Vitamin D3 supplementation does not modify cardiovascular risk profile of adults with inadequate vitamin D status.

PURPOSE: The Nutrition Societies in Germany, Austria, and Switzerland recommend a daily intake of 20 µg vitamin D3 for adults when endogenous synthesis is absent. The current study aimed to elucidate whether this vitamin D3 dose impacts cardiovascular risk markers of adults during the winter months. METHODS: The study was conducted in Halle (Saale), Germany (51o northern latitude) as a placebo-controlled, double-blinded, randomised trial (from January to April). A total of 105 apparently healthy subjects (male and female, 20-71 years old) were included. Subjects were randomly allocated to two groups. One group received a daily 20-µg vitamin D3 dose (n = 54), and the other group received a placebo (n = 51) for 12 weeks. Outcome measures included blood pressure, heart rate, concentrations of renin, aldosterone, serum lipids and vascular calcification markers, and haematologic variables such as pro-inflammatory monocytes. RESULTS: Blood pressure and systemic cardiovascular risk markers remained unchanged by vitamin D3 supplementation, although serum 25-hydroxyvitamin D3 increased from 38 ± 14 to 73 ± 16 nmol/L at week 12. The placebo and vitamin D groups did not differ in their final cardiovascular risk profile. CONCLUSION: Daily supplementation of 20 µg vitamin D3 during winter is unlikely to change cardiovascular risk profile.

Vitamin D3 supplementation: Response and predictors of vitamin D3 metabolites - A randomized controlled trial.

BACKGROUND & AIMS: Large parts of the population are insufficiently supplied with vitamin D, in particular when endogenous synthesis is absent. Therefore many health care providers recommend the use of vitamin D supplements. The current study aimed to investigate the efficacy of an once-daily oral dose of 20 µg vitamin D3 to improve the vitamin D status and to evaluate predictors of response. METHODS: The study was conducted as a double-blind, randomized, placebo-controlled parallel trial from January till April 2013. In total, 105 subjects (20-71 years) were allocated to receive either a vitamin D3 supplement (20 µg/d) or a placebo for 12 weeks. Circulating levels of vitamin D3 metabolites such as the 25(OH)D3 and the 24,25(OH)2D3, and biomarkers of calcium and phosphate metabolism were quantified. RESULTS: The 25(OH)D3 serum concentrations in the placebo group decreased from 38 ± 15 nmol/L at baseline to 32 ± 14 nmol/L and 32 ± 13 nmol/L at weeks 8 and 12 of the study, respectively (p < 0.01). In the vitamin D3 group, the serum 25(OH)D3 concentration increased from 38 ± 14 nmol/L at baseline to 70 ± 15 nmol/L and 73 ± 16 nmol/L at weeks 8 and 12 of vitamin D3 supplementation (p < 0.001), respectively. As a result, 94% of the vitamin D3-supplemented participants reached 25(OH)D3 concentrations of ≥50 nmol/L and thereof 46% attained 25(OH)D3 levels of ≥75 nmol/L until the end of the study. The extent of the 25(OH)D3 increase upon vitamin D3 supplementation depended on 25(OH)D3 baseline levels, age, body weight and circulating levels of triglycerides. In contrast to 25(OH)D3, the response of 24,25(OH)2D3 to the vitamin D3 treatment was affected only by baseline levels of 24,25(OH)2D3 and age. CONCLUSIONS: The average improvement of 25(OH)D3 levels in individuals who received 20 µg vitamin D3 per day during the winter months was 41 nmol/L compared to individuals without supplementation. As a result almost all participants with the vitamin D3 supplementation attained 25(OH)D3 concentrations of 50 nmol/L and higher. The suitability of 24,25(OH)2D3 as a marker of vitamin D status needs further investigation. Clinical trial registration number at clinicaltrials.gov: NCT01711905.

Capsaicin, nonivamide and trans-pellitorine decrease free fatty acid uptake without TRPV1 activation and increase acetyl-coenzyme A synthetase activity in Caco-2 cells.

Red pepper and its major pungent component, capsaicin, have been associated with hypolipidemic effects in rats, although mechanistic studies on the effects of capsaicin and/or structurally related compounds on lipid metabolism are scarce. In this work, the effects of capsaicin and its structural analog nonivamide, the aliphatic alkamide trans-pellitorine and vanillin as the basic structural element of all vanilloids on the mechanisms of intestinal fatty acid uptake in differentiated intestinal Caco-2 cells were studied. Capsaicin and nonivamide were found to reduce fatty acid uptake, with IC50 values of 0.49 µM and 1.08 µM, respectively. trans-Pellitorine was shown to reduce fatty acid uptake by 14.0±2.14% at 100 µM, whereas vanillin was not effective, indicating a pivotal role of the alkyl chain with the acid amide group in fatty acid uptake by Caco-2 cells. This effect was associated neither with the activation of the transient receptor potential cation channel subfamily V member 1 (TRPV1) or the epithelial sodium channel (ENaC) nor with effects on paracellular transport or glucose uptake. However, acetyl-coenzyme A synthetase activity increased (p<0.05) in the presence of 10 µM capsaicin, nonivamide or trans-pellitorine, pointing to an increased fatty acid biosynthesis that might counteract the decreased fatty acid uptake.

Structure-dependent effects of pyridine derivatives on mechanisms of intestinal fatty acid uptake: regulation of nicotinic acid receptor and fatty acid transporter expression.

Pyridines are widely distributed in foods. Nicotinic acid (NA), a carboxylated pyridine derivative, inhibits lipolysis in adipocytes by activation of the orphan NA receptor (HM74A) and is applied to treat hyperlipidemia. However, knowledge on the impact of pyridine derivatives on intestinal lipid metabolism is scarce. This study was performed to identify the structural determinants of pyridines for their effects on fatty acid uptake in enterocyte-like Caco-2 cells and to elucidate the mechanisms of action. The impact of 17 pyridine derivatives on fatty acid uptake was tested. Multiple regression analysis revealed the presence of a methyl group to be the structural determinant at 0.1 mM, whereas at 1 mM, the presence of a carboxylic group and the N-methylation presented further structural characteristics to affect the fatty acid uptake. NA, showing a stimulating effect on FA uptake, and N-methyl-4-phenylpyridinium (MPP), inhibiting FA uptake, were selected for mechanistic studies. Gene expression of the fatty acid transporters CD36, FATP2 and FATP4, and the lipid metabolism regulating transcription factors peroxisome proliferator-activated receptor (PPAR) α and PPARγ was up-regulated upon NA treatment. Caco-2 cells were demonstrated to express the low-affinity NA receptor HM74 of which the gene expression was up-regulated upon NA treatment. We hypothesize that the NA-induced fatty acid uptake might result from NA receptor activation and related intracellular signaling cascades. In contrast, MPP increased transepithelial electrical resistance. We therefore conclude that NA and MPP, both sharing the pyridine motif core, exhibit their contrary effects on intestinal FA uptake by activation of different mechanisms.

N-methylpyridinium, a degradation product of trigonelline upon coffee roasting, stimulates respiratory activity and promotes glucose utilization in HepG2 cells.

N-Methylpyridinium (NMP) is a thermal degradation product of trigonelline formed upon coffee roasting and hypothesized to exert several health benefits in humans. Since for trigonelline evidence for hypoglycemic effects exists, we examined whether NMP also affects mechanisms of glucose utilization and cellular energy formation. For this purpose, the impact of trigonelline and NMP on respiratory activity, extracellular acidification, cellular adenosine nucleotides, energy supply from fatty acids and glucose as well as thermogenesis in HepG2 cells was analyzed. A 24 hour incubation with nanomolar concentrations of NMP enhanced oxygen consumption rates, resulting in increased ATP levels. Glucose was identified as the prevalent energy substrate as its uptake was augmented up to 18.1% ± 7.44% by NMP at 0.09 µM, whereas the uptake of fatty acids decreased upon NMP treatment. Cellular glucose uptake was also stimulated by trigonelline administration; however, a shift to the anaerobic energy production pathway was monitored. Both pyridine derivatives induced thermogenesis, although trigonelline presumably promoted proton leaks, while NMP increased the concentration of the uncoupling protein-2. We provide evidence that both compounds appear to stimulate cellular energy metabolism in HepG2 cells. Human intervention studies are warranted to ensure these effects in vivo.

Caffeine dose-dependently induces thermogenesis but restores ATP in HepG2 cells in culture.

Caffeine has been hypothesised as a thermogenic agent that might help to maintain a healthy body weight. Since very little is known about its actions on cellular energy metabolism, we investigated the effect of caffeine on mitochondrial oxidative phosphorylation, cellular energy supply and thermogenesis in HepG2 cells, and studied its action on fatty acid uptake and lipid accumulation in 3T3-L1 adipocytes at concentrations ranging from 30-1500 µM. In HepG2 cells, caffeine induced a depolarisation of the inner mitochondrial membrane, a feature of mitochondrial thermogenesis, both directly and after 24 h incubation. Increased concentrations of uncoupling protein-2 (UCP-2) also indicated a thermogenic activity of caffeine. Energy generating pathways, such as mitochondrial respiration, fatty acid oxidation and anaerobic lactate production, were attenuated by caffeine treatment. Nevertheless, HepG2 cells demonstrated a higher energy charge potential after exposure to caffeine that might result from energy restoration through attenuation of energy consuming pathways, as typically found in hibernating animals. In 3T3-L1 cells, in contrast, caffeine increased fatty acid uptake, but did not affect lipid accumulation. We provide evidence that caffeine stimulates thermogenesis but concomitantly causes energy restoration that may compensate enhanced energy expenditure.