Isovalerylcarnitine

Circulating Isovalerylcarnitine and Lung Cancer Risk: Evidence from Mendelian Randomization and Prediagnostic Blood Measurements

Background: Tobacco exposure causes 8 of 10 lung cancers, and identifying additional risk factors is challenging due to confounding introduced by smoking in traditional observational studies. Materials and methods: We used Mendelian randomization (MR) to screen 207 metabolites for their role in lung cancer predisposition using independent genome-wide association studies (GWAS) of blood metabolite levels (n = 7,824) and lung cancer risk (n = 29,266 cases/56,450 controls). A nested case-control study (656 cases and 1,296 matched controls) was subsequently performed using prediagnostic blood samples to validate MR association with lung cancer incidence data from population-based cohorts (EPIC and NSHDS). Results: An MR-based scan of 207 circulating metabolites for lung cancer risk identified that blood isovalerylcarnitine (IVC) was associated with a decreased odds of lung cancer after accounting for multiple testing (log10-OR = 0.43; 95% CI, 0.29-0.63). Molar measurement of IVC in prediagnostic blood found similar results (log10-OR = 0.39; 95% CI, 0.21-0.72). Results were consistent across lung cancer subtypes. Conclusions: Independent lines of evidence support an inverse association of elevated circulating IVC with lung cancer risk through a novel methodologic approach that integrates genetic and traditional epidemiology to efficiently identify novel cancer biomarkers. Impact: Our results find compelling evidence in favor of a protective role for a circulating metabolite, IVC, in lung cancer etiology. From the treatment of a Mendelian disease, isovaleric acidemia, we know that circulating IVC is modifiable through a restricted protein diet or glycine and L-carnatine supplementation. IVC may represent a modifiable and inversely associated biomarker for lung cancer.

Isovalerylcarnitine is a specific activator of calpain of human neutrophils

Isovalerylcarnitine (IVC) a product of the catabolism of L-leucine, is a potent activator of the Ca2+-dependent proteinase (calpain) of human neutrophils. At concentrations of Ca2+ in the low micromolar range, activation was 12 to 15-fold, and the activity exceeded that observed with millimolar concentrations of Ca2+ in the absence of the activator. Of the acylcarnitine derivatives tested, IVC was most active; D-isovalerylcarnitine was much less effective and palmitylcarnitine was ineffective. IVC did not increase the activity of calpain that was fully activated by an endogenous cytoskeleton-associated activator protein, but at low concentrations of the latter synergistic effects of the two activators were observed. Activation of neutrophil calpain by IVC is fully reversible. Inhibition by calpastatin was also reversed by IVC.

Isovalerylcarnitine is a specific activator of the high calcium requiring calpain forms

Isovalerylcarnitine, a product of the catabolism of L-leucine, is a potent activator of rat calpains isolated from erythrocytes, kidney, liver, skeletal and heart muscle. Only calpains II, but not calpains I, are activated by IVC, with the only exception of rat erythrocyte calpain I, the only species present in these cells which has a Ca2+ requirement higher than that of most calpain I isoenzymes. Activation by IVC involves a dual effect: 1) a ten fold increase in the affinity of calpain for Ca2+, and 2) an increase in the Vmax 1.3-1.6 fold above the values observed with the native enzymes at saturating [Ca2+] as well as with the autolyzed fully active calpain form at 5 microM Ca2+. The increased affinity for calcium results in an increased rate of autoproteolysis of calpain II. Activation by IVC is additive to that promoted by interaction (or association) to phospholipids vesicles. Together these results suggest that IVC may operate as a selective activator of calpain both in the cytosol and at the membrane level; in the latter case in synergism with the activation induced by association of the proteinase to the cell membrane.

Evaluation of carnitine, acetylcarnitine and isovalerylcarnitine on immune function and apoptosis

The pool of different carnitine derivatives is formed by carnitine, acetylcarnitine, propionylcarnitine and isovalerylcarnitine. Isovalerylcarnitine is a compound performing activities that differ from those of the other carnitine esters. Its activity on proteolytic enzymes and on the calpain system has been demonstrated in the past. Both the calpain and the caspase systems belong to the protease family and lead to cytochrome activation and apoptosis. The two systems can interact to promote apoptosis. In view of this proapoptotic activity of isovalerylcarnitine, studies were carried out to ascertain whether this carnitine derivative influences cell-reaction processes associated with apoptosis. U937 leukemic cells were selected for these studies because they are a well-established model for the assessment of cellular immune responses. In addition to nuclear morphologic alterations produced by apoptosis that can be detected by specific histochemical and microscopic methods, we also took other cell functions into consideration, such as phagocytosis, cell killing and cell growth, which are indices of immune function related to apoptosis. Unlike reference carnitine forms, isovalerylcarnitine produced an early and marked increase in phagocytosis and also an increase in cell killing. Cell proliferation was reduced. The hypothesis is set forth that isovalerylcarnitine may be a caspase-activating, proapoptotic factor that resembles various anticancer agents, which induce early apoptosis that coincides with early activation of caspase. This hypothesis is supported by the ability of isovalerylcarnitine to induce early phagocytosis and cell killing.

The Correlation between Gut Microbiota and Serum Metabolomic in Elderly Patients with Chronic Heart Failure

Objective: Chronic heart failure (CHF) refers to a state of persistent heart failure that can be stable, deteriorated, or decompensated. The mechanism and pathogenesis of myocardial remodeling remain unknown. Based on 16S rDNA sequencing and metabolomics technology, this study analyzed the gut microbiota and serum metabolome in elderly patients with CHF to provide new insights into the microbiota and metabolic phenotypes of CHF.
Methods: Blood and fecal samples were collected from 25 elderly patients with CHF and 25 healthy subjects. The expression of inflammatory factors in blood was detected by ELISA. 16S rDNA sequencing was used to analyze the changes in microorganisms in the samples. The changes of small molecular metabolites in serum samples were analyzed by LC-MS/MS. Spearman correlation coefficients were used to analyze the correlation between gut microbiota and serum metabolites.
Results: Our results showed that the IL-6, IL-8, and TNF-α levels were significantly increased, and the IL-10 level was significantly decreased in the elderly patients with CHF compared with the healthy subjects. The diversity of the gut microbiota was decreased in the elderly patients with CHF. Moreover, Escherichia Shigella was negatively correlated with biocytin and RIBOFLAVIN. Haemophilus was negatively correlated with alpha-lactose, cellobiose, isomaltose, lactose, melibiose, sucrose, trehalose, and turanose. Klebsiella was positively correlated with bilirubin and ethylsalicylate. Klebsiella was negatively correlated with citramalate, hexanoylcarnitine, inosine, isovalerylcarnitine, methylmalonate, and riboflavin.
Conclusion: The gut microbiota is simplified by the disease, and serum small-molecule metabolites evidently change in elderly patients with CHF. Serum and fecal biomarkers could be used for elderly patients with CHF screening.