Regulation of endogenic metabolites by rosuvastatin in hyperlipidemia patients: An integration of metabolomics and lipidomics

Lee, Hyunbeom; Choi, Jong Min; Cho, Joo Youn; Kim, Tae Eun; Lee, Hwa Jeong; Jung, Byung Hwa

doi:10.1016/j.chemphyslip.2018.05.005

Cited by 31 publications

(34 citation statements)

References 42 publications

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“…Lipidomics is a mean of global mapping of lipid metabolites which may provide further detailed information of the effects of atorvastatin in patients with VTE, which has not been published previously. Previous studies have evaluated detailed lipidomic pro les as effects of simvastatin or rosuvastain in patients with hyperlipidemia (32,33). We found in our study that VTE patients receiving atorvastatin in addition to anticoagulation had reduced CE (cholesterol ester), CER (ceramides), PC (phosphatidylcholine) and SM (sphingomyelin), as well as increased LCER (lactosyl ceramide) at 3 months.…”

Section: Discussionsupporting

confidence: 51%

A Pilot Randomized Study of Atorvastatin As Adjunct Therapy in Patients with Acute Venous Thromboembolism

Wang

Waller

Lin

et al. 2020

Preprint

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Background: Venous thromboembolism (VTE) is a considerable public health threat. Improving the management of VTE may achieve better long-term outcomes. In this single-center pilot study, we sought to investigate the effects of statins in addition to anticoagulation in patients with acute VTE.Methods: We enrolled patients over the age of 18 presenting with an acute proximal lower extremity deep vein thrombosis with or without pulmonary embolism. Patients were randomized to anticoagulation alone (with either warfarin or rivaroxaban) or anticoagulation plus atorvastatin 40 mg daily and followed for 9 months. The primary objective was to determine if adjunct atorvastatin reduced thrombin generation, estimated by endogenous thrombin potential and/or peak thrombin concentration. Secondary endpoints included recurrent VTE, arterial thrombosis, bleeding events, and more.Results: A total of 21 patients (11 randomized to anticoagulation only and 10 to anticoagulation plus atorvastatin) were enrolled over 3.5 years. The addition of atorvastatin significantly reduced the mean low-density lipoproteins at 3 months, but did not reduce either endogenous thrombin potential, peak thrombin, D-dimer, or high sensitivity-C reactive protein. Given the low recruitment rate, continuation of the study was deemed futile and the study was terminated early. Barriers to enrollment and completion of study included the many ineligible patients due to the exclusion criteria (e.g. pre-existing statin use, active malignancy, etc) and high rate of lost follow-up.Conclusions: The pilot study did not enroll sufficient number of patients, but was able to inform obstacles for future similar studies investigating the effects of statins in the management of patients with VTE.Trial registration: The study was registered with ClinicalTrials.gov (NCT02331095), January 6, 2015. https://clinicaltrials.gov/ct2/show/NCT02331095

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Section: Discussionsupporting

confidence: 51%

A Pilot Randomized Study of Atorvastatin As Adjunct Therapy in Patients with Acute Venous Thromboembolism

Wang

Waller

Lin

et al. 2020

Preprint

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“…In epidemiological studies, the statin-mediated lipidomic changes in individuals with the metabolic syndrome or type 2 diabetes showed a significant shift towards the lipid profile of control individuals, indicative of a marked trend towards a normolipidemic phenotype [38]. Moreover, administration of rosuvastatin for 3-8 weeks in individuals with hyperlipidaemia was associated with decreased levels of phosphatidylcholines and acylcarnitines and increased levels of polyunsaturated fatty acids, favouring an improvement of the atherogenic lipid profile [39]. Thus, we would expect a favourable effect of statins towards a normalisation of the plasma lipidome which could rather attenuate the associations between HRV indices and lipid metabolites observed herein.…”

Section: Discussionmentioning

confidence: 99%

Association of cardiac autonomic dysfunction with higher levels of plasma lipid metabolites in recent-onset type 2 diabetes

et al. 2020

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Aims/hypothesis Emerging evidence suggests that in addition to hyperglycaemia, dyslipidaemia could represent a contributing pathogenetic factor to diabetic neuropathy, while obesity and insulin resistance play a role in the development of diabetic cardiac autonomic neuropathy (CAN) characterised by reduced heart rate variability (HRV), particularly in type 2 diabetes. We hypothesised that distinct lipid metabolites are associated with diminished HRV in recent-onset type 2 diabetes rather than type 1 diabetes. Methods We analysed 127 plasma lipid metabolites (11 acylcarnitines, 39 NEFA, 12 sphingomyelins (SMs), 56 phosphatidylcholines and nine lysophosphatidylcholines) using MS in participants from the German Diabetes Study baseline cohort recently diagnosed with type 1 (n = 100) and type 2 diabetes (n = 206). Four time-domain HRV indices (number of normal-to-normal (NN) intervals >50 ms divided by the number of all NN intervals [pNN50]; root mean square of successive differences [RMSSD]; SD of NN intervals [SDNN]; and SD of differences between adjacent NN intervals) and three frequency-domain HRV indices (very-low-frequency [VLF], low-frequency [LF] and high-frequency [HF] power spectrum) were computed from NN intervals recorded during a 3 h hyperinsulinaemic–euglycaemic clamp at baseline and in subsets of participants with type 1 (n = 60) and type 2 diabetes (n = 95) after 5 years. Results In participants with type 2 diabetes, after Bonferroni correction and rigorous adjustment, SDNN was inversely associated with higher levels of diacyl-phosphatidylcholine (PCaa) C32:0, PCaa C34:1, acyl-alkyl-phosphatidylcholine (PCae) C36:0, SM C16:0 and SM C16:1. SD of differences between NN intervals was inversely associated with PCaa C32:0, PCaa C34:1, PCaa C34:2, PCae C36:0 and SM C16:1, and RMSSD with PCae C36:0. For VLF power, inverse associations were found with PCaa C30:0, PCaa C32:0, PCaa C32:1, PCaa C34:2 and SM C16:1, and for LF power inverse associations were found with PCaa C32:0 and SM C16:1 (r = −0.242 to r = −0.349; p ≤ 0.0005 for all correlations). In contrast, no associations of lipid metabolites with measures of cardiac autonomic function were noted in participants recently diagnosed with type 1 diabetes. After 5 years, HRV declined due to ageing rather than diabetes, whereby prediction analyses for lipid metabolites were hampered. Conclusions/interpretation Higher plasma levels of specific lipid metabolites are closely linked to cardiac autonomic dysfunction in recent-onset type 2 diabetes but not type 1 diabetes, suggesting a role for perturbed lipid metabolism in the early development of CAN in type 2 diabetes.

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“…Together with the abovementioned systems, an Acquity ® UPLC HSS T3 column (1.8 µm particle size, 2.1 × 100 mm, Waters, USA) at 40 • C was used. For gradient elution, we have employed our method that was previously reported [27]. In brief, mobile phase A (0.1% formic acid in Milli-Q water) and mobile phase B (0.1% formic acid in methanol) at a flow rate of 0.4 mL•min −1 was used with the following gradient program: the initial conditions, 99% A and 1% B (v/v), were maintained for 1 min, and a linear gradient was initiated to reach 20% B over 2 min.…”

Section: Lc-ms/ms Instrumentationmentioning

confidence: 99%

Deciphering Fatty Acid Synthase Inhibition-Triggered Metabolic Flexibility in Prostate Cancer Cells through Untargeted Metabolomics

Jung

Park

et al. 2020

Cells

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Fatty acid synthase (FAS) is a key enzyme involved in de novo lipogenesis that produces lipids that are necessary for cell growth and signal transduction, and it is known to be overexpressed, especially in cancer cells. Although lipid metabolism alteration is an important metabolic phenotype in cancer cells, the development of drugs targeting FAS to block lipid synthesis is hampered by the characteristics of cancer cells with metabolic flexibility leading to rapid adaptation and resistance. Therefore, to confirm the metabolic alterations at the cellular level during FAS inhibition, we treated LNCaP-LN3 prostate cancer cells with FAS inhibitors (Fasnall, GSK2194069, and TVB-3166). With untargeted metabolomics, we observed significant changes in a total of 56 metabolites in the drug-treated groups. Among the altered metabolites, 28 metabolites were significantly changed in all of the drug-treated groups. To our surprise, despite the inhibition of FAS, which is involved in palmitate production, the cells increase their fatty acids and glycerophospholipids contents endogenously. Also, some of the notable changes in the metabolic pathways include polyamine metabolism and energy metabolism. This is the first study to compare and elucidate the effect of FAS inhibition on cellular metabolic flexibility using three different FAS inhibitors through metabolomics. We believe that our results may provide key data for the development of future FAS-targeting drugs.

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Regulation of endogenic metabolites by rosuvastatin in hyperlipidemia patients: An integration of metabolomics and lipidomics

Cited by 31 publications

References 42 publications

A Pilot Randomized Study of Atorvastatin As Adjunct Therapy in Patients with Acute Venous Thromboembolism

A Pilot Randomized Study of Atorvastatin As Adjunct Therapy in Patients with Acute Venous Thromboembolism

Association of cardiac autonomic dysfunction with higher levels of plasma lipid metabolites in recent-onset type 2 diabetes

Deciphering Fatty Acid Synthase Inhibition-Triggered Metabolic Flexibility in Prostate Cancer Cells through Untargeted Metabolomics

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