformation ◽  
Conformational Plasticity ◽  
Cellular Stress Responses

Temperature is a variable component of the environment and all organisms must deal with or adapt to temperature change. Acute temperature change activates cellular stress responses resulting in the refolding or removal of damaged proteins. However, how organisms adapt to long-term temperature change remains largely unexplored. Here, we report that budding yeast responds to long-term high temperature challenge by switching from chaperone induction to the reduction of temperature sensitive proteins and re-localizing a portion of its proteome. Surprisingly, we also find many proteins adopt an alternative conformation. Using Fet3p as an example, we find that the temperature-dependent conformational difference is accompanied by distinct thermostability, subcellular localization, and importantly, cellular functions. We postulate that in addition to the known mechanisms of adaptation, conformational plasticity allows some polypeptides to acquire new biophysical properties and functions when environmental change endures.

scholarly journals Fatty Acid Synthase: Association with Insulin Resistance, Type 2 Diabetes, and Cancer

2009 ◽  
Vol 55 (3) ◽  
pp. 425-438 ◽  
Author(s):  
Javier A Menendez ◽  
Alejandro Vazquez-Martin ◽  
Francisco Jose Ortega ◽  
Jose Manuel Fernandez-Real
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Fatty Acid Synthase ◽  
Metabolic Diseases ◽  
De Novo ◽  
Genetic Alterations ◽  
Insulin Resistant

Abstract Background: An emerging paradigm supports the notion that deregulation of fatty acid synthase (FASN)-catalyzed de novo FA biogenesis could play a central role in the pathogenesis of metabolic diseases sharing the hallmark of insulin-resistance. Content: We reviewed pharmacological and genetic alterations of FASN activity that have been shown to significantly influence energy expenditure rates, fat mass, insulin sensitivity, and cancer risk. This new paradigm proposes that insulin-resistant conditions such as obesity, type 2 diabetes, and cancer arise from a common FASN-driven “lipogenic state”. An important question then is whether the development or the progression of insulin-related metabolic disorders can be prevented or reversed by the modulation of FASN status. If we accept the paradigm of FASN dysfunction as a previously unrecognized link between insulin resistance, type 2 diabetes, and cancer, the use of insulin sensitizers in parallel with forthcoming FASN inhibitors should be a valuable therapeutic approach that, in association with lifestyle interventions, would concurrently improve energy-flux status, ameliorate insulin sensitivity, and alleviate the risk of lipogenic carcinomas. Conclusions: Although the picture is currently incomplete and researchers in the field have plenty of work ahead, the latest clinical and experimental evidence that we discuss illuminates a functional and drug-modifiable link that connects FASN-driven endogenous FA biosynthesis, insulin action, and glucose homeostasis in the natural history of insulin-resistant pathologies.

scholarly journals Correlation of HbA1c levels with Triglyceride, LDL and HDL levels in Type 2 Diabetes Mellitus Patients

2021 ◽  
Vol 3 (2) ◽  
pp. 138-145
Author(s):  
Tri Prasetyorini ◽  
Cindy ◽  
Salbiah
Keyword(s):  
Diabetes Mellitus ◽  
Blood Glucose ◽  
Significant Relationship ◽  
Metabolic Diseases ◽  
Blood Glucose Control ◽  
Design Data ◽  
Type 2 Dm ◽  
Hba1c Levels

Diabetes mellitus (DM) is a group of metabolic diseases with characteristics of increased blood glucose levels that occur due to abnormal insulin secretion, insulin action or both. It is necessary to monitor long-term glycemic status by measuring HbA1c levels to determine the quality of long-term blood glucose control. People with Type 2 DM are more at risk of suffering from cardiovascular disease characterized by dyslipidemia, with a characteristic description of high plasma triglyceride levels, elevated LDL levels and decreased HDL levels. The purpose of this study was to determine the relationship between HbA1c levels and levels of triglycerides, LDL and HDL. This study was an analytic observational study using a cross-sectional design. Data on each variable is secondary data obtained from patients with Type 2 DM at Jakarta Friendship Hospital for the period January-December 2018. The research sample used was 97 data of Type 2 DM patients. Chi-Square test showed an association between HbA1c levels and triglyceride levels with a value of p = 0.046 (< 0.05), there was a relationship between HbA1c levels and LDL levels with p = 0.742 (p > 0.05), and there was a relationship between HbA1c levels and HDL levels with p = 0.241 (p > 0.05). The conclusion obtained in this study is that there is a significant relationship between HbA1c levels and triglyceride levels and there was no significant relationship between HbA1c levels and LDL and HDL levels.

scholarly journals Cellular Stress Responses: Cell Survival and Cell Death

2010 ◽  
Vol 2010 ◽  
pp. 1-23 ◽  
Author(s):  
Simone Fulda ◽  
Adrienne M. Gorman ◽  
Osamu Hori ◽  
Afshin Samali
Keyword(s):  
Cell Death ◽  
Stress Responses ◽  
Cellular Stress ◽  
World Health ◽  
Health Issues ◽  
Survival Pathways ◽  
Cellular Stress Responses ◽  
A Cell ◽  
Exogenous Factors ◽  
Stressed Cell

Cells can respond to stress in various ways ranging from the activation of survival pathways to the initiation of cell death that eventually eliminates damaged cells. Whether cells mount a protective or destructive stress response depends to a large extent on the nature and duration of the stress as well as the cell type. Also, there is often the interplay between these responses that ultimately determines the fate of the stressed cell. The mechanism by which a cell dies (i.e., apoptosis, necrosis, pyroptosis, or autophagic cell death) depends on various exogenous factors as well as the cell's ability to handle the stress to which it is exposed. The implications of cellular stress responses to human physiology and diseases are manifold and will be discussed in this review in the context of some major world health issues such as diabetes, Parkinson's disease, myocardial infarction, and cancer.

scholarly journals Regulation of corticotropin-releasing factor and its types 1 and 2 receptors by leptin in rats subjected to treadmill running-induced stress

2006 ◽  
Vol 191 (1) ◽  
pp. 179-188 ◽  
Author(s):  
Qingling Huang ◽  
Elena Timofeeva ◽  
Denis Richard
Keyword(s):  
De Novo ◽  
Third Ventricle ◽  
Corticotropin Releasing Factor ◽  
Treadmill Running ◽  
Hypothalamic Nucleus ◽  
Long Term Effects ◽  
Induced Stress

The present study was conducted to investigate the long-term effects of subchronic elevation of central leptin levels on the expression of corticotropin-releasing factor (CRF) and its types 1 and 2 receptors in the brain of rats subjected to treadmill running-induced stress. PBS or recombinant murine leptin was infused continuously for a period of 5 days into the third ventricle of rats with the aid of osmotic minipumps at a delivery rate of 2 μg/day. On the fifth day of infusion, rats were killed under resting conditions or after a session of treadmill running, which is known to induce a stress response in rats. Leptin treatment significantly decreased food intake, body weight, white adipose tissue weight, glucose and insulin plasma contents, and blunted the treadmill running-induced elevation in plasma levels of corticosterone. Leptin infusion prevented stress-induced de novo synthesis of CRF in the paraventricular hypothalamic nucleus (PVN), which was measured using the intronic probe for CRF heteronuclear RNA. The induction of the type 1 CRF receptor (CRF1R) in the PVN and supraoptic nucleus in running rats was also significantly blunted by leptin. In contrast, leptin treatment strongly increased the expression of type 2 CRF receptor (CRF2R) in the ventromedial hypothalamic nucleus (VMH). The present results suggest that subchronic elevation of central levels of leptin blunts treadmill running-induced activation of the hypothalamic–pituitary–adrenal axis through the inhibition of activation of the CRFergic PVN neurons, and potentially enhances the anorectic CRF effects via the stimulation of expression of CRF2R in the VMH.

scholarly journals A high content of Slowly Digestible Starch decreases glycemic and insulinemic responses similarly in Asians and Caucasians

2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Aurélie Goux ◽  
Lola Neufcourt ◽  
Olivier Brack ◽  
Fiona Atkinson ◽  
Sophie Vinoy
Keyword(s):  
Metabolic Diseases ◽  
Scientific Evidence ◽  
Controlled Study ◽  
Lower Glucose ◽  
Set Up ◽  
The University ◽  
Slowly Digestible Starch ◽  
Product Effect

AbstractIntroductionGlucose intolerance and type 2 diabetes are increasing worldwide. Current scientific evidence tends to demonstrate that people with an Asian phenotype have a lower glucose tolerance compared to Caucasian phenotype. In addition, in Caucasian population, consumption of products with a high content of Slowly Digestible Starch (SDS) significantly decreases postprandial glycemic and insulinemic responses compared to products with a low-SDS content. The aim of this study was to evaluate the effect of consuming products with varying levels of SDS on postprandial glycemic and insulinemic responses, both in Asian and Caucasian populations.Materials and methodsFive products with varying starch digestibility profiles (determined by the SDS method developed by Englyst) and one glucose solution were tested. A randomized cross-over controlled study was set up in the University of Sydney to study the products’ Glycemic and Insulinemic Indexes (GI and II) and postprandial responses over 2 hours. 12 Caucasian and 12 Asian participants were recruited and consumed 50 g of available carbohydrates from each product (norm ISO-26642(2010)).ResultsAsian participants were 28.0 ± 2.6 yo with a body mass index (BMI) of 21.4 ± 0.3 kg/m2 and Caucasians were 26.0 ± 1.1 yo with a BMI of 22.4 ± 0.5 kg/m2 (no difference between groups). Among the products tested, 3 had a high-SDS content (26 to 28 g SDS / 100g) and 2 had a low-SDS content (0 to 2 g SDS / 100g). GI values for Asian participants ranged between 44 and 54 for high-SDS products (low GI) and were medium (64) or high (90) for low-SDS products. GI values for Caucasian participants ranged between 40 and 48 for high-SDS products (low GI) and between 60 and 79 for low-SDS products. In a statistical model including product effect, ethnicity effect, session effect, and the interaction term product*ethnicity, the product effect was the only significant parameter and products were split according to their SDS content. Furthermore, products with a high-SDS content decrease the glycemic peak value by about 1 mM, both in Asian and Caucasian participants. Consumption of high-SDS products also decreases the insulin demand by 29% and 32% in Asians and Caucasians respectively compared to low-SDS products.DiscussionOur study demonstrates that consumption of products with a high-SDS content similarly decreases the glycemic and insulinemic responses in both Asian and Caucasian participants. This decrease may be beneficial in the long term to prevent metabolic diseases.

scholarly journals Intestinal SGLT1 in metabolic health and disease

2016 ◽  
Vol 310 (11) ◽  
pp. G887-G898 ◽  
Author(s):  
Anders Lehmann ◽  
Pamela J. Hornby
Keyword(s):  
Metabolic Diseases ◽  
Apical Membrane ◽  
Peptide Yy ◽  
Metabolic Effects ◽  
New Class ◽  
Health And Disease ◽  
Glucose Exposure ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The Na+-glucose cotransporter 1 (SGLT1/SLC5A1) is predominantly expressed in the small intestine. It transports glucose and galactose across the apical membrane in a process driven by a Na+ gradient created by Na+-K+-ATPase. SGLT2 is the major form found in the kidney, and SGLT2-selective inhibitors are a new class of treatment for type 2 diabetes mellitus (T2DM). Recent data from patients treated with dual SGLT1/2 inhibitors or SGLT2-selective drugs such as canagliflozin (SGLT1 IC50 = 663 nM) warrant evaluation of SGLT1 inhibition for T2DM. SGLT1 activity is highly dynamic, with modulation by multiple mechanisms to ensure maximal uptake of carbohydrates (CHOs). Intestinal SGLT1 inhibition lowers and delays the glucose excursion following CHO ingestion and augments glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) secretion. The latter is likely due to increased glucose exposure of the colonic microbiota and formation of metabolites such as L cell secretagogues. GLP-1 and PYY secretion suppresses food intake, enhances the ileal brake, and has an incretin effect. An increase in colonic microbial production of propionate could contribute to intestinal gluconeogenesis and mediate positive metabolic effects. On the other hand, a threshold of SGLT1 inhibition that could lead to gastrointestinal intolerability is unclear. Altered Na+ homeostasis and increased colonic CHO may result in diarrhea and adverse gastrointestinal effects. This review considers the potential mechanisms contributing to positive metabolic and negative intestinal effects. Compounds that inhibit SGLT1 must balance the modulation of these mechanisms to achieve therapeutic efficacy for metabolic diseases.

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