Medium & long-chain acylcarnitine’s relation to lipid metabolism as potential predictors for diabetic cardiomyopathy: a metabolomic study

Abstract

Background Acylcarnitine is an intermediate product of fatty acid oxidation. It is reported to be closely associated with the occurrence of diabetic cardiomyopathy (DCM). However, the mechanism of acylcarnitine affecting myocardial disorders is yet to be explored. This current research explores the different chain lengths of acylcarnitines as biomarkers for the early diagnosis of DCM and the mechanism of acylcarnitines for the development of DCM in-vitro. Methods In a retrospective non-interventional study, 50 simple type 2 diabetes mellitus patients and 50 DCM patients were recruited. Plasma samples from both groups were analyzed by high throughput metabolomics and cluster heat map using mass spectrometry. Principal component analysis was used to compare the changes occurring in the studied 25 acylcarnitines. Multivariable binary logistic regression was used to analyze the odds ratio of each group for factors and the 95% confidence interval in DCM. Myristoylcarnitine (C14) exogenous intervention was given to H9c2 cells to verify the expression of lipid metabolism-related protein, inflammation-related protein expression, apoptosis-related protein expression, and cardiomyocyte hypertrophy and fibrosis-related protein expression. Results Factor 1 (C14, lauroylcarnitine, tetradecanoyldiacylcarnitine, 3-hydroxyl-tetradecanoylcarnitine, arachidic carnitine, octadecanoylcarnitine, 3-hydroxypalmitoleylcarnitine) and factor 4 (octanoylcarnitine, hexanoylcarnitine, decanoylcarnitine) were positively correlated with the risk of DCM. Exogenous C14 supplementation to cardiomyocytes led to increased lipid deposition in cardiomyocytes along with the obstacles in adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathways and affecting fatty acid oxidation. This further caused myocardial lipotoxicity, ultimately leading to cardiomyocyte hypertrophy, fibrotic remodeling, and increased apoptosis. However, this effect was mitigated by the AMPK agonist acadesine. Conclusions The increased plasma levels in medium and long-chain acylcarnitine extracted from factors 1 and 4 are closely related to the risk of DCM, indicating that these factors can be an important tool for DCM risk assessment. C14 supplementation associated lipid accumulation by inhibiting the AMPK/ACC/CPT1 signaling pathway, aggravated myocardial lipotoxicity, increased apoptosis apart from cardiomyocyte hypertrophy and fibrosis were alleviated by the acadesine.

Several serum lipid metabolites are associated with relapse risk in pediatric-onset multiple sclerosis

“…Acylcarnitines are important metabolites in cellular energy metabolism pathways, particularly beta-oxidation. 23 Reduction in some acylcarnitines has been reported as part of the metabolic changes associated with MS. 24–26 In contrast with these results, studies of other systemic diseases, like diabetes, have found acylcarnitines to be elevated in these states as a possible result of mitochondrial dysfunction and impaired fatty acid oxidation. 27 It has also been shown that medium-chain acylcarnitines (C8–C14) can induce the production of proinflammatory cytokines.…”

Combining data acquisition modes in liquid-chromatography–tandem mass spectrometry for comprehensive determination of acylcarnitines in human serum

“…Another study carried out by Guasch-Ferré et al (2019) found that SCAC and LCAC levels were significantly associated with high cardiovascular risk in a Mediterranean cohort. Zheng et al (2021) related the high levels of LCACs and MCACs with risk of diabetic cardiomyopathy in nonobese patients. Concerning physiological contents, relative concentrations were estimated by equivalence to IL-ISs (Table S3).…”

Metabolomics Analysis Identifies Differential Metabolites as Biomarkers for Acute Myocardial Infarction

“…In addition, the accumulation of medium-and long-chain acylcarnitine also causes the disorder of adenosine 5 ′ -monophosphate-activated protein kinase (AMPK) signaling pathway, leading to the increase in lipid deposition in myocardial cells, and eventually causing myocardial lipotoxicity, hypertrophy, fibrotic remodeling, and increased apoptosis [23][24][25].…”