S-adenosyl-L-methionine protects the liver against the cholestatic, cytotoxic, and vasoactive effects of leukotriene D4: a study with isolated and perfused rat liver

Cysteinyl-leukotrienes can cause cholestasis and liver damage when administered at nanomolar concentrations. Using the isolated and perfused rat liver we analyzed whether S-adenosyl-L-methionine (SAMe) may protect this organ against the noxious effects of leukotriene-D4 (LTD4). We observed that a 2 nmol bolus of this compound decreased bile flow (-12.6% +/- 1.6%, P < .02), and bile salt excretion (-23.5% +/- 2.2%, P < .02; both compared with baseline values), caused the release of glutamic-oxaloacetic transaminase (GOT) and lactic dehydrogenase (LDH) to the hepatic effluent, and increased significantly the perfusion pressure as compared with a control group not receiving LTD4 (6.0 +/- 1.1 vs. 0.2 +/- 0.02 mm hg, respectively; P < .001). The cholestatic effect of LTD4 was attenuated by infusion of SAMe which, at rates of 67 and 100 microg/min, totally prevented the decrease in bile salt excretion. Likewise, in SAMe infused livers, the release to the effluent of GOT and LDH was lower than in the group receiving LTD4 only, and was even lower than in the control group. We also found that the increase in perfusion pressure induced by LTD4 was prevented by SAMe in a dose-dependent manner. Of interest, SAMe increased the biliary excretion of the eicosanoid in a dose-related fashion. We conclude that SAMe reverts the cholestatic, cytotoxic, and hemodynamic effects of LTD4 on the liver, and that these protective effects might be partly because of a stimulation of the biliary excretion of the leukotriene

Taurocholate-stimulated leukotriene C4 biosynthesis and leukotriene C4-stimulated choleresis in isolated rat liver

BACKGROUND/AIMS: Cysteinyl-containing leukotrienes seem to exert a cholestatic effect. However, leukotriene inhibitors were found to reduce bile salt efflux in isolated rat hepatocytes, suggesting a role for leukotrienes in bile flow formation. METHODS: In the isolated rat liver, the effects of two different concentrations of leukotriene C4 on bile flow and bile salt excretion are analyzed, as well as the possible effect of taurocholate on the hepatic production of cysteinyl-containing leukotrienes. RESULTS: Leukotriene C4 (0.25 fmol) increased bile salt excretion (+22.2%; P < 0.05), whereas a much higher dose (0.25 x 10(6) fmol) showed the known cholestatic effect, reducing bile salt excretion (-25.9%; P < 0.01). These dose-dependent biphasic effects were specific because they could be prevented by the simultaneous administration of cysteinyl-containing leukotriene antagonists. On the other hand, taurocholate administration induced a dose-dependent increase in biliary excretion of cysteinyl-containing leukotrienes. Furthermore, taurocholate increased messenger RNA levels of 5-lipoxygenase, a key enzyme in leukotriene biosynthesis. Taurocholate increase of hepatocyte intracellular calcium was not significant, suggesting that taurocholate effects are not mediated by stimulation of calcium metabolism. CONCLUSIONS: These results constitute evidence for the existence of a positive feedback mechanism by which bile salts stimulate the synthesis of leukotrienes that, in turn, stimulate bile salt excretion

Validity of Resting Energy Expenditure Predictive Equations before and after an Energy-Restricted Diet Intervention in Obese Women

Background We investigated the validity of REE predictive equations before and after 12-week energy-restricted diet intervention in Spanish obese (30 kg/m2>BMI<40 kg/m2) women. Methods We measured REE (indirect calorimetry), body weight, height, and fat mass (FM) and fat free mass (FFM, dual X-ray absorptiometry) in 86 obese Caucasian premenopausal women aged 36.7±7.2 y, before and after (n = 78 women) the intervention. We investigated the accuracy of ten REE predictive equations using weight, height, age, FFM and FM. Results At baseline, the most accurate equation was the Mifflin et al. (Am J Clin Nutr 1990; 51: 241–247) when using weight (bias:−0.2%, P = 0.982), 74% of accurate predictions. This level of accuracy was not reached after the diet intervention (24% accurate prediction). After the intervention, the lowest bias was found with the Owen et al. (Am J Clin Nutr 1986; 44: 1–19) equation when using weight (bias:−1.7%, P = 0.044), 81% accurate prediction, yet it provided 53% accurate predictions at baseline. Conclusions There is a wide variation in the accuracy of REE predictive equations before and after weight loss in non-morbid obese women. The results acquire especial relevance in the context of the challenging weight regain phenomenon for the overweight/obese population.The present study was supported by the University of the Basque Country (UPV 05/80), Social Foundation of the Caja Vital- Kutxa and by the Department of Health of the Government of the Basque Country (2008/111062), and by the Spanish Ministry of Science and Innovation (RYC-2010-05957)

Birth weight and blood lipid levels in Spanish adolescents: Influence of selected APOE, APOC3 and PPARgamma2 gene polymorphisms. The AVENA Study

Background There is increasing evidence indicating that genes involved in certain metabolic processes of cardiovascular diseases may be of particular influence in people with low body weight at birth. We examined whether the apolipoprotein (APO) E, APOC3 and the peroxisome proliferator-activated receptor-γ-2 (PPARγ2) polymorphisms influence the association between low birth weight and blood lipid levels in healthy adolescents aged 13–18.5 years. Methods A cross-sectional study of 502 Spanish adolescents born at term was conducted. Total (TC) and high density lipoprotein cholesterol (HDLc), triglycerides (TG), apolipoprotein (apo) A and B, and lipoprotein(a) [Lp(a)] were measured. Low density lipoprotein cholesterol (LDLc), TC-HDLc, TC/HDLc and apoB/apoA were calculated. Results Low birth weight was associated with higher levels of TC, LDLc, apoB, Lp(a), TC-HDLc, TC/HDLc and apoB/apoA in males with the APOE ε3ε4 genotype, whereas in females, it was associated with lower HDLc and higher TG levels. In males with the APOC3 S1/S2 genotype, low birth weight was associated with lower apoA and higher Lp(a), yet this association was not observed in females. There were no associations between low birth weight and blood lipids in any of the PPARγ2 genotypes. Conclusion The results indicate that low birth weight has a deleterious influence on lipid profile particularly in adolescents with the APOE ε3/ε4 genotype. These findings suggest that intrauterine environment interact with the genetic background affecting the lipid profile in later life.The AVENA study was supported by the Spanish Ministry of Health Instituto de Salud Carlos III (FIS PI021830), the Spanish Ministry of Health, FEDER-FSE funds FIS n° 00/0015, CSD grants 05/UPB32/0, 109/UPB31/03 and 13/UPB20/04, the Spanish Ministry of Education (AP-2004-2745; EX-2007-1124), scholarships from Panrico S.A., Madaus S.A. and Procter and Gamble S.A

Effects of an Exercise Program on Brain Health Outcomes for Children With Overweight or Obesity The ActiveBrains Randomized Clinical Trial

IMPORTANCE Pediatric overweight and obesity are highly prevalent across the world, with implications for poorer cognitive and brain health. Exercise might potentially attenuate these adverse consequences. OBJECTIVES To investigate the effects of an exercise program on brain health indicators, including intelligence, executive function, academic performance, and brain outcomes, among children with overweight or obesity and to explore potential mediators and moderators of the main effects of exercise. DESIGN, SETTING, AND PARTICIPANTS All preexercise and postexercise data for this 20-week randomized clinical trial of 109 children aged 8 to 11 years with overweight or obesity were collected from November 21, 2014, to June 30, 2016, with neuroimaging data processing and analyses conducted between June 1, 2017, and December 20, 2021. All 109 children were included in the intention-to-treat analyses; 90 children (82.6%) completed the postexercise evaluation and attended 70% or more of the recommended exercise sessions and were included in per-protocol analyses. INTERVENTIONS All participants received lifestyle recommendations. The control group continued their usual routines, whereas the exercise group attended a minimum of 3 supervised 90-minute sessions per week in an out-of-school setting. MAIN OUTCOMES AND MEASURES Intelligence, executive function (cognitive flexibility, inhibition, and working memory), and academic performance were assessed with standardized tests, and hippocampal volume was measured with magnetic resonance imaging. RESULTS The 109 participants included 45 girls (41.3%); participants had a mean (SD) body mass index of 26.8 (3.6) and a mean (SD) age of 10.0 (1.1) years at baseline. In per-protocol analyses, the exercise intervention improved crystallized intelligence, with the exercise group improving from before exercise to after exercise (mean z score, 0.62 [95% CI, 0.44-0.80]) compared with the control group (mean z score, -0.10 [95% CI, -0.28 to 0.09]; difference between groups, 0.72 SDs [95% CI, 0.46-0.97]; P &amp;lt; .001). Total intelligence also improved significantly more in the exercise group (mean z score, 0.69 [95% CI, 0.48-0.89]) than in the control group (mean z score, 0.07 [95% CI, -0.14 to 0.28]; difference between groups, 0.62 SDs [95% CI, 0.31-0.91]; P &amp;lt; .001). Exercise also positively affected a composite score of cognitive flexibility (mean z score: exercise group, 0.25 [95% CI, 0.05-0.44]; control group, -0.17 [95% CI, -0.39 to 0.04]; difference between groups, 0.42 SDs [95% CI, 0.13-0.71]; P = .005). These main effects were consistent in intention-to-treat analyses and after multiple-testing correction. There was a positive, small-magnitude effect of exercise on total academic performance (mean z score: exercise group, 0.31 [95% CI, 0.18-0.44]; control group, 0.10 [95% CI, -0.04 to 0.24]; difference between groups, 0.21 SDs [95% CI, 0.01-0.40]; P = .03), which was partially mediated by cognitive flexibility. Inhibition, working memory, hippocampal volume, and other brain magnetic resonance imaging outcomes studied were not affected by the exercise program. The intervention increased cardiorespiratory fitness performance as indicated by longer treadmill time to exhaustion (mean z score: exercise group, 0.54 [95% CI, 0.27-0.82]; control group, 0.13 [95% CI, -0.16 to 0.41]; difference between groups, 0.42 SDs [95% CI, 0.01-0.82]; P = .04), and these changes in fitness mediated some of the effects (small percentage of mediation [approximately 10%-20%]). The effects of exercise were overall consistent across the moderators tested, except for larger improvements in intelligence among boys compared with girls. CONCLUSIONS AND RELEVANCE In this randomized clinical trial, exercise positively affected intelligence and cognitive flexibility during development among children with overweight or obesity. However, the structural and functional brain changes responsible for these improvements were not identified.Funding Agencies|Spanish Ministry of Economy and Competitiveness [DEP2013-47540, DEP2016-79512-R, DEP2017-91544-EXP]; European Regional Development Fund (ERDF); European Commission [667302]; Alicia Koplowitz Foundation; ERDF (FEDER in Spanish) [B-CTS-355-UGR18]; University of Granada, Plan Propio de Investigacion, Visiting Scholar grants; Junta de Andalucia, Consejeria de Conocimiento, Investigacion y Universidades; Unit of Excellence on Exercise, Nutrition and Health (UCEENS); ERDF [SOMM17/6107/UGR]; EXERNET Research Network on Exercise and Health [DEP2005-00046/ACTI]; High Council of Sports [09/UPB/19]; Spanish Ministry of Science and Innovation [FPU 14/06837, FPI-BES-2014-068829, FJC2018-037925-I, FJCI-2014-19563, IJCI-2017-33642, RYC2019-027287-I, FPU15/02645, FJCI-2017-33396, IJC2019-041916-I]; Junta de Andalucia; National Agency for Research and Development (ANID)/BECAS Chile [72180543]; Ramon Areces Foundation</p