Pharmacological inhibition to examine the role of DGAT1 in dietary lipid absorption in rodents and humans

2013 ◽  
Vol 304 (11) ◽  
pp. G958-G969 ◽  
Author(s):  
Benjamin S. Maciejewski ◽  
Jennifer L. LaPerle ◽  
Danny Chen ◽  
Avijit Ghosh ◽  
William J. Zavadoski ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Human Subjects ◽  
Plasma Concentrations ◽  
Large Family ◽  
Dietary Lipid ◽  
Lipid Absorption ◽  
Pharmacological Intervention ◽  
Dependent Inhibition ◽  
The Impact

Alterations in fat metabolism, in particular elevated plasma concentrations of free fatty acids and triglycerides (TG), have been implicated in the pathogenesis of Type 2 diabetes, obesity, and cardiovascular disease. Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a member of the large family of membrane-bound O-acyltransferases, catalyzes the final step in triacylglycerol formation. In the intestine, DGAT1 is one of the acyltransferases responsible for the reesterficiation of dietary TG. Following a single dose of a selective pharmacological inhibitor of DGAT1, PF-04620110, a dose-dependent inhibition of TG and vitamin A absorption postprandially was demonstrated in rodents and human subjects. In C57/BL6J mice, acute DGAT1 inhibition alters the temporal and spatial pattern of dietary lipid absorption. To understand the impact of DGAT1 inhibition on enterocyte lipid metabolism, lipomic profiling was performed in rat intestine and plasma as well as human plasma. DGAT1 inhibition causes an enrichment of polyunsaturated fatty acids within the TG class of lipids. This pharmacological intervention gives us insight as to the role of DGAT1 in human dietary lipid absorption.

scholarly journals Antioxidants Promote Intestinal Tumor Progression in Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 241
Author(s):  
Zhiyuan V. Zou ◽  
Kristell Le Gal ◽  
Ahmed E. El Zowalaty ◽  
Lara E. Pehlivanoglu ◽  
Viktor Garellick ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Tumor Progression ◽  
Human Subjects ◽  
Plasma Concentrations ◽  
Intestinal Tumor ◽  
Adenomatous Polyposis ◽  
Intestinal Tumors ◽  
The Impact

Dietary antioxidants and supplements are widely used to protect against cancer, even though it is now clear that antioxidants can promote tumor progression by helping cancer cells to overcome barriers of oxidative stress. Although recent studies have, in great detail, explored the role of antioxidants in lung and skin tumors driven by RAS and RAF mutations, little is known about the impact of antioxidant supplementation on other cancers, including Wnt-driven tumors originating from the gut. Here, we show that supplementation with the antioxidants N-acetylcysteine (NAC) and vitamin E promotes intestinal tumor progression in the ApcMin mouse model for familial adenomatous polyposis, a hereditary form of colorectal cancer, driven by Wnt signaling. Both antioxidants increased tumor size in early neoplasias and tumor grades in more advanced lesions without any impact on tumor initiation. Importantly, NAC treatment accelerated tumor progression at plasma concentrations comparable to those obtained in human subjects after prescription doses of the drug. These results demonstrate that antioxidants play an important role in the progression of intestinal tumors, which may have implications for patients with or predisposed to colorectal cancer.

scholarly journals The Effect of Fusarium verticillioides Fumonisins on Fatty Acids, Sphingolipids, and Oxylipins in Maize Germlings

2021 ◽  
Vol 22 (5) ◽  
pp. 2435
Author(s):  
Marzia Beccaccioli ◽  
Manuel Salustri ◽  
Valeria Scala ◽  
Matteo Ludovici ◽  
Andrea Cacciotti ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fusarium Verticillioides ◽  
Fungal Growth ◽  
Defense Responses ◽  
Ceramide Synthase ◽  
Ear Rot ◽  
In Planta ◽  
Disease Symptoms ◽  
The Impact

Fusarium verticillioides causes multiple diseases of Zea mays (maize) including ear and seedling rots, contaminates seeds and seed products worldwide with toxic chemicals called fumonisins. The role of fumonisins in disease is unclear because, although they are not required for ear rot, they are required for seedling diseases. Disease symptoms may be due to the ability of fumonisins to inhibit ceramide synthase activity, the expected cause of lipids (fatty acids, oxylipins, and sphingolipids) alteration in infected plants. In this study, we explored the impact of fumonisins on fatty acid, oxylipin, and sphingolipid levels in planta and how these changes affect F. verticillioides growth in maize. The identity and levels of principal fatty acids, oxylipins, and over 50 sphingolipids were evaluated by chromatography followed by mass spectrometry in maize infected with an F. verticillioides fumonisin-producing wild-type strain and a fumonisin-deficient mutant, after different periods of growth. Plant hormones associated with defense responses, i.e., salicylic and jasmonic acid, were also evaluated. We suggest that fumonisins produced by F. verticillioides alter maize lipid metabolism, which help switch fungal growth from a relatively harmless endophyte to a destructive necrotroph.

scholarly journals The Role of Micronutrients in Support of the Immune Response against Viral Infections

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3198 ◽  
Author(s):  
Francesco Pecora ◽  
Federica Persico ◽  
Alberto Argentiero ◽  
Cosimo Neglia ◽  
Susanna Esposito
Keyword(s):  
Fatty Acids ◽  
Immune Response ◽  
Immune System ◽  
Viral Infections ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Optimal Function ◽  
The Impact

Viral infections are a leading cause of morbidity and mortality worldwide, and the importance of public health practices including handwashing and vaccinations in reducing their spread is well established. Furthermore, it is well known that proper nutrition can help support optimal immune function, reducing the impact of infections. Several vitamins and trace elements play an important role in supporting the cells of the immune system, thus increasing the resistance to infections. Other nutrients, such as omega-3 fatty acids, help sustain optimal function of the immune system. The main aim of this manuscript is to discuss of the potential role of micronutrients supplementation in supporting immunity, particularly against respiratory virus infections. Literature analysis showed that in vitro and observational studies, and clinical trials, highlight the important role of vitamins A, C, and D, omega-3 fatty acids, and zinc in modulating the immune response. Supplementation with vitamins, omega 3 fatty acids and zinc appears to be a safe and low-cost way to support optimal function of the immune system, with the potential to reduce the risk and consequences of infection, including viral respiratory infections. Supplementation should be in addition to a healthy diet and fall within recommended upper safety limits set by scientific expert bodies. Therefore, implementing an optimal nutrition, with micronutrients and omega-3 fatty acids supplementation, might be a cost-effective, underestimated strategy to help reduce the burden of infectious diseases worldwide, including coronavirus disease 2019 (COVID-19).

scholarly journals Mitochondrial-Targeted Antioxidant MitoQ Prevents E. coli Lipopolysaccharide-Induced Accumulation of Triacylglycerol and Lipid Droplets Biogenesis in Epithelial Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Ekaterina Fock ◽  
Vera Bachteeva ◽  
Elena Lavrova ◽  
Rimma Parnova
Keyword(s):  
Fatty Acids ◽  
Epithelial Cells ◽  
Lipid Droplets ◽  
Cellular Respiration ◽  
Mitochondrial Activity ◽  
Energy Regulation ◽  
Metabolic Shift ◽  
Functional Connections ◽  
The Impact

The effect of bacterial lipopolysaccharide (LPS) on eukaryotic cell could be accompanied by a significant metabolic shift that includes accumulation of triacylglycerol (TAG) in lipid droplets (LD), ubiquitous organelles associated with fatty acid storage, energy regulation and demonstrated tight spatial and functional connections with mitochondria. The impairment of mitochondrial activity under pathological stimuli has been shown to provoke TAG storage and LD biogenesis. However the potential mechanisms that link mitochondrial disturbances and TAG accumulation are not completely understood. We hypothesize that mitochondrial ROS (mROS) may play a role of a trigger leading to subsequent accumulation of intracellular TAG and LD in response to a bacterial stimulus. Using isolated epithelial cells from the frog urinary bladder, we showed that LPS decreased fatty acids oxidation, enhanced TAG deposition, and promoted LD formation. LPS treatment did not affect the mitochondrial membrane potential but increased cellular ROS production and led to impairment of mitochondrial function as revealed by decreased ATP production and a reduced maximal oxygen consumption rate (OCR) and OCR directed at ATP turnover. The mitochondrial-targeted antioxidant MitoQ at a dose of 25 nM did not prevent LPS-induced alterations in cellular respiration, but, in contrast to nonmitochondrial antioxidant α-tocopherol, reduced the effect of LPS on the generation of ROS, restored the LPS-induced decline of fatty acids oxidation, and prevented accumulation of TAG and LD biogenesis. The data obtained indicate the key signaling role of mROS in the lipid metabolic shift that occurs under the impact of a bacterial pathogen in epithelial cells.

scholarly journals Adrenal adaptation in potassium-depleted men: role of progesterone?

2019 ◽  
Vol 35 (11) ◽  
pp. 1901-1908
Author(s):  
Anne Blanchard ◽  
Sylvie Brailly Tabard ◽  
Antonin Lamaziere ◽  
Damien Bergerot ◽  
Valentina Zhygalina ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Human Subjects ◽  
Plasma Concentrations ◽  
Plasma Renin ◽  
Plasma Potassium ◽  
Potassium Depletion ◽  
Healthy Human ◽  
Plasma Aldosterone Concentration ◽  
Tandem Mass Spectroscopy

AbstractBackgroundIn rodents, the stimulation of adrenal progesterone is necessary for renal adaptation under potassium depletion. Here, we sought to determine the role of progesterone in adrenal adaptation in potassium-depleted healthy human volunteers and compared our findings with data collected in patients with Gitelman syndrome (GS), a salt-losing tubulopathy.MethodsTwelve healthy young men were given a potassium-depleted diet for 7 days at a tertiary referral medical centre (NCT02297048). We measured by liquid chromatography coupled to tandem mass spectroscopy plasma steroid concentrations at Days 0 and 7 before and 30 min after treatment with tetracosactide. We compared these data with data collected in 10 GS patients submitted to tetracosactide test.ResultsThe potassium-depleted diet decreased plasma potassium in healthy subjects by 0.3 ± 0.1 mmol/L, decreased plasma aldosterone concentration by 50% (P = 0.0332) and increased plasma 17-hydroxypregnenolone concentration by 45% (P = 0.0232) without affecting other steroids. CYP17 activity, as assessed by 17-hydroxypregnenolone/pregnenolone ratio, increased by 60% (P = 0.0389). As compared with healthy subjects, GS patients had 3-fold higher plasma concentrations of aldosterone, 11-deoxycortisol (+30%) and delta 4-androstenedione (+14%). Their post-tetracosactide progesterone concentration was 2-fold higher than that of healthy subjects and better correlated to plasma potassium than to plasma renin.ConclusionThe increase in 17-hydroxypregnenolone concentration after mild potassium depletion in otherwise healthy human subjects suggests that 17 hydroxylation of pregnenolone prevents the increase in progesterone observed in potassium-depleted mice. The unexpected over-response of non-mineralocorticoid steroids to tetracosactide in GS subjects suggests that the adrenal system not only adapts to sodium depletion but may also respond to hypokalaemia.

The Role of Dietary Lipid in the Regulation of Unconjugated Hyperbilirubinaemia in Gunn Rats

1979 ◽  
Vol 57 (4) ◽  
pp. 327-337 ◽  
Author(s):  
J. L. Gollan ◽  
D. R. Hole ◽  
Barbara H. Billing
Keyword(s):  
Fatty Acid ◽  
Plasma Concentrations ◽  
Dietary Lipid ◽  
Normal Diet ◽  
Degree Of Saturation ◽  
Bilirubin Concentration ◽  
Fatty Acid Chain ◽  
Gunn Rats ◽  
Plasma Bilirubin

1. The purpose of this study was to characterize the mechanisms of diet-induced hyperbilirubinaemia in Gunn rats with emphasis on the role of lipids, and to examine their relationship with regard to fasting hyperbilirubinaemia. 2. A lipid-free normocaloric diet produced a threefold increase in plasma bilirubin concentration (baseline 109.4 μmol/l), which was maximal by 10 days and thereafter remained constant. The level of hyperbilirubinaemia attained was not influenced by fasting or phenobarbitone, and returned to baseline concentration within 10 days of resuming a normal diet. 3. Determination of hepatic bilirubin showed that the magnitude of the hepatic bilirubin pool was increased by the lipid-free diet but was unchanged by fasting. Hepatic ligandin concentrations were comparable in fasted Gunn rats and those fed normal or lipid-free diets, although total hepatic ligandin was reduced in the fasted animals. 4. The hyperbilirubinaemic effect of the lipid-free diet was largely reversed by the inclusion of 10% lipid in the diet and was affected to a lesser extent by 5% lipid. Similar reductions in plasma bilirubin concentration were observed with a variety of other lipids (10%), regardless of their fatty acid chain length or degree of saturation. 5. In fasting animals a direct correlation was observed between plasma bilirubin and free fatty acid concentrations and insulin levels were greatly depressed, whereas in those fed on the lipid-free diet no significant changes were evident in plasma concentrations of free fatty acids or insulin. 6. Plasma bilirubin concentration was unrelated to alterations in plasma triglycerides produced by the administration of clofibrate. However, an unexplained decrease in plasma bilirubin (40%) without a significant change in triglycerides was noted when clofibrate was added to the lipid-free diet. 7. Analysis of kinetic data obtained from [14C]bilirubin clearance studies revealed that hyperbilirubinaemia associated with the lipid-free diet reflected a marked reduction (60%) in plasma clearance with no change in bilirubin turnover. This was accompanied by a relative redistribution of bilirubin from the extravascular pool to the plasma pool. 8. Although these studies indicate that fasting and the withdrawal of dietary lipid have some similar effects on bilirubin metabolism, it seems likely that different mechanisms are responsible for the hyperbilirubinaemia.

scholarly journals Is apolipoprotein A-IV rate limiting in the intestinal transport and absorption of triglyceride?

2013 ◽  
Vol 304 (12) ◽  
pp. G1128-G1135 ◽  
Author(s):  
Alison B. Kohan ◽  
Fei Wang ◽  
Xiaoming Li ◽  
Abbey E. Vandersall ◽  
Sarah Huesman ◽  
...  
Keyword(s):  
Intestinal Mucosa ◽  
Dietary Fat ◽  
Intestinal Transport ◽  
Dietary Lipid ◽  
Lipid Absorption ◽  
Lymphatic Transport ◽  
Apolipoprotein A ◽  
Rate Limiting

Apolipoprotein A-IV (apoA-IV) is synthesized by the intestine and secreted when dietary fat is absorbed and transported into lymph associated with chylomicrons. We have recently demonstrated that loss of apoA-IV increases chylomicron size and delays its clearance from the blood. There is still uncertainty, however, about the precise role of apoA-IV on the transport of dietary fat from the intestine into the lymph. ApoA-IV knockout (KO) mice do not have a gross defect in dietary lipid absorption, as measured by oral fat tolerance and fecal fat measurements. Here, using the in vivo lymph fistula mouse model, we show that the cumulative secretion of triglyceride (TG) into lymph in apoA-IV KO mice is very similar to that of wild-type (WT) mice. However, the apoA-IV KO mice do have subtle changes in TG accumulation in the intestinal mucosa during a 6-h continuous, but not bolus, infusion of lipid. There are no changes in the ratio of esterified to free fatty acids in the intestinal mucosa of the apoA-IV KO, however. When we extended these findings, by giving a higher dose of lipid (6 μmol/h) and for a longer infusion period (8 h), we found no effect of apoA-IV KO on intestinal TG absorption. This higher lipid infusion most certainly stresses the intestine, as we see a drastically lower absorption of TG (in both WT and KO mice); however, the loss of A-IV does not exacerbate this effect. This supports our hypothesis that apoA-IV is not required for TG absorption in the intestine. Our data suggest that the mechanisms by which the apoA-IV KO intestine responds to intestinal lipid may not be different from their WT counterparts. We conclude that apoA-IV is not required for normal lymphatic transport of TG.

Adolescent Obesity and Eating Disorders: Can Calorie Restriction have a Positive Impact

2020 ◽  
Vol 16 (4) ◽  
pp. 433-443
Author(s):  
Naveen Visweswaraiah ◽  
Kousalya Nathan
Keyword(s):  
Calorie Restriction ◽  
Lifestyle Modification ◽  
Positive Impact ◽  
Food Preferences ◽  
Accelerated Aging ◽  
Adolescent Obesity ◽  
Premature Aging ◽  
Pharmacological Intervention ◽  
The Impact

Background: The current obesogenic environment with relatively increased affordability and availability of high calorie food and beverages, has led to an alarming increase in the prevalence of obesity and related lifestyle disorders in children and adolescents, predisposing them to accelerated aging. The increased prevalence may be due to the eating behavior of adolescents, their genetic and molecular etiology and/or due to the impact of psychological stress and their wrong lifestyle choices. Calorie restriction has been extensively researched for reducing the obesity in adolescents and adults but is yet to be successfully implemented. Objective: The present review paper focuses on the types of calorie restriction diets, the role of its mimics and the nutrigenomic mechanisms that may be helpful in reducing obesity and related disorders in the adolescents. The role of behavioral therapeutic techniques and physical activity has also been highlighted in addition to the calorie restricted diet for bringing about an overall lifestyle modification in the management of obesity. Conclusion: Food preferences are acquired in childhood and sound nutritional practices should be established in childhood to prevent lifestyle disorders and premature aging. Though CR is a known and preferred non-pharmacological intervention in the management of obesity, its implemention has not been explored and evaluated extensively. This is a vital area that needs scientific research as the goals of obesity managements are no longer just weight loss through dietary restrictions. An interdisciplinary method to lifestyle modification in the management of adolescent obesity addressing all physiological and psychosocial aspects is recommended.

Meal fatty acids and postprandial vascular reactivity

2007 ◽  
Vol 35 (3) ◽  
pp. 451-453 ◽  
Author(s):  
K.G. Jackson ◽  
C.K. Armah ◽  
A.M. Minihane
Keyword(s):  
Fatty Acids ◽  
Vascular Reactivity ◽  
Vascular Dysfunction ◽  
Postprandial Lipaemia ◽  
Fasted State ◽  
Important Target ◽  
Time Period ◽  
The Impact ◽  
Progression Of Atherosclerosis

With increasing recognition of the pivotal role of vascular dysfunction in the progression of atherosclerosis, the vasculature has emerged as an important target for dietary therapies. Recent studies have indicated that chronic fatty acid manipulation alters vascular reactivity, when measured after an overnight fast. However, individuals spend a large proportion of the day in the postprandial (non-fasted) state. Several studies have shown that high fat meals can impair endothelial function within 3–4 h, a time period often associated with peak postprandial lipaemia. Although the impact of meal fatty acids on the magnitude and duration of the postprandial lipaemic response has been extensively studied, very little is known about their impact on vascular reactivity after a meal.

Abstract P226: Decreasing Cardiovascular Risk via Hypertriglyceridemia Treatment: The Impact of Medical Education on Physician Understanding of the Role of Omega-3 Fatty Acids

Circulation ◽  
2015 ◽  
Vol 131 (suppl_1) ◽  
Author(s):  
Amy Larkin ◽  
George Boutsalis ◽  
Michael LaCouture
Keyword(s):  
Fatty Acids ◽  
Medical Education ◽  
Effect Size ◽  
Further Education ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
The Impact ◽  
Post Assessment ◽  
Assessment Questions

Introduction: Triglycerides, although lacking the strong atherogenic potential of LDL-C, are an independent risk factor for cardiovascular disease (CVD), as demonstrated by the correlation between hypertriglyceridemia and cardiovascular (CV) death, CV events, and myocardial infarction. The impact of continuing medical education (CME) on improving the knowledge and competence of cardiologists in treating hypertriglyceridemia with omega-3 fatty acids was measured. Methods: Cardiologists in the US who treat patients with hypertriglyceridemia participated in an online CME activity on the role of omega-3 fatty acids in treating hypertriglyceridemia and the differences between available formulations. The educational impact was assessed using linked pre- and post-assessment questions, and participants were classified into one of 3 learning categories: improved learners (incorrect pre, correct post), reinforced learners (correct pre and post), and unaffected learners (incorrect pre and post). The educational effect size was calculated using Cohen's d formula. Results: A total of 169 cardiologists participated in the CME activity, completed the pre- and post-assessment, and were included in the analysis. Comparison of pre- and post-assessment responses for each individual question demonstrated a statistically significant improvement in knowledge and competence among cardiologists ( P <.05). After completion of the CME activity, correct responses on post-assessment questions increased between 25% to 158% across all questions compared to pre-assessment responses, with an overall large effect size of 1.065 (Small effect ,<0.4; intermediate effect, 0.4-0.8; large effect, >0.8). Between 17% and 51% of participants showed improvement in understanding individual learning concepts; these concepts were reinforced in 18% to 28% of participants. Improvement was demonstrated in understanding recent American College of Cardiology (ACC)/American Heart Association (AHA) guideline recommendations on the treatment of hypertriglyceridemia. There was a need for further education in understanding the mechanism of action of omega-3 fatty acids, the differences between prescription and supplement forms of omega-3 fatty acids, and the pharmacodynamic differences between the different formulations of omega-3 fatty acids. Conclusion: This study demonstrated the success of a targeted educational intervention on improving the knowledge and competence of US cardiologists on the role of omega-3 fatty acids to treat hypertriglyceridemia and reduce CVD. However, the need for additional education was also demonstrated among cardiologists with regard to understanding the different omega-3 fatty acid formulations and their mechanisms of action in order to effectively use these agents.

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