Differences in the Distribution of Ceramides and Sphingosine among Lipoprotein and Lipoprotein-Depleted Fractions in Patients with Type 2 Diabetes Mellitus

Abstract

In addition to the quantity and quality, the carriers, such as lipoproteins and albumin, can affect the physiological properties and clinical significance of lipids. This study aimed to elucidate the modulation of the levels of ceramides and sphingosine, which are considered as proatherosclerotic lipids, in lipoproteins and lipoprotein-depleted fractions in subjects with type 2 diabetes. Methods:We separated the serum samples collected from healthy subjects (n = 22) and subjects with type 2 diabetes (n=39) into Triglyceride (TG)-rich lipoproteins (TRL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and lipoprotein-depleted fractions via ultracentrifugation. Then, we measured the levels of six species of ceramides, sphingosine, and dihydrosphingosine via LC-MS/MS and statistically analyzed them to identify the sphingolipids in each fraction, which are associated with diabetes as well as cardiovascular and renal complications. Results:In subjects with diabetes, the levels of sphingosine and dihydrosphingosine in the TRL, LDL, and lipoprotein-depleted fractions were higher, whereas those in the HDL were lower. In addition, the ceramide levels in HDL were lower, whereas those in lipoprotein-depleted fractions were higher. Furthermore, The levels of ceramides in lipoproteins, especially LDL, were negatively associated with the presence of cardiovascular diseases and stage 4 diabetic nephropathy. Conclusions:The contents of ceramides and sphingosine in lipoproteins and lipoprotein-depleted fractions were differently modulated in diabetes and associated with cardiovascular diseases and diabetic nephropathy. The carrier might be an important factor for the biological properties and clinical significance of these sphingolipids. been well investigated. For example, saturated fatty acids can induce lipid toxicities, such as endoplasmic reticulum stress, oxidative stress, and inflammation 1) . Furthermore, ω6 fatty acids can induce inflammation, whereas ω3 fatty acids exhibit anti-inflammatory properties 2) . In fact, the ratio of ω3 fatty acids to ω6

Diagnostic and predictive values of serum metabolic profiles in sudden sensorineural hearing loss patients

“…Sphingosine, an important member of sphingolipids, is a ubiquitous component of the cell membrane and serves a pivotal role in cell growth, metabolism regulation, signal transduction, and various physiological function ( Gaggini et al, 2022 ; Grewe et al, 2022 ). Previous publications demonstrated that sphingosine and sphingosine-1-phosphate (its downstream product) were bioactive biomolecules which exerted proinflammatory effects and promoted proapoptotic properties in the vascular endothelial cell, contributing to the occurrence and development of cardiovascular diseases ( Bernacchioni et al, 2022 ; Kurano et al, 2022 ). In recent studies, sphingosine levels were proven to be shifted in the inner tissues and perilymph and aggravated the oxidative stress and inflammation in sensorineural hearing loss and ototoxicity ( Romero-Guevara et al, 2015 ; Cencetti et al, 2019 ; Wang et al, 2020 ; Ramkumar et al, 2021 ).…”

Sphingolipids: Friends or Foes?

“…This is an inevitable and important question and deserves further investigation. Kurano et al found that Cer(18:1) behaves a differently from other ceramides in the HDL of patients with diabetes 8) . It is reasonable to speculate that each ceramide affects metabolism differently depending on…”

“…In this issue of Journal of Atherosclerosis and Thrombosis, Kurano et al reported that they measured ceramides and sphingosine, including dihydrosphingosine, a molecule that is closely related to sphingosine (Fig. 1), in each serum lipoprotein and lipoprotein-deleted fraction of healthy controls and patients with diabetes and compared the distribution of these sphingolipids between the two populations 8) . Some of their patients with type 2 diabetic mellitus had complications related to cardiovascular diseases and diabetic nephropathy.…”

“…The amount of ceramides measured in serum is related to atherosclerosis and type 2 diabetes, as mentioned above. Kurano et al revealed a significant difference in the distribution of ceramides among lipoproteins and lipoprotein-deleted fractions of serum when comparing patients with diabetes to healthy subjects 8) . Moreover, in patients with diabetes, ceramides increase in LDL, but they decrease in HDL compared to normal subjects.…”

“…Ceramides contained in lipoproteins behave differently in atherogenesis and metabolic conditions than those existing in lipoprotein-deleted fractions or bound to albumin. Kurano et al described an interesting finding in their previous research that sphingosine 1-phosphate (S1P), a sphingolipid, is anti-atherogenic when it is bound to HDL via apoprotein M, but it exerts harmful effects on atherosclerosis when it is bound to albumin 8) . So, do the ceramides have the same effect as S1P?…”