Lipidome‐ and Genome‐Wide Study to Understand Sex Differences in Circulatory Lipids

Tabassum, Rubina; Ruotsalainen, Sanni; Ottensmann, Linda; Gerl, Mathias J.; Klose, Christian; Tukiainen, Taru; Pirinen, Matti; Simons, Kai; Widén, Elisabeth; Ripatti, Samuli

doi:10.1161/jaha.122.027103

Cited by 28 publications

(26 citation statements)

References 55 publications

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“…In line with previous evidence for a sex difference in blood pressure 54 or lipid profile, 55,56 we found that sex significantly modulates the associations of 4 lipids, including CE(16:1), PC(32:1), PC(34:1), and PE(36:4) B, with the prevalence of hypertension in American Indians. The associations of longitudinal changes in 3 lipids, including FA(14:1), FA(16:1), and SM(d39:1) A, with change in SBP were also significantly different between men and women.…”

Section: Discussionsupporting

confidence: 92%

Longitudinal Lipidomic Profile of Hypertension in American Indians: Findings From the Strong Heart Family Study

et al. 2023

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BACKGROUND: Dyslipidemia is an important risk factor for hypertension and cardiovascular disease. Standard lipid panel cannot reflect the complexity of blood lipidome. The associations of individual lipid species with hypertension remain to be determined in large-scale epidemiological studies, especially in a longitudinal setting. METHODS: Using liquid chromatography-mass spectrometry, we repeatedly measured 1542 lipid species in 3699 fasting plasma samples at 2 visits (1905 at baseline, 1794 at follow-up, ~5.5 years apart) from 1905 unique American Indians in the Strong Heart Family Study. We first identified baseline lipids associated with prevalent and incident hypertension, followed by replication of top hits in Europeans. We then conducted repeated measurement analysis to examine the associations of changes in lipid species with changes in systolic blood pressure, diastolic blood pressure, and mean arterial pressure. Network analysis was performed to identify lipid networks associated with the risk of hypertension. RESULTS: Baseline levels of multiple lipid species, for example, glycerophospholipids, cholesterol esters, sphingomyelins, glycerolipids, and fatty acids, were significantly associated with both prevalent and incident hypertension in American Indians. Some lipids were confirmed in Europeans. Longitudinal changes in multiple lipid species, for example, acylcarnitines, phosphatidylcholines, fatty acids, and triacylglycerols, were significantly associated with changes in blood pressure measurements. Network analysis identified distinct lipidomic patterns associated with the risk of hypertension. CONCLUSIONS: Baseline plasma lipid species and their longitudinal changes are significantly associated with hypertension development in American Indians. Our findings shed light on the role of dyslipidemia in hypertension and may offer potential opportunities for risk stratification and early prediction of hypertension.

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Section: Discussionsupporting

confidence: 92%

Longitudinal Lipidomic Profile of Hypertension in American Indians: Findings From the Strong Heart Family Study

et al. 2023

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“…With the exception of SM d42:6, many sphingolipids including SM d44:1 and SM d38:1 are more abundant in females compared to males. This is consistent with human data that shows a similar trend wheremost sphingomyelins are more abundant in females 33,34 . Notably, lipids with the greatest fold change contain polyunsaturated 22:6 fatty acyl, for example TG 22:6_22:6_22:6 (TG 66:18), TG 18:0_22:6_22:6 (TG 62:12) and PC 18:0_22:6 (PC 40:6).…”

Section: Unsupervised Clustering Revealed Better Association Of Metab...supporting

confidence: 93%

Plasma metabolomics supports non-fasted sampling for early detection of impaired glucose tolerance in the Nile rat model of type 2 diabetes

Toh

Anderson

Curtis

et al. 2023

Preprint

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Type 2 diabetes is a challenge in modern healthcare, and animal models are necessary to identify underlying mechanisms, where we can achieve much better environmental control than what is practical in human studies. The Nile rat (Arvicanthis niloticus) develops diet-induced diabetes rapidly on a conventional rodent chow diet without genetic or chemical manipulation. Unlike common laboratory models, the outbred Nile rat model is diurnal and can progress to advanced diabetic complications, better mimicking the human condition. Some human studies indicate that compared to fasting glucose, post-prandial blood glucose is more sensitive to the initial stages of diabetes, suggesting that we should capture the non-fasted state to study early diabetes. However, it is unknown if ad libitum feeding in the Nile rats leads to increased variance thus masking diabetes-related metabolic changes in the plasma. In this study, we compared the repeatability within triplicate non-fasted or fasted plasma samples and assessed prediction of impaired glucose tolerance in fasted and non-fasted plasma. We used liquid chromatography-mass spectrometry lipidomics and polar metabolomics to measure relative metabolite abundances in the plasma samples. Metabolite measurements in non-fasted plasma were less variable than measurements in fasted plasma. We detected 66 metabolites in non-fasted plasma associated with glucose tolerance in elastic net and individual metabolite linear regression models. Low metabolite replicate variance was reproduced in a cohort of mature 30-week male and female Nile rats. Our results support using non-fasted plasma metabolomics for early detection of impaired glucose tolerance in Nile rats.

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“…15). Higher male circulating TAG and APOB levels were also reported in humans 43,44 . These observations could be explained by a shift of TAGs to the liver in female mice, fitting with our model of higher hepatic VLDL uptake, possibly explaining why clearance of circulating VLDL-associated TAGs in humans is faster in women 16,45 .…”

Section: Resultsmentioning

confidence: 67%

A sexually dimorphic hepatic cycle of periportal VLDL generation and subsequent pericentral VLDLR-mediated lipoprotein re-uptake

Martini,

Gobet,

Salati

et al. 2023

Preprint

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The liver shows striking sexual dimorphism, which is reflected in differences between women and men in pathologies inherently associated with hepatic function. Recent single-cell transcriptomes revealed spatiotemporal programmes of liver function on the sublobular scale. However, how sexual dimorphism affects this space-time logic remains poorly understood. To address this, we performed single-cell RNA-seq in the mouse liver, which allowed us to model how lobular position, circadian time and sex shape the transcriptome. We found that sex, space and time markedly influence xenobiotic detoxification and lipid processing, including lipoprotein metabolism. Crucially, the very low density lipoprotein receptor (VLDLR) is restricted to the pericentral zone, with significantly higher mRNA and protein levels in female mice, which is conserved in the human liver. In addition, several genes involved in VLDL assembly are periportally biased, and we corroborated periportal VLDL generation with electron microscopy. Together, this suggests a hepatic cycle of periportal formation and pericentral uptake of VLDL. In addition, we demonstrated that in humans VLDLR expression depends also on age and body mass index. Crucially, these processes provide a new window into the sexual dimorphism characterizing atherosclerotic cardiovascular disease.

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Lipidome‐ and Genome‐Wide Study to Understand Sex Differences in Circulatory Lipids

Cited by 28 publications

References 55 publications

Longitudinal Lipidomic Profile of Hypertension in American Indians: Findings From the Strong Heart Family Study

Longitudinal Lipidomic Profile of Hypertension in American Indians: Findings From the Strong Heart Family Study

Plasma metabolomics supports non-fasted sampling for early detection of impaired glucose tolerance in the Nile rat model of type 2 diabetes

A sexually dimorphic hepatic cycle of periportal VLDL generation and subsequent pericentral VLDLR-mediated lipoprotein re-uptake

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