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The Pharmacokinetics of Triheptanoin and Its Metabolites in Healthy Subjects and Patients With Long-Chain Fatty Acid Oxidation Disorders.
Lee, SK, Gupta, M, Shi, J, McKeever, K
Clinical pharmacology in drug development. 2021;(11):1325-1334
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Abstract
Long-chain fatty acid oxidation disorders (LC-FAODs) are a group of life-threatening autosomal recessive disorders caused by defects in nuclear genes encoding mitochondrial enzymes involved in the conversion of dietary long-chain fatty acids into energy. Triheptanoin is an odd-carbon, medium-chain triglyceride consisting of 3 fatty acids with 7 carbons each on a glycerol backbone developed to treat adult and pediatric patients with LC-FAODs. The pharmacokinetics of triheptanoin and circulating metabolites were explored in healthy subjects and patients with LC-FAODs using noncompartmental analyses. Systemic exposure to triheptanoin following an oral administration was negligible, as triheptanoin is extensively hydrolyzed to glycerol and heptanoate in the gastrointestinal tract. Multiple peaks for triheptanoin metabolites were observed in the plasma following oral administration of triheptanoin, generally coinciding with the time that meals were served. Heptanoate, the pharmacologically active metabolite of triheptanoin supplementing energy sources in patients with LC-FAODs, showed the greatest exposure among the metabolites of triheptanoin in human plasma following oral administration of triheptanoin. The exposure of heptanoate was approximately 10-fold greater than that of beta-hydroxypentoate, a downstream metabolite of heptanoate. Exposure to triheptanoin metabolites appeared to increase following multiple doses as compared with the single dose, and with the increase in triheptanoin dose levels.
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Linking the Endocannabinoidome with Specific Metabolic Parameters in an Overweight and Insulin-Resistant Population: From Multivariate Exploratory Analysis to Univariate Analysis and Construction of Predictive Models.
Depommier, C, Flamand, N, Pelicaen, R, Maiter, D, Thissen, JP, Loumaye, A, Hermans, MP, Everard, A, Delzenne, NM, Di Marzo, V, et al
Cells. 2021;(1)
Abstract
The global obesity epidemic continues to rise worldwide. In this context, unraveling new interconnections between biological systems involved in obesity etiology is highly relevant. Dysregulation of the endocannabinoidome (eCBome) is associated with metabolic complications in obesity. This study aims at deciphering new associations between circulating endogenous bioactive lipids belonging to the eCBome and metabolic parameters in a population of overweight or obese individuals with metabolic syndrome. To this aim, we combined different multivariate exploratory analysis methods: canonical correlation analysis and principal component analysis, revealed associations between eCBome subsets, and metabolic parameters such as leptin, lipopolysaccharide-binding protein, and non-esterified fatty acids (NEFA). Subsequent construction of predictive regression models according to the linear combination of selected endocannabinoids demonstrates good prediction performance for NEFA. Descriptive approaches reveal the importance of specific circulating endocannabinoids and key related congeners to explain variance in the metabolic parameters in our cohort. Analysis of quartiles confirmed that these bioactive lipids were significantly higher in individuals characterized by important levels for aforementioned metabolic variables. In conclusion, by proposing a methodology for the exploration of large-scale data, our study offers additional evidence of the existence of an interplay between eCBome related-entities and metabolic parameters known to be altered in obesity.
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Free fatty acid processing diverges in human pathologic insulin resistance conditions.
Sekizkardes, H, Chung, ST, Chacko, S, Haymond, MW, Startzell, M, Walter, M, Walter, PJ, Lightbourne, M, Brown, RJ
The Journal of clinical investigation. 2020;(7):3592-3602
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Abstract
BACKGROUNDPostreceptor insulin resistance (IR) is associated with hyperglycemia and hepatic steatosis. However, receptor-level IR (e.g., insulin receptor pathogenic variants, INSR) causes hyperglycemia without steatosis. We examined 4 pathologic conditions of IR in humans to examine pathways controlling lipid metabolism and gluconeogenesis.METHODSCross-sectional study of severe receptor IR (INSR, n = 7) versus postreceptor IR that was severe (lipodystrophy, n = 14), moderate (type 2 diabetes, n = 9), or mild (obesity, n = 8). Lipolysis (glycerol turnover), hepatic glucose production (HGP), gluconeogenesis (deuterium incorporation from body water into glucose), hepatic triglyceride (magnetic resonance spectroscopy), and hepatic fat oxidation (plasma β-hydroxybutyrate) were measured.RESULTSLipolysis was 2- to 3-fold higher in INSR versus all other groups, and HGP was 2-fold higher in INSR and lipodystrophy versus type 2 diabetes and obesity (P < 0.001), suggesting severe adipose and hepatic IR. INSR subjects had a higher contribution of gluconeogenesis to HGP, approximately 77%, versus 52% to 59% in other groups (P = 0.0001). Despite high lipolysis, INSR subjects had low hepatic triglycerides (0.5% [interquartile range 0.1%-0.5%]), in contrast to lipodystrophy (10.6% [interquartile range 2.8%-17.1%], P < 0.0001). β-hydroxybutyrate was 2- to 7-fold higher in INSR versus all other groups (P < 0.0001), consistent with higher hepatic fat oxidation.CONCLUSIONThese data support a key pathogenic role of adipose tissue IR to increase glycerol and FFA availability to the liver in both receptor and postreceptor IR. However, the fate of FFA diverges in these populations. In receptor-level IR, FFA oxidation drives gluconeogenesis rather than being reesterified to triglyceride. In contrast, in postreceptor IR, FFA contributes to both gluconeogenesis and hepatic steatosis.TRIAL REGISTRATIONClinicalTrials.gov NCT01778556, NCT00001987, and NCT02457897.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases, US Department of Agriculture/Agricultural Research Service 58-3092-5-001.
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Temporal Changes in Breast Milk Fatty Acids Contents: A Case Study of Malay Breastfeeding Women.
Khor, GL, Tan, SS, Stoutjesdijk, E, Ng, KWT, Khouw, I, Bragt, M, Schaafsma, A, Dijck-Brouwer, DAJ, Muskiet, FAJ
Nutrients. 2020;(1)
Abstract
The composition of human breast milk changes in the first two months of life, adapting itself to the evolving needs of the growing new-born. Lipids in milk are a source of energy, essential fatty acids (FA), fat-soluble vitamins, and vital bioactive components. Information on breast milk FA of Malaysian lactating women is scarce. Based on convenience sampling, a total of 20 Malay breastfeeding women who fulfilled the inclusion criteria were recruited. Breast milk was collected three times from each subject at consecutive intervals of 2-3 weeks apart. A total of 60 breast milk samples were collected and classified into "transitional milk" (n = 8), "early milk" (n = 26) and "mature milk" (n = 26). All milk samples were air freighted to University of Groningen, Netherlands for analysis. The dominant breast milk FA were oleic acid, constituting 33% of total fatty acids, followed by palmitic acid (26%). Both these FA and the essential FA, linoleic acid (10%) and alpha-linolenic acid (0.4%), showed no significant changes from transitional to mature milk. Breast milk ratio of n-6:n-3 polyunsaturated fatty acids (PUFA) was comparatively high, exceeding 10 throughout the lactation period, suggesting a healthier balance of PUFA intake is needed in pregnancy and at postpartum.
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Postprandial Lipemic Responses to Various Sources of Saturated and Monounsaturated Fat in Adults.
Sciarrillo, CM, Koemel, NA, Tomko, PM, Bode, KB, Emerson, SR
Nutrients. 2019;(5)
Abstract
BACKGROUND Postprandial lipemia (PPL) is a cardiovascular disease risk factor. However, the effects of different fat sources on PPL remain unclear. We aimed to determine the postprandial response in triglycerides (TG) to four dietary fat sources in adults. METHODS Participants completed four randomized meal trials. For each meal trial, participants (n = 10; 5M/5F) consumed a high-fat meal (HFM) (13 kcal/kg; 61% of total kcal from fat) with the fat source derived from butter, coconut oil, olive oil, or canola oil. Blood was drawn hourly for 6 h post-meal to quantify PPL. RESULTS Two-way ANOVA of TG revealed a time effect (p < 0.0001), but no time-meal interaction (p = 0.56), or meal effect (p = 0.35). Meal trials did not differ with regard to TG total (p = 0.33) or incremental (p = 0.14) area-under-the-curve. When stratified by sex and the TG response was averaged across meals, two-way ANOVA revealed a time effect (p < 0.0001), time-group interaction (p = 0.0001), and group effect (p = 0.048), with men exhibiting a greater response than women, although this difference could be attributed to the pronounced difference in BMI between men and women within the sample. CONCLUSION In our sample of young adults, postprandial TG responses to a single HFM comprised of different fat sources did not differ.
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Is There a Link between Zinc Intake and Status with Plasma Fatty Acid Profile and Desaturase Activities in Dyslipidemic Subjects?
Knez, M, Pantovic, A, Zekovic, M, Pavlovic, Z, Glibetic, M, Zec, M
Nutrients. 2019;(1)
Abstract
The prevalence of obesity and dyslipidemia has increased worldwide. The role of trace elements in the pathogenesis of these conditions is not well understood. This study examines the relationship between dietary zinc (Zn) intake and plasma concentrations of Zn, copper (Cu) and iron (Fe) with lipid profile indicators, fatty acid composition in plasma phospholipids and desaturase enzyme activities in a dyslipidemic population. The role of the newly proposed biomarker of Zn status, the linoleic:dihomo-gama-linolenic acid (LA:DGLA) ratio, in predicting Zn status of dyslipidemic subjects has been explored. The study included 27 dyslipidemic adults, 39-72 years old. Trace elements were determined using atomic absorption spectrometry and fatty acid composition by a liquid gas chromatography. Desaturase activities were calculated from product-precursor fatty acid ratios. Dietary data were obtained using 24 h recall questionnaires. Insufficient dietary intake of Zn, low plasma Zn concentrations and an altered Cu:Zn ratio is related to modified fatty acid profile in subjects with dyslipidemia. Plasma Zn status was associated with obesity. There was no correlation between dietary Zn intake and plasma Zn status. The LA:DGLA ratio was inversely linked to dietary Zn intake. Cu, in addition to Zn, may directly or indirectly, affect the activity of desaturase enzymes.
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Carotenoids, fatty acids and disease burden in obese minority adolescents with asthma.
Tobias, TAM, Wood, LG, Rastogi, D
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2019;(6):838-846
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Abstract
BACKGROUND Paediatric obesity-related asthma causes high disease burden, is associated with metabolic abnormalities, has few therapeutic options, and disproportionately affects urban minority children. Although poor diet quality is linked to asthma, the association of nutritional status with disease burden among children with obesity-related asthma is not well understood. OBJECTIVE To quantify nutritional status, defined as concentrations of serum carotenoids and n-3 fatty acids, and its association with pulmonary function and metabolic markers among obese asthmatic children. METHODS We quantified serum carotenoids and fatty acids in a study cohort of 158 urban minority adolescents including 39 obese asthmatics, 39 healthy weight asthmatics, 38 obese controls and 42 healthy weight controls and compared between the groups. We correlated carotenoid and fatty acid levels with pulmonary function indices and with insulin resistance and dyslipidemia. RESULTS Mean total carotenoids were lowest in obese asthmatic children (0.41 μg/mL), lower than healthy weight asthmatics (0.52 μg/mL, P < 0.05) and healthy weight controls (0.60 μg/mL, P < 0.001). n-6/n-3 polyunsaturated fatty acid (PUFA) ratio also differed between the groups (P < 0.05). Total carotenoids positively correlated with per cent-predicted FEV1 and inversely correlated with insulin resistance among obese asthmatics only. n-6/n-3 PUFA ratio inversely correlated with per cent-predicted FEV1 in obese asthmatics. CONCLUSIONS & CLINICAL RELEVANCE Our findings suggest that carotenoids, which are lowest in obese asthmatic children, may have protective effects on metabolic health and pulmonary function among obese asthmatic children. Similarly, n-3 PUFA appear to be protective for pulmonary function.
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Results from a 78-week, single-arm, open-label phase 2 study to evaluate UX007 in pediatric and adult patients with severe long-chain fatty acid oxidation disorders (LC-FAOD).
Vockley, J, Burton, B, Berry, GT, Longo, N, Phillips, J, Sanchez-Valle, A, Tanpaiboon, P, Grunewald, S, Murphy, E, Bowden, A, et al
Journal of inherited metabolic disease. 2019;(1):169-177
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Abstract
Long-chain fatty acid oxidation disorders (LC-FAOD) are rare disorders characterized by acute crises of energy metabolism and severe energy deficiency that may present with cardiomyopathy, hypoglycemia, and/or rhabdomyolysis, which can lead to frequent hospitalizations and early death. An open-label Phase 2 study evaluated the efficacy of UX007, an investigational odd-carbon medium-chain triglyceride, in 29 subjects with severe LC-FAOD. UX007 was administered over 78 weeks at a target dose of 25-35% total daily caloric intake (mean 27.5%). The frequency and duration of major clinical events (hospitalizations, emergency room visits, and emergency home interventions due to rhabdomyolysis, hypoglycemia, and cardiomyopathy) occurring during 78 weeks of UX007 treatment was compared with the frequency and duration of events captured retrospectively from medical records for 78 weeks before UX007 initiation. The mean annualized event rates decreased from 1.69 to 0.88 events/year following UX007 initiation (p = 0.021; 48.1% reduction). The mean annualized duration rate decreased from 5.96 to 2.96 days/year (p = 0.028; 50.3% reduction). Hospitalizations due to rhabdomyolysis, the most common event, decreased from 1.03 to 0.63 events/year (p = 0.104; 38.7% reduction). Initiation of UX007 eliminated hypoglycemia events leading to hospitalization (from 11 pre-UX007 hospitalizations, 0.30 events/year vs. 0; p = 0.067) and intensive care unit (ICU) care (from 2 pre-UX007 ICU admissions, 0.05 events/year vs. 0; p = 0.161) and reduced cardiomyopathy events (3 events vs. 1 event; 0.07 to 0.02 events/year; 69.7% decrease). The majority of treatment-related adverse events (AEs) were mild to moderate gastrointestinal symptoms, including diarrhea, vomiting, and abdominal or gastrointestinal pain, which can be managed with smaller, frequent doses mixed with food.
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Absorption and Safety With Sustained Use of RELiZORB Evaluation (ASSURE) Study in Patients With Cystic Fibrosis Receiving Enteral Feeding.
Stevens, J, Wyatt, C, Brown, P, Patel, D, Grujic, D, Freedman, SD
Journal of pediatric gastroenterology and nutrition. 2018;(4):527-532
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Abstract
OBJECTIVES Pancreatic insufficiency (PI) and malabsorption of fats lead to reduced caloric intake, inability to maintain weight, and increased gastrointestinal symptoms. Thus, enteral nutrition (EN) is used in patients with cystic fibrosis (CF) and poor nutritional status. The current study evaluated safety, tolerability, and improvement of fatty acid (FA) status in red blood cell (RBC) membranes, a marker of long-term FA absorption, with an in-line digestive cartridge (RELiZORB) that hydrolyzes fat in enteral formula. METHODS Patients with CF receiving EN participated in a multicenter, 90-day open-label study during which RELiZORB was used with overnight EN. The primary endpoint was change over time in RBC uptake of docosahexaenoic acid (DHA)+ eicosapentaenoic acid (EPA). Gastrointestinal symptoms were collected to evaluate safety and tolerability. Several clinical and anthropometric parameters were also assessed throughout the study. RESULTS A total of 36 subjects completed the study with a mean age of 13.8 years, body mass index of 17.7 and 6.2 years mean use of overnight EN. Fat absorption significantly improved as shown by increased RBC levels of DHA+EPA, improved ω-6/ω-3 ratio, and increased plasma levels of DHA+EPA. RELiZORB use was not associated with any unanticipated adverse events. CONCLUSIONS RELiZORB use was found to be safe, well tolerated, and resulted in increased levels of FAs in RBCs and plasma. This is the first prospective study to show EN can improve FA abnormalities in CF. Because improvement in omega-3 levels has been shown to help pulmonary and inflammatory status as well as anthropometric parameters in CF, RELiZORB may have important long-term therapeutic benefits in patients with CF.
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Dietary Fatty Acid Modification for the Treatment of Aspirin-Exacerbated Respiratory Disease: A Prospective Pilot Trial.
Schneider, TR, Johns, CB, Palumbo, ML, Murphy, KC, Cahill, KN, Laidlaw, TM
The journal of allergy and clinical immunology. In practice. 2018;(3):825-831
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BACKGROUND The high levels of eicosanoid production and the clinical efficacy of leukotriene-modifying pharmacotherapies for patients with aspirin-exacerbated respiratory disease (AERD) suggest that other interventions targeting arachidonic acid dysregulation may also improve disease control. OBJECTIVE To assess the utility of a high omega-3/low omega-6 diet for the treatment of AERD. METHODS Prospective, nonblinded dietary intervention in 10 adult patients with AERD at Brigham and Women's Hospital in Boston, MA. The primary objective was for subjects to reduce dietary omega-6 fatty acid consumption to less than 4 g/d and increase omega-3 intake to more than 3 g/d. The primary outcome was change in urinary leukotriene E4, with changes in other eicosanoids, platelet activation, lung function, and patient-reported questionnaires also assessed. RESULTS Of the 10 subjects who screened for the study, all 10 completed the dietary intervention. Urinary leukotriene E4 decreased by 0.17 ng/mg (95% CI, -0.29 to -0.04; P = .02) and tetranor prostaglandin D-M decreased by 0.66 ng/mg creatinine (95% CI, -1.21 to -0.11; P = .02). There was a 15.1-point reduction in the 22-item Sino-Nasal Outcome Test score (95% CI, -24.3 to -6.0; P = .01), a 0.27-point reduction in the 7-item Asthma Control Questionnaire score (95% CI, -0.52 to -0.03; P = .03), and no change in FEV1 % predicted (P = .92) or forced vital capacity % predicted (P = .74). All patients lost some weight over the 2-week intervention period, and there were no diet-associated adverse events. CONCLUSIONS A high omega-3/low omega-6 diet may be an appropriate adjunct treatment option for patients with AERD.