Tricaprin

Effect of Tricaprin on Cardiac Proteome in a Mouse Model for Triglyceride Deposit Cardiomyovasculopathy.[Pubmed:33177279]

J Oleo Sci. 2020 Nov 25;69(12):1569-1577.

Triglyceride deposit cardiomyovasculopathy (TGCV), a rare cardiovascular disorder caused by genetic or acquired dysfunction of adipose triglyceride lipase (ATGL), is marked by defective intracellular lipolysis that results in excessive accumulation of triglycerides (TGs) in the myocardium and coronary arteries, leading to intractable heart failure (HF). We have developed a specific treatment for TGCV using Tricaprin, a medium chain TG, as part of a governmental rare disease project in Japan. We recently reported that Tricaprin diet improved cardiac TG metabolism and left ventricular function in an ATGL-knockout (KO) mouse, a mouse model for TGCV. Here, we report the effect of Tricaprin on the myocardial proteome of KO mice to elucidate the mechanisms of action of Tricaprin at protein expression levels. We compared proteomic changes in the hearts of KO mice fed control or Tricaprin diet. Tandem mass tag-based shotgun proteomics identified 1832 proteins common to all sample groups. Whole proteomic distribution in the heart was largely up-regulated in KO mice fed control diet. When using cut-off values (>1.5 or <0.67, FDR-adjusted p value<0.01), in fact, 65 proteins were up-regulated whereas only 2 proteins were down-regulated in the hearts of KO mice fed control diet. The former included proteins assigned to "Cardiac Arrhythmia", and "Cardiac Damage" reflecting HF by a toxicity function analysis. One of the latter was Ces1d, which is known to regulate intracellular TG metabolism. These proteomic changes observed in KO mice were dramatically rescued by the Tricaprin diet. These results indicated that Tricaprin diet ameliorated HF in a TGCV mouse model at protein expression levels and also provided important clues to understand mechanisms for the beneficial effect of Tricaprin.

Low-Protein Diet Supplemented with Medium-Chain Fatty Acid Glycerides Improves the Growth Performance and Intestinal Function in Post-Weaning Piglets.[Pubmed:33053685]

Animals (Basel). 2020 Oct 12;10(10). pii: ani10101852.

Medium-chain fatty acid glycerides have been shown to provide energy for rapid oxidation in the body. The study was conducted to investigate the effects of dietary supplementation with medium-chain fatty acid glyceride on the growth performance and intestinal health of weaned piglets fed with a low-protein diet. Nighty healthy weaned piglets were randomly divided into five treatments: NP (Normal protein treatment, normal-protein diet no antibiotics included); NC (Negative control, low-protein diet no antibiotics included); PC (Positive control, low-protein diet +75 mg/kg quinocetone, 20 mg/kg virginiamycin and 50 mg/kg aureomycin); MCT (tricaprylin + Tricaprin treatment, low-protein diet + tricaprylin + Tricaprin); GML (glycerol monolaurate treatment, low-protein diet + glycerol monolaurate). The results showed that the average daily feed intake (ADFI) of the MCT treatment was significantly higher than that of the NP, NC treatments (p < 0.05). In the jejunum, the villus height of the GML treatment was significantly lower than that of the PC treatment (p < 0.05), and the number of goblet cells in the GML treatment was higher than that in the NC treatment (p < 0.05). Compared with the NC treatment, the MCT treatment significantly increased the level of claudin-1, Zonula occludens-1(ZO-1), while the GML treatment significantly increased the level of claudin-1, occludin, ZO-1 (p < 0.05). In the ileum, the level of ZO-1 in the GML treatment was significantly higher than that in the NP, NC, PC treatments (p < 0.05). Compared with the NC treatment, the GML treatment significantly increased the level of Secretory immunoglobulin A (SIgA) in the ileum and serum, while the MCT treatment significantly increased the level of SIgA and decreased the level of interleukin-6 (IL-6) in the ileum (p < 0.05). These results showed that the addition of medium-chain fatty acid glycerides to a low-protein diet could improve the growth performance and intestinal functional barrier of weaned piglets and also improve the immune function of weaned piglets.

The effect of medium chain and long chain triglycerides incorporated in self-nano emulsifying drug delivery systems on oral absorption of cannabinoids in rats.[Pubmed:32147493]

Int J Pharm. 2020 Apr 30;580:119201.

The aim of this research was to investigate the effect of the lipid component in self-emulsifying drug delivery systems on the oral absorption of major cannabinoids Delta(9)-tetrahydrocannabinol (THC) and Cannabidiol (CBD). The investigated lipids were either long chain triglycerides (LCT) or medium chain triglycerides (MCT) with different composition, fatty acid chain length, degree of saturation and their absorption pathway to the systemic circulation. Formulations were developed with the purpose of creating thermodynamically stable oil-in-water nano emulsions/suspensions with particle size of 50 nm or less which carry the lipophilic drug and increase water solubility. Following a methodic screening of suitable excipients in-vitro, leading formulations based on sesame oil or MIGLYOL(R) 812N (Type I LCT/MCT SNEDDS) and cocoa butter or Tricaprin (Type II LCT/MCT SNEDDS) were investigated in the freely moving rat model. Results in rat model demonstrated that the effect of each type of lipid on bioavailability of cannabinoids is not straightforwardly anticipated. The differences in the effect of LCT and MCT on absorption was not substantial for Type I formulations, however, more prominent for Type II formulations. This unpredictable behavior in-vivo demonstrates the importance of investigating each vehicle pre-clinically, following the in-vitro development.

Solubility of pharmaceutical ingredients in triglycerides.[Pubmed:31682903]

Eur J Pharm Biopharm. 2019 Dec;145:113-120.

Lipid-based drug delivery systems (LBDDS) are highly relevant as pharmaceutical formulations significantly enhancing the bioavailability of active pharmaceutical ingredients (APIs). These formulations often are complex mixtures of APIs, various lipids, and other excipients (e.g. surfactants). In their simplest form, LBDDS contain one API being dissolved in a pure lipid, which often is a triglyceride (TG). In this work, solubilities of the APIs indomethacin, ibuprofen, and fenofibrate in pure TGs of different chain lengths (C chain 8-18) and degree of saturation were investigated. Solubilities of APIs in TGs were measured via differential scanning calorimetry, hot-stage microscopy, high-performance liquid chromatography, and Raman spectroscopy. The influence of fatty-acid chain length and degree of saturation on the API solubility in the TGs was investigated. APIs showed a higher solubility in saturated (wIBU=10.5wt% at 25 degrees C in tricaprylin) TGs compared to unsaturated ones (wIBU=4.0wt% at 25 degrees C in triolein). The fatty-acid chain length of TGs only slightly affects the solubility of ibuprofen and fenofibrate, but strongly influences the eutectic temperature of the API/TG mixtures. API solubilities in TGs and TG mixtures (mixtures of tricaprylin and Tricaprin) were successfully modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) accounting for the intermolecular API/TG interactions providing a deep understanding of the energetic and structural impact of the TGs on API solubility.

Plasma Ketone and Medium Chain Fatty Acid Response in Humans Consuming Different Medium Chain Triglycerides During a Metabolic Study Day.[Pubmed:31058159]

Front Nutr. 2019 Apr 16;6:46.

Background: Medium chain triglycerides (MCT) are ketogenic but the relationship between the change in plasma ketones and the change plasma medium chain fatty acids (MCFA)-octanoate, decanoate, or dodecanoate-after an oral dose of MCT is not well-known. An 8 h metabolic study day is a suitable model to assess the acute effects on plasma ketones and MCFA after a dose of tricaprylin (C8), Tricaprin (C10), trilaurin (C12) or mixed MCT (C8C10). Objective: To assess in healthy humans the relationship between the change in plasma ketones, and octanoate, decanoate and dodecanoate in plasma total lipids during an 8 h metabolic study day in which a first 20 ml dose of the homogenized test oil is taken with breakfast and a second 20 ml dose is taken 4 h later without an accompanying meal. Results: The change in plasma acetoacetate, beta-hydroxybutyrate and total ketones was highest after C8 (0.5 to 3 h post-dose) and was lower during tests in which octanoate was absent or was diluted by C10 in the test oil. The plasma ketone response was also about 2 fold higher without an accompanying meal (P = 0.012). However, except during the pure C10 test, the response of octanoate, decanoate or dodecanoate in plasma total lipids to the test oils was not affected by consuming an accompanying meal. Except with C12, the 4 h area-under-the-curve of plasma beta-hydroxybutyrate/acetoacetate was 2-3 fold higher when no meal was consumed (P < 0.04). Conclusion: C8 was about three times more ketogenic than C10 and about six times more ketogenic than C12 under these acute metabolic test conditions, an effect related to the post-dose increase in octanoate in plasma total lipids.

Tricaprin Rescues Myocardial Abnormality in a Mouse Model of Triglyceride Deposit Cardiomyovasculopathy.[Pubmed:30012901]

J Oleo Sci. 2018 Aug 1;67(8):983-989.

Triglyceride deposit cardiomyovasculopathy (TGCV) is an intractable cardiovascular disease for which a specific treatment is urgently required. In TGCV, adipose triglyceride lipase (ATGL) deficiency results in the abnormal intracellular metabolism of long-chain fatty acid (LCFA) which leads to TG deposition. Medium-chain triglycerides have been used as an important functional food for various human diseases. To address the potential activities of Tricaprin, a medium-chain triglyceride, on cardiac dysfunctions of TGCV, we examined the effects of Tricaprin diet on Atgl knock out (KO) mice, an animal model for TGCV. Cardiac imaging tests showed that the Tricaprin diet reduced TG accumulation, resulting from improvement of LCFA metabolism, and improved left ventricular function in Atgl KO mice compared to that in mice fed the control diet. In conclusion, Tricaprin improved myocardial abnormality in the TGCV model, thus, it may be useful for the treatment of patients with TGCV.

Modified Gas Chromatographic Method to Determine Monoacylglycerol and Diacylglycerol Contents in Edible Fats and Oils.[Pubmed:28515375]

J Oleo Sci. 2017 Jun 1;66(6):601-606.

Monoacylglycerol (MAG) and diacylglycerol (DAG) are minor components of edible fats and oils, and they relate to the quality of these foods. The AOCS official method Cd 11b-91 has been used to determine MAG and DAG contents in fats and oils. There are, however, difficulties in the determination of MAG and DAG using this analytical procedure. Therefore, we improved this method by modifying the trimethylsilyl derivatization procedure and replacing the internal standard (IS) material. In our modified method, TMS-HT (mixture of hexamethyldisilazane and trimethylchlorosilane) was used for derivatization of MAG and DAG, which was followed by liquid-liquid extraction with water and n-hexane solution containing the IS, Tricaprin. Using the modified method, we demonstrated superior repeatability in comparison with that of the AOCS method by reducing procedural difficulties. The relative standard deviation of distearin peak areas was 1.8% or 2.9% in the modified method, while it was 5.6% in the AOCS method. In addition, capillary columns, such as DB-1ht and DB-5ht could be used in this method.

Tricaprylin Alone Increases Plasma Ketone Response More Than Coconut Oil or Other Medium-Chain Triglycerides: An Acute Crossover Study in Healthy Adults.[Pubmed:29955698]

Curr Dev Nutr. 2017 Mar 22;1(4):e000257.

Background: Ketones are the brain's main alternative fuel to glucose. Dietary medium-chain triglyceride (MCT) supplements increase plasma ketones, but their ketogenic efficacy relative to coconut oil (CO) is not clear. Objective: The aim was to compare the acute ketogenic effects of the following test oils in healthy adults: coconut oil [CO; 3% tricaprylin (C8), 5% Tricaprin (C10)], classical MCT oil (C8-C10; 55% C8, 35% C10), C8 (>95% C8), C10 (>95% C10), or CO mixed 50:50 with C8-C10 or C8. Methods: In a crossover design, 9 participants with mean +/- SD ages 34 +/- 12 y received two 20-mL doses of the test oils prepared as an emulsion in 250 mL lactose-free skim milk. During the control (CTL) test, participants received only the milk vehicle. The first test dose was taken with breakfast and the second was taken at noon but without lunch. Blood was sampled every 30 min over 8 h for plasma acetoacetate and beta-hydroxybutyrate (beta-HB) analysis. Results: C8 was the most ketogenic test oil with a day-long mean +/- SEM of +295 +/- 155 micromol/L above the CTL. C8 alone induced the highest plasma ketones expressed as the areas under the curve (AUCs) for 0-4 and 4-8 h (780 +/- 426 micromol h/L and 1876 +/- 772 micromol h/L, respectively); these values were 813% and 870% higher than CTL values (P < 0.01). CO plasma ketones peaked at +200 micromol/L, or 25% of the C8 ketone peak. The acetoacetate-to-beta-HB ratio increased 56% more after CO than after C8 after both doses. Conclusions: In healthy adults, C8 alone had the highest net ketogenic effect over 8 h, but induced only half the increase in the acetoacetate-to-beta-HB ratio compared with CO. Optimizing the type of MCT may help in developing ketogenic supplements designed to counteract deteriorating brain glucose uptake associated with aging. This trial was registered at clinicaltrials.gov as NCT 02679222.

Non-invasive Quantitative Analysis of Specific Fat Accumulation in Subcutaneous Adipose Tissues using Raman Spectroscopy.[Pubmed:27845402]

Sci Rep. 2016 Nov 15;6:37068.

Subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and fat beneath the dermis layer were investigated using a ball lens top hollow optical fiber Raman probe (BHRP). Hamsters were fed with trilinolein (TL) and Tricaprin (TC) for six weeks and measurements were carried out every two weeks. The BHRP with an 800 mum diameter fused-silica ball lens was able to obtain information on the subcutaneous fat in a totally non-invasive manner. Changes in the concentration of TL and TC during the treatment were analyzed, and the relationship between fat accumulation and dietary fat was studied. It was found that SAT had, in general, a higher degree of unsaturation than VAT. The accumulation rate of TC found in SAT and VAT was 0.52 +/- 0.38 and 0.58 +/- 0.4%, respectively, while the TL accumulation rate was 4.45 +/- 1.6 and 4.37 +/- 2.4%, respectively. The results suggest different metabolic pathways for TC, a typical medium-chain fatty acid, and TL, a long-chain unsaturated fatty acid. Raman subsurface spectra were successfully obtained and used to analyze the subcutaneous fat layer. The accumulation rates of TL and TC found in skin fat were 5.01 +/- 3.53% and 0.45 +/- 0.36%, respectively. The results demonstrate the high feasibility of Raman spectroscopy for non-invasive analysis of adipose tissue.

Rapid determination of drug solubilization versus supersaturation in natural and digested lipids.[Pubmed:27609663]

Int J Pharm. 2016 Nov 20;513(1-2):164-174.

Lipid-based formulations (LBFs) represent one of the successful formulation approaches that enable oral delivery of poorly water-soluble drugs. This work presents a simple equilibrium approach based on solubility in lipids and their corresponding digestion media to estimate a maximum drug supersaturation ratio (SRmax). This value of drug concentration normalized by the solubility in the aqueous digestion phase indicates the propensity for drug precipitation. A set of 16 structurally diverse drugs was first measured for their solubility in Tricaprin and tricaprylin and results were compared to an empirical model based on molecular predictors. In the next step, digestion media were either prepared by in vitro lipolysis or by assembling a composition to mimic the endpoint of digestion. It was found that drug solubility in the pure lipids mainly was related to the melting point in that increased values resulted in reduced solubility. The solubility values measured in the lipolysis media correlated well with those obtained from assembled digestion media. Interestingly, the solubilization upon digestion was typically higher when using Tricaprin than tricaprylin in spite of that the latter oil (as pure excipient) generally was a more potent solvent. This work suggests that a simplified digestion screen can be used to facilitate evaluation of formulations during early development. Estimation of SRmax provides an early risk assessment of drug precipitation for LBFs. The method is easily scaled down to the microtiter plate format and can be used for selecting candidate formulations that merit further evaluation in more complex and dynamic in vitro tests.

Selective deuteration for molecular insights into the digestion of medium chain triglycerides.[Pubmed:26151129]

Chem Phys Lipids. 2015 Sep;190:43-50.

Medium chain triglycerides (MCTs) are a unique form of dietary fat that have a wide range of health benefits. They are molecules with a glycerol backbone esterified with medium chain (6-12 carbon atoms) fatty acids on the two outer (sn-1 and sn-3) and the middle (sn-2) positions. During lipid digestion in the gastrointestinal tract, pancreatic lipase stereoselectively hydrolyses the ester bonds of these triglycerides on the sn-1 and sn-3 positions resulting in sn-2 monoglyceride and fatty acids as major products. However, the sn-2 monoglycerides are thermodynamically less stable than their sn-1/3 counterparts. Isomerization or fatty acid migration from the sn-2 monoglyceride to sn-1/3 monoglyceride may occur spontaneously and would lead to glycerol and fatty acid as final products. Here, Tricaprin (C10) with selectively deuterated fatty acid chains was used for the first time to monitor chain migration and the stereoselectivity of the pancreatic lipase-catalyzed hydrolysis of ester bonds. The intermediate and final digestion products were studied using NMR and mass spectrometry under biologically relevant conditions. The hydrolysis of the sn-2 monocaprin to glycerol and capric acid did not occur within biologically relevant timescales and fatty acid migration occurs only in limited amounts as a result of the presence of undigested diglyceride species over long periods of time in the digestion medium. The slow kinetics for the exchange of the sn-2 fatty acid chain and the stereoselectivity of pancreatic lipase on MCTs is relevant for industrial processes that involve enzymatic interesterification and the production of high-value products such as specific structured triacylglycerols, confectionery fats and nutritional products.

Analysis of the effects of dietary fat on body and skin lipids of hamsters by Raman spectroscopy.[Pubmed:25920444]

Analyst. 2015 Jun 21;140(12):4238-44.

Raman spectroscopy has previously been applied for studying lipid metabolism. In this study, a ball lens-installed hollow optical fiber Raman probe (BHRP) was used for the noninvasive measurement of skin lipids in hamsters. Our analysis suggested that multi-unsaturated lipids, once converted into a structure containing conjugated double bonds, were oxidized to form peroxides. These results were applied for analyzing lipid metabolism in adipose and skin tissues in hamsters fed Tricaprin, saturated medium-chain triglyceride and trilinolein, unsaturated long-chain triglyceride fat diets. Unsaturated lipids formed conjugated structures in skin tissue but not in adipose tissue. Principal component analysis (PCA) revealed that the dietary fat intake correlated strongly with lipid composition in body and skin tissues. Hence, the present results successfully demonstrate that Raman spectroscopy with a BHRP can be a powerful tool for analyzing lipid metabolism.