scholarly journals LuHui Derivative, A Novel Compound That Inhibits the Fat Mass and Obesity-Associated (FTO), Alleviates the Inflammatory Response and Injury in Hyperlipidemia-Induced Cardiomyopathy

2021 ◽  
Vol 9 ◽  
Author(s):  
Ying Yu ◽  
Yumiao Pan ◽  
Ziyi Fan ◽  
Silun Xu ◽  
Zhiyuan Gao ◽  
...  
Keyword(s):  
Palmitic Acid ◽  
Fat Mass ◽  
Systolic Dysfunction ◽  
Saturated Fatty Acids ◽  
Cell Surface Receptor ◽  
Inflammatory Infiltration ◽  
Cardiac Inflammation ◽  
Cd36 Expression ◽  
New Strategy ◽  
The Impact

Hyperlipidemia is a major risk factor for metabolic disorders and cardiovascular injury. The excessive deposition of saturated fatty acids in the heart leads to chronic cardiac inflammation, which in turn causes myocardial damage and systolic dysfunction. However, the effective suppression of cardiac inflammation has emerged as a new strategy to reduce the impact of hyperlipidemia on cardiovascular disease. In this study, we identified a novel monomer, known as LuHui Derivative (LHD), which reduced the serum levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and reduced lipid deposition in cardiomyocytes. In addition, LHD treatment improved cardiac function, reduced hyperlipidemia-induced inflammatory infiltration in cardiomyocytes and suppressed the release of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). From a mechanistic perspective, cluster of differentiation 36 (CD36), an important cell surface receptor, was identified as a downstream target following the LHD treatment of palmitic acid-induced inflammation in cardiomyocytes. LHD specifically binds the pocket containing the regulatory sites of RNA methylation in the fat mass and obesity-associated (FTO) protein that is responsible for elevated intracellular m6A levels. Moreover, the overexpression of the N6-methyladenosine (m6A) demethylase FTO markedly increased CD36 expression and suppressed the anti-inflammatory effects of LHD. Conversely, loss-of-function of FTO inhibited palmitic acid-induced cardiac inflammation and altered CD36 expression by diminishing the stability of CD36 mRNA. Overall, our results provide evidence for the crucial role of LHD in fatty acid-induced cardiomyocyte inflammation and present a new strategy for the treatment of hyperlipidemia and its complications.

Effect of inhibition of ErbB2-tyrosine kinase domain with lapatinib on cardiac dysfunction compared to the antibody trastuzumab in mice.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11052-e11052
Author(s):  
Carlo G. Tocchetti ◽  
Carmela Coppola ◽  
Domenica Rea ◽  
Noemi Castaldo ◽  
Lorena Guarino ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cardiac Dysfunction ◽  
Systolic Dysfunction ◽  
Myocardial Strain ◽  
Kinase Domain ◽  
Positive Control ◽  
Point Of View ◽  
Tyrosine Kinase Domain ◽  
Cardiac Inflammation ◽  
The Impact

e11052 Background: Lapatinib (L) inhibits ErbB2-tyrosine kinase domain and has been reported (in the few existing trials) to be associated with a low risk of cardiac dysfunction (2%), while the prototypical Trastuzumab (T) increases the frequency of asymptomatic ejection fraction decrease by 3-18%, and the risk of heart failure by 2-4%. Here, we characterize our L murine cardiotoxicity model. Methods: Cardiac function was measured with fractional shortening (FS) by M-mode echocardiography, and with radial myocardial strain (%) with speckle tracking (ST) in sedated C57BL6 mice (2-4 mo. old) at day 0, and after 2 and 7 days of daily administration of L (100mg/kg/day orally), and in control mice. For comparison we used our well-established models with T (2.25 mg/kg/day, ip), and Doxorubicin (D, 2.17 mg/kg/day ip) as positive control. On excised hearts, we evaluated TNFα and CD68 by immunohistochemistry. Results: FS was reduced with D at 2 days: 52±0.2%, p<.001 vs 60±0.4% (sham), while L and T decreased FS only at 7 days (56±2 and 49±1.5%, respectively, both p<.05 vs 60±0.5% for sham). Interestingly, FS reduction with L was milder (p=.01) than with T. By immunohistochemistry, all treatments increased cardiac inflammation significantly vs controls. In particular, with T more myocytes were positive for TNFα (6±1%), and there were more CD68 cells/mm2 (72±6) compared to L (2±.2% and 27±4, respectively, both p<.02 vs T). D-treated hearts exhibited the highest values. Importantly, from a diagnostic point of view, with ST-echocardiogaphy, myocardial strain was reduced early at 2 days with L and T, predicting cardiotoxicity: 34±7% for L, 44±7% for T (p=NS), both p<.05 vs sham (66±.6%). Conclusions: Specifically targeting the tyrosine kinase domain of ErbB2 with L is less cardiotoxic than T. Nevertheless, both dysfunctions occur later than D. Myocardial strain identifies systolic dysfunction earlier than conventional echo and can be useful to predict cardiotoxicity in these settings. From a clinical point of view, we plan to evaluate the impact of ST echocardiography in early prediction of anti-ErbB2 toxicity in patients, while dissecting myocardial toxicity mechanisms in our animal models.

scholarly journals Docosahexaenoic and Eicosapentaenoic Acids Prevent Altered-Muc2 Secretion Induced by Palmitic Acid by Alleviating Endoplasmic Reticulum Stress in LS174T Goblet Cells

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2179
Author(s):  
Quentin Escoula ◽  
Sandrine Bellenger ◽  
Michel Narce ◽  
Jérôme Bellenger
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Palmitic Acid ◽  
Er Stress ◽  
Unsaturated Fatty Acids ◽  
Saturated Fatty Acids ◽  
Goblet Cells ◽  
The Impact

Diets high in saturated fatty acids (FA) represent a risk factor for the development of obesity and associated metabolic disorders, partly through their impact on the epithelial cell barrier integrity. We hypothesized that unsaturated FA could alleviate saturated FA-induced endoplasmic reticulum (ER) stress occurring in intestinal secretory goblet cells, and consequently the reduced synthesis and secretion of mucins that form the protective mucus barrier. To investigate this hypothesis, we treated well-differentiated human colonic LS174T goblet cells with palmitic acid (PAL)—the most commonly used inducer of lipotoxicity in in vitro systems—or n-9, n-6, or n-3 unsaturated fatty acids alone or in co-treatment with PAL, and measured the impact of such treatments on ER stress and Muc2 production. Our results showed that only eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids protect goblet cells against ER stress-mediated altered Muc2 secretion induced by PAL, whereas neither linolenic acid nor n-9 and n-6 FA are able to provide such protection. We conclude that EPA and DHA could represent potential therapeutic nutrients against the detrimental lipotoxicity of saturated fatty acids, associated with type 2 diabetes and obesity or inflammatory bowel disease. These in vitro data remain to be explored in vivo in a context of dietary obesity.

scholarly journals Breakfast Cereals Intended for Children: Opportunities for Reformulation and Potential Impact on Nutrient Intake

Foods ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1772
Author(s):  
Mariana Santos ◽  
Filipa Matias ◽  
Ana Isabel Rito ◽  
Isabel Castanheira ◽  
Duarte Torres ◽  
...  
Keyword(s):  
Dietary Fiber ◽  
Nutritional Quality ◽  
Saturated Fatty Acids ◽  
World Health ◽  
Health Concern ◽  
Regional Office ◽  
Nutrient Profile ◽  
Dietary Fiber Intake ◽  
Directorate General ◽  
The Impact

Ready-to-eat cereals (RTECs) have become a popular breakfast option claiming to provide important nutrients to children’s diets, despite being a source of excess sugar and, therefore, a health concern. Thus, food reformulation constitutes an important public health strategy that could benefit from inputs provided by nutrient profiling. This study aimed to assess the adequacy of the RTECs for children available in Portuguese supermarkets, applying three nutrient profile models (NPMs)—the nutrient profile model of the World Health Organization’s Regional Office for Europe (WHO-EURO), the profile of the private-sector EU Pledge (EU-Pledge), and the national model developed by the Directorate-General of Health (NPM-PT)—in order to explore the potential for reformulation of the RTECs identified as not adequate and evaluate the impact of RTECs’ reformulation on the nutritional quality of Portuguese children’s diets. In total, 78 RTECs intended for children were assessed and two scenarios—current (not considering reformulation) and alternative (considering reformulation to accomplish the nutrient profile requirements)—were considered to assess the impact of reformulation on nutritional quality. Across all RTECs, only 5.1% could be promoted to children according to the considered NPMs. The most common nutrients requiring reformulation were sugar, saturated fatty acids (SFA), salt, and dietary fiber. The scenarios of reformulation considered could reduce the RTECs average content of total sugars, SFA, and salt by 43%, 8.7%, and 1.1%, respectively, and dietary fiber intake could be increased by 34%. Thus, these results support policies to implement reformulation strategies for developing healthier food products to be promoted to children.

scholarly journals Differential Deleterious Impact of Highly Saturated Versus Monounsaturated Fat Intake on Vascular Function, Structure, and Mechanics in Mice

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 1003
Author(s):  
Elena Vega-Martín ◽  
Marta Gil-Ortega ◽  
Raquel González-Blázquez ◽  
Sara Benedito ◽  
Jesús Fernández-Felipe ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Arterial Stiffness ◽  
Thoracic Aorta ◽  
Vascular Function ◽  
Saturated Fatty Acids ◽  
Vascular Wall ◽  
Monounsaturated Fatty Acids ◽  
Mesenteric Arteries ◽  
Monounsaturated Fat ◽  
The Impact

Vegetable oils such as palm oil (enriched in saturated fatty acids, SFA) and high-oleic-acid sunflower oil (HOSO, containing mainly monounsaturated fatty acids, MUFA) have emerged as the most common replacements for trans-fats in the food industry. The aim of this study is to analyze the impact of SFA and MUFA-enriched high-fat (HF) diets on endothelial function, vascular remodeling, and arterial stiffness compared to commercial HF diets. Five-week-old male C57BL6J mice were fed a standard (SD), a HF diet enriched with SFA (saturated oil-enriched Food, SOLF), a HF diet enriched with MUFA (unsaturated oil-enriched Food, UOLF), or a commercial HF diet for 8 weeks. Vascular function was analyzed in the thoracic aorta. Structural and mechanical parameters were assessed in mesenteric arteries by pressure myography. SOLF, UOLF, and HF diet reduced contractile responses to phenylephrine and induced endothelial dysfunction in the thoracic aorta. A significant increase in the β-index, and thus in arterial stiffness, was also detected in mesenteric arteries from the three HF groups, due to enhanced deposition of collagen in the vascular wall. SOLF also induced hypotrophic inward remodeling. In conclusion, these data demonstrate a deleterious effect of HF feeding on obesity-related vascular alterations that is exacerbated by SFA.

scholarly journals Gestational Diabetes Mellitus and Infant Adiposity at Birth: A Systematic Review and Meta-Analysis of Therapeutic Interventions

2021 ◽  
Vol 10 (4) ◽  
pp. 835
Author(s):  
Manoja P. Herath ◽  
Jeffrey M. Beckett ◽  
Andrew P. Hills ◽  
Nuala M. Byrne ◽  
Kiran D. K. Ahuja
Keyword(s):  
Diabetes Mellitus ◽  
Adipose Tissue ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Fat Mass ◽  
Metabolic Disorders ◽  
Later Life ◽  
Therapeutic Interventions ◽  
Increased Risk ◽  
The Impact

Exposure to untreated gestational diabetes mellitus (GDM) in utero increases the risk of obesity and type 2 diabetes in adulthood, and increased adiposity in GDM-exposed infants is suggested as a plausible mediator of this increased risk of later-life metabolic disorders. Evidence is equivocal regarding the impact of good glycaemic control in GDM mothers on infant adiposity at birth. We systematically reviewed studies reporting fat mass (FM), percent fat mass (%FM) and skinfold thicknesses (SFT) at birth in infants of mothers with GDM controlled with therapeutic interventions (IGDMtr). While treating GDM lowered FM in newborns compared to no treatment, there was no difference in FM and SFT according to the type of treatment (insulin, metformin, glyburide). IGDMtr had higher overall adiposity (mean difference, 95% confidence interval) measured with FM (68.46 g, 29.91 to 107.01) and %FM (1.98%, 0.54 to 3.42) but similar subcutaneous adiposity measured with SFT, compared to infants exposed to normal glucose tolerance (INGT). This suggests that IGDMtr may be characterised by excess fat accrual in internal adipose tissue. Given that intra-abdominal adiposity is a major risk factor for metabolic disorders, future studies should distinguish adipose tissue distribution of IGDMtr and INGT.

scholarly journals Palmitic acid promotes resistin-induced insulin resistance and inflammation in SH-SY5Y human neuroblastoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hamza Amine ◽  
Yacir Benomar ◽  
Mohammed Taouis
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Palmitic Acid ◽  
Lipid Rafts ◽  
Acid Treatment ◽  
Protective Action ◽  
Saturated Fatty Acids ◽  
Membrane Lipid ◽  
Human Neuroblastoma ◽  
Peripheral Tissues

AbstractSaturated fatty acids such as palmitic acid promote inflammation and insulin resistance in peripheral tissues, contrasting with the protective action of polyunsaturated fatty acids such docosahexaenoic acid. Palmitic acid effects have been in part attributed to its potential action through Toll-like receptor 4. Beside, resistin, an adipokine, also promotes inflammation and insulin resistance via TLR4. In the brain, palmitic acid and resistin trigger neuroinflammation and insulin resistance, but their link at the neuronal level is unknown. Using human SH-SY5Yneuroblastoma cell line we show that palmitic acid treatment impaired insulin-dependent Akt and Erk phosphorylation whereas DHA preserved insulin action. Palmitic acid up-regulated TLR4 as well as pro-inflammatory cytokines IL6 and TNFα contrasting with DHA effect. Similarly to palmitic acid, resistin treatment induced the up-regulation of IL6 and TNFα as well as NFκB activation. Importantly, palmitic acid potentiated the resistin-dependent NFkB activation whereas DHA abolished it. The recruitment of TLR4 to membrane lipid rafts was increased by palmitic acid treatment; this is concomitant with the augmentation of resistin-induced TLR4/MYD88/TIRAP complex formation mandatory for TLR4 signaling. In conclusion, palmitic acid increased TLR4 expression promoting resistin signaling through TLR4 up-regulation and its recruitment to membrane lipid rafts.

Abstract MP014: Very Long Chain Saturated Fatty Acids and Diabetes Risk: Meta-Analysis of Cohort Studies in the FORCE Consortium

Circulation ◽  
2017 ◽  
Vol 135 (suppl_1) ◽  
Author(s):  
Amanda Fretts ◽  
Fumiaki Imamura ◽  
Chaoyu Yu ◽  
Alexis C Frazier-Wood ◽  
Maria Lankinen ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Palmitic Acid ◽  
Lower Risk ◽  
Fixed Effects ◽  
Meta Analysis ◽  
Arachidic Acid ◽  
Saturated Fatty Acids ◽  
Diabetes Risk ◽  
Incident Diabetes ◽  
Long Chain

Background: Circulating saturated fatty acids are biomarkers of diet and metabolism that may influence the pathogenesis of diabetes. Unlike palmitic acid (16:0), which has been extensively studied, little is known of the relationship of very long-chain saturated fatty acids (VLSFAs), with 20 carbons or more, to diabetes risk. Objective: To investigate the associations of circulating levels of VLSFA with incident diabetes. Methods: A meta-analysis was conducted within a consortium of prospective (cohort or nested case-control) studies having circulating measures of one or more VLSFAs, including arachidic acid (20:0), behenic acid (22:0) and lignoceric acid (24:0). Standardized analysis was conducted in each study using pre-specified models, exposures, outcomes, and covariates. Study-specific estimates were pooled using fixed effects meta-analysis. Results: Current findings were based on 9 participating studies, including 46,549 total participants and 13,750 incident diabetes. In multivariable-adjusted analyses, higher levels of all 3 VLSFAs were associated with lower risk of incident diabetes. Pooled RRs (95% CI) per interquintile range were 0.80 (0.71-0.90) for 20:0; 0.83 (0.76-0.91) for 22:0; and 0.70 (0.63-0.79) for 24:0, after adjustment for demographics, lifestyle factors and clinical conditions. Additional adjustments for circulating palmitic acid and triglyceride levels moved the RRs toward the null (illustrated for 24:0, in model 3 of the Figure ). Conclusions: Based on meta-analysis of results from several studies around the world, biomarker levels of VLSFA are associated with lower risk of incident diabetes, potentially mediated by effects on circulating triglycerides and 16:0.

scholarly journals Dairy Fat Consumption and the Risk of Metabolic Syndrome: An Examination of the Saturated Fatty Acids in Dairy

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2200 ◽  
Author(s):  
Unger ◽  
Torres-Gonzalez ◽  
Kraft
Keyword(s):  
Metabolic Syndrome ◽  
Fatty Acids ◽  
Disease Risk ◽  
Saturated Fatty Acids ◽  
Saturated Fat ◽  
Dietary Guidelines ◽  
The Body ◽  
Specific Chemical ◽  
Dairy Consumption ◽  
The Impact

Lifestyle is a key modifiable risk factor involved in the manifestation of metabolic syndrome and, in particular, diet plays a pivotal role in its prevention and development. Current dietary guidelines discourage the consumption of saturated fat and dietary sources rich in saturated fat, such as dairy products, despite data suggesting that full-fat dairy consumption is protective against metabolic syndrome. This narrative review assessed the recent epidemiological and clinical research that examined the consumption of dairy-derived saturated fatty acids (SFA) on metabolic syndrome risk. In addition, this review evaluated studies of individual SFA to gain insight into the potential mechanisms at play with intake of a diet enriched with these dairy-derived fatty acids. This work underscores that SFA are a heterogenous class of fatty acids that can differ considerably in their biological activity within the body depending on their length and specific chemical structure. In summary, previous work on the impact of dairy-derived SFA consumption on disease risk suggests that there is currently insufficient evidence to support current dietary guidelines which consolidate all dietary SFA into a single group of nutrients whose consumption should be reduced, regardless of dietary source, food matrix, and composition.

Ethnic differences in sympathetic nervous system-mediated energy expenditure

1991 ◽  
Vol 261 (6) ◽  
pp. E789-E794 ◽  
Author(s):  
M. F. Saad ◽  
S. A. Alger ◽  
F. Zurlo ◽  
J. B. Young ◽  
C. Bogardus ◽  
...  
Keyword(s):  
Nervous System ◽  
Energy Expenditure ◽  
Sympathetic Nervous System ◽  
Fat Mass ◽  
Weight Maintenance ◽  
Resting Metabolic Rate ◽  
Fat Free Mass ◽  
Beta Adrenoceptor ◽  
Sympathetic Nervous ◽  
The Impact

The impact of sympathetic nervous system (SNS) activity on energy expenditure (EE) was evaluated in nondiabetic Caucasian and Pima Indian men while on a weight-maintenance diet using two approaches as follows. 1) The relationship between 24-h EE, measured in a respiratory chamber, and 24-h urinary norepinephrine was studied in 36 Caucasians [32 +/- 8 (SD) yr, 95 +/- 41 kg, 22 +/- 13% fat] and 33 Pimas (29 +/- 6 yr, 103 +/- 28 kg, 30 +/- 9% fat). There was no difference between the two groups in 24-h EE (2,422 vs. 2,523 kcal/24 h) and in urinary norepinephrine (28 vs. 31 micrograms/24 h), even after adjusting for body size and composition. Twenty-four-hour EE correlated significantly with 24-h urinary norepinephrine in Caucasians (r = 0.78, P less than 0.001) but not in Pimas (r = 0.03), independent of fat-free mass (FFM), fat mass, and age. 2) The effect of beta-adrenoceptor blockade with propranolol (120 micrograms/kg FFM bolus and 1.2 micrograms.kg FFM-1.min-1 for 45 min) on the resting metabolic rate (RMR) was evaluated in 36 Caucasians (30 +/- 6 yr, 103 +/- 36 kg, 25 +/- 11% fat) and 32 Pimas (28 +/- 6 yr, 100 +/- 34 kg, 27 +/- 10% fat). The RMR was similar in the two groups (2,052 vs. 1,973 kcal/24 h) even after adjustment for FFM, fat mass, and age and dropped significantly after propranolol infusion in Caucasians (-3.9%, P less than 0.001) but not in Pimas (-0.8%, P = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Antagonism Between Saturated and Unsaturated Fatty Acids in ROS Mediated Lipotoxicity in Rat Insulin-Producing Cells

2015 ◽  
Vol 36 (3) ◽  
pp. 852-865 ◽  
Author(s):  
Wiebke Gehrmann ◽  
Wiebke Würdemann ◽  
Thomas Plötz ◽  
Anne Jörns ◽  
Sigurd Lenzen ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Oleic Acid ◽  
Palmitic Acid ◽  
Unsaturated Fatty Acids ◽  
Saturated Fatty Acids ◽  
H2o2 Production ◽  
Β Cell ◽  
Specific Expression ◽  
Insulin Producing Cells ◽  
H2o2 Formation

Background/Aims: Elevated levels of non-esterified fatty acids (NEFAs) are under suspicion to mediate β-cell dysfunction and β-cell loss in type 2 diabetes, a phenomenon known as lipotoxicity. Whereas saturated fatty acids show a strong cytotoxic effect upon insulin-producing cells, unsaturated fatty acids are not toxic and can even prevent toxicity. Experimental evidence suggests that oxidative stress mediates lipotoxicity and there is evidence that the subcellular site of ROS formation is the peroxisome. However, the interaction between unsaturated and saturated NEFAs in this process is unclear. Methods: Toxicity of rat insulin-producing cells after NEFA incubation was measured by MTT and caspase assays. NEFA induced H2O2 formation was quantified by organelle specific expression of the H2O2 specific fluorescence sensor protein HyPer. Results: The saturated NEFA palmitic acid had a significant toxic effect on the viability of rat insulin-producing cells. Unsaturated NEFAs with carbon chain lengths >14 showed, irrespective of the number of double bonds, a pronounced protection against palmitic acid induced toxicity. Palmitic acid induced H2O2 formation in the peroxisomes of insulin-producing cells. Oleic acid incubation led to lipid droplet formation, but in contrast to palmitic acid induced neither an ER stress response nor peroxisomal H2O2 generation. Furthermore, oleic acid prevented palmitic acid induced H2O2 production in the peroxisomes. Conclusion: Thus unsaturated NEFAs prevent deleterious hydrogen peroxide generation during peroxisomal β-oxidation of long-chain saturated NEFAs in rat insulin-producing cells.

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