Sphingolipid Metabolic Pathway Impacts Thiazide Diuretics Blood Pressure Response: Insights From Genomics, Metabolomics, and Lipidomics

Shahin, Mohamed H.; Gong, Yan; Frye, Reginald F.; Rotroff, Daniel M.; Beitelshees, Amber L.; Baillie, Rebecca; Chapman, Arlene B.; Gums, John G.; Turner, Stephen T.; Boerwinkle, Eric; Motsinger‐Reif, Alison A.; Fiehn, Oliver; Cooper‐DeHoff, Rhonda M.; Han, Xianlin; Kaddurah‐Daouk, Rima

doi:10.1161/jaha.117.006656

Cited by 20 publications

(17 citation statements)

References 61 publications

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“…In rodents, sphingomyelin supplementation has been shown to help reduce the intestinal absorption of serum lipids such as cholesterol and triglycerides [12]. Sphingomyelin levels have also been associated with mild-to-moderate hypertension [29]. Based on these findings, supplementation could be an avenue to explore in the context of dyslipidemia in type 1 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Changes in the lipidome in type 1 diabetes following low carbohydrate diet: a randomized crossover trial

Al-Sari

Schmidt

Suvitaival

et al. 2020

Preprint

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Aims/hypothesis: Lipid metabolism might be compromised in type 1 diabetes and the understanding of their physiology is critically important. This study aimed to compare the change in plasma lipid concentrations during carbohydrate dietary changes in individuals with type 1 diabetes and identify predictive biomarkers and early-stage pathophysiology for dyslipidaemia. We hypothesized that: (1) the lipidomics profiles before and after ingesting low or high carbohydrate diet for 12 weeks would be different; and (2) specific annotated lipid species would have significant associations with metabolic outcomes. Methods: Ten adults with type 1 diabetes (mean+/-SD: age 43.6+/-13.8 years, diabetes duration 24.5+/-13.4 years, BMI 24.9+/-2.1 kg/m2, HbA1c 57.67+/-2.6 mmol/mol) using insulin pumps participated in a randomized 2-period crossover study with a 12-week intervention period of low carbohydrate diet (< 100 g carbohydrates/day) or high carbohydrate diet (> 250 g carbohydrates/day) respectively, separated by a 12-week washout period. A large-scale non-targeted lipidomics was performed with mass spectrometry for fasting plasma samples obtained before and after each diet intervention. Logitudinal lipid levels were analysed using linear mixed-effects models. Results: In total, 289 lipid species were identified from 14 major lipid classes (triacylglycerides, phosphatidylcholines, phosphatidylethanolamines, hexosyl-ceramide, sphingomyelins, lyso-phosphatidylcholines, ceramides, lactosyl-ceramide, lyso-phoshatidylethanolamine, free fatty acids, phosphatidylinositols, phosphatidylglycerols, phosphatidylserines and sulfatides). Comparing the two diets, 11 lipid species belonging to sphingomyelins, phosphatidylcholines and LPC(O-16:0) were changed. All the 11 lipid species were significantly elevated during low carbohydrate diet. Two lipid species were most differentiated between diets, namely SM(d36:1) (B+/-SE: 1.44+/-0.28, FDR = 0.010) and PC(P-36:4)/PC(O-36:5) (B+/-SE: 1.34+/-0.25, FDR = 0.009) species. Poly-unsaturated PC(35:4) was inversely associated with BMI and positively associated with HDL-cholesterol (p < 0.001). Conclusion/interpretation: Lipidome-wide outcome analysis of a randomized cross-over trial of individuals with type 1 diabetes following a low carbohydrate diet showed an increase in sphingomyelins and phosphatidylcholines which are thought to reduce dyslipidaemia. The poly-unsaturated phosphatidylcholine 35:4 was inversely associated with BMI and positively associated with HDL-cholesterol (p < 0.001). Results from this study warrant for more investigation on the long-term effect of PC(35:4) lipid-species in lipid homeostasis in type 1 diabetes. Trial registration Clinicaltrials.gov NCT02888691 Keywords Biomarker ∙ Cardiovascular disease ∙ Dyslipidaemia ∙ Lipidomics ∙ Low carbohydrate diet ∙ Randomized trial ∙ Type 1 diabetes.

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Section: Discussionmentioning

confidence: 99%

Changes in the lipidome in type 1 diabetes following low carbohydrate diet: a randomized crossover trial

Al-Sari

Schmidt

Suvitaival

et al. 2020

Preprint

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“…Of great importance is the coupling of the genome and metabolome to inform about treatment outcomes. This is a concept referred to as pharmacometabolomics informs pharmacogenomic', which was applied initially to the study of antidepressants [88,89] and then enlarged to the study of many drug classes [75,76,90]. Here, information from both baseline and the change in metabolism was able to benefit from and add to information derived from the genome [18,88,91].…”

Section: Pmx Data and Pgx Datamentioning

confidence: 99%

“…In the last decade, PMx has shown the ability to improve predictions when combined with PGx [18,88,90,120]. The concept that "pharmacometabolomics informs pharmacogenomics" is now being tested in many clinical centers.…”

Section: Where We Are Today and The Future Of Pmxmentioning

confidence: 99%

Current Concepts in Pharmacometabolomics, Biomarker Discovery, and Precision Medicine

2020

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Pharmacometabolomics (PMx) studies use information contained in metabolic profiles (or metabolome) to inform about how a subject will respond to drug treatment. Genome, gut microbiome, sex, nutrition, age, stress, health status, and other factors can impact the metabolic profile of an individual. Some of these factors are known to influence the individual response to pharmaceutical compounds. An individual’s metabolic profile has been referred to as his or her “metabotype.” As such, metabolomic profiles obtained prior to, during, or after drug treatment could provide insights about drug mechanism of action and variation of response to treatment. Furthermore, there are several types of PMx studies that are used to discover and inform patterns associated with varied drug responses (i.e., responders vs. non-responders; slow or fast metabolizers). The PMx efforts could simultaneously provide information related to an individual’s pharmacokinetic response during clinical trials and be used to predict patient response to drugs making pharmacometabolomic clinical research valuable for precision medicine. PMx biomarkers can also be discovered and validated during FDA clinical trials. Using biomarkers during medical development is described in US Law under the 21st Century Cures Act. Information on how to submit biomarkers to the FDA and their context of use is defined herein.

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“…In terms of baseline protein expression in responders and nonresponders, responders had greater mRNA baseline levels of a number of proteins including vasodilator-stimulated phosphoprotein (VASP) and metabolites of the sphingolipid metabolic pathway (Turner et al, 2013; Shahin et al, 2017; Sá et al, 2018). It was suggested that increased baseline VASP expression and the sphingolipid metabolic pathway were responsible for TZD efficacy of arterial blood pressure reduction (Shahin et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…The involvement of these pathways in TZD reduction of arterial pressure warrants additional investigation. Indeed, it remains unclear whereby, e.g., increased sphingolipid metabolism would result in greater efficacy of TZD reduction of arterial pressure (Shahin et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Thiazide Diuretic Arterial Pressure Reduction: The Search Continues

Rapoport

Soleimani

2019

Front. Pharmacol.

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Thiazide diuretic (TZD)-mediated chronic reduction of arterial pressure is thought to occur through decreased total peripheral vascular resistance. Further, the decreased peripheral vascular resistance is accomplished through TZD activation of an extrarenal target, resulting in inhibition of vascular constriction. However, despite greater than five decades of investigation, little progress has been made into the identification of the TZD extrarenal target. Proposed mechanisms range from direct inhibition of constrictor and activation of relaxant signaling pathways in the vascular smooth muscle to indirect inhibition through decreased neurogenic and hormonal regulatory pathways. Surprisingly, particularly in view of this lack of progress, comprehensive reviews of the subject are absent. Moreover, even though it is well recognized that 1) several types of hypertension are insensitive to TZD reduction of arterial pressure and, further, TZD fail to reduce arterial pressure in normotensive subjects and animals, and 2) different mechanisms underlie acute and chronic TZD, findings derived from these models and parameters remain largely undifferentiated. This review 1) comprehensively describes findings associated with TZD reduction of arterial pressure; 2) differentiates between observations in TZD-sensitive and TZD-insensitive hypertension, normotensive subjects/animals, and acute and chronic effects of TZD; 3) critically evaluates proposed TZD extrarenal targets; 4) proposes guiding parameters for relevant investigations into extrarenal TZD target identification; and 5) proposes a working model for TZD chronic reduction of arterial pressure through vascular dilation.

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Sphingolipid Metabolic Pathway Impacts Thiazide Diuretics Blood Pressure Response: Insights From Genomics, Metabolomics, and Lipidomics

Cited by 20 publications

References 61 publications

Changes in the lipidome in type 1 diabetes following low carbohydrate diet: a randomized crossover trial

Changes in the lipidome in type 1 diabetes following low carbohydrate diet: a randomized crossover trial

Current Concepts in Pharmacometabolomics, Biomarker Discovery, and Precision Medicine

Mechanism of Thiazide Diuretic Arterial Pressure Reduction: The Search Continues

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