Association of apolipoprotein M and sphingosine-1-phosphate with brown adipose tissue after cold exposure in humans.

The HDL-associated apolipoprotein M (apoM) and its ligand sphingosine-1-phosphate (S1P) may control energy metabolism. ApoM deficiency in mice is associated with increased vascular permeability, brown adipose tissue (BAT) mass and activity, and protection against obesity. In the current study, we explored the connection between plasma apoM/S1P levels and parameters of BAT as measured via 18F-FDG PET/CT after cold exposure in humans. Fixed (n = 15) vs personalized (n = 20) short-term cooling protocols decreased and increased apoM (- 8.4%, P = 0.032 vs 15.7%, P < 0.0005) and S1P (- 41.0%, P < 0.0005 vs 19.1%, P < 0.005) plasma levels, respectively. Long-term cooling (n = 44) did not affect plasma apoM or S1P levels. Plasma apoM and S1P did not correlate significantly to BAT volume and activity in the individual studies. However, short-term studies combined, showed that increased changes in plasma apoM correlated with BAT metabolic activity (ß: 0.44, 95% CI [0.06-0.81], P = 0.024) after adjusting for study design but not BAT volume (ß: 0.39, 95% CI [- 0.01-0.78], P = 0.054). In conclusion, plasma apoM and S1P levels are altered in response to cold exposure and may be linked to changes in BAT metabolic activity but not BAT volume in humans. This contrasts partly with observations in animals and highlights the need for further studies to understand the biological role of apoM/S1P complex in human adipose tissue and lipid metabolism.

Association between plasma apolipoprotein M and cardiac autonomic neuropathy in type 1 diabetes.

AIM: Diabetes may lead to severe complications e.g. cardiac autonomic neuropathy (CAN) characterized by an increased risk of cardiovascular mortality. CAN is diagnosed by a decreased heart rate viability (HRV). Sphingosine-1-Phosphate (S1P) carried by the HDL-associated apolipoprotein M (apoM) is linked to a reduction in the heart rate, and treatment with an S1P-agonist increases HRV. The present study aimed to investigate if plasma apoM was associated with an increased risk of CAN. METHODS: The study includes 278 individuals with Type 1 Diabetes recruited from Steno Diabetes Center in Copenhagen from 2010 to 2012. RESULTS: A change of 0.1 µM plasma apoM was associated with the diagnosis of CAN (Odds ratio: 1.11 (1.02; 1.21), p = 0.013). ApoM plasma levels were also positively associated with CAN when adjusted for age and gender (Odds ratio: 1.11 (1.02; 1.21), p = 0.013) as well as lipids, beta-blockers, blood pressure, and alcohol (Odds ratio: 1.14 (1.04; 1.26), p = 0.005) and Hbga1c and time with diabetes (Odds ratio: 1.13 (1.02; 1.25), p = 0.01). Plasma apoM was also associated with a significantly lower SDNN as well as high frequency power in all adjusted models. CONCLUSION: Increased plasma apoM was associated with an increased risk of CAN as well as a significant reduction in HRV indices. This could represent changes in parasympathetic activity, but, further studies are needed to also explore additional molecular alterations behind such observations.

Increased plasma apoM levels impair triglyceride turnover in mice.

OBJECTIVE: Apolipoprotein M (apoM) is an essential transporter of plasma Sphingosine-1-Phosphate (S1P), typically attached to all lipoprotein classes, but with a majority bound to high density lipoproteins (HDL). ApoM-deficient mice display an increased activity in brown adipose tissue and a concomitant fast turnover of triglycerides. In what manner apoM/S1P affect the triglyceride metabolism is however still unknown and explored in the present study. METHODS: Triglyceride turnover and potentially associated metabolic pathways were studied in the female human apoM transgenic mouse model (apoM-Tg) with increased plasma apoM and S1P levels. The model was compared with wild type (WT) mice. RESULTS: ApoM-Tg mice had a reduced plasma triglyceride turnover rate and a lower free fatty acid uptake in subcutaneous adipocytes compared to WT mice. Screening for potential molecular mechanisms furthermore revealed a reduction in plasma lipase activity in apoM-Tg animals. Overexpression of apoM also reduced the plasma levels of fibroblast growth factor 21 (FGF21). CONCLUSIONS: The study features the significant role of the apoM/S1P axis in maintaining a balanced triglyceride metabolism. Further, it also highlights the risk of inducing dyslipidaemia in patients receiving S1P-analouges and additionlly emphasizes the apoM/S1P axis as a potential therapeutic target in treatment of hypertriglyceridemia.

The Apolipoprotein M/S1P Axis Controls Triglyceride Metabolism and Brown Fat Activity.

Apolipoprotein M (apoM) is the carrier of sphingosine-1-phosphate (S1P) in plasma high-density lipoproteins. S1P is a bioactive lipid interacting with five receptors (S1P1-5). We show that lack of apoM in mice increases the amount of brown adipose tissue (BAT), accelerates the clearance of postprandial triglycerides, and protects against diet-induced obesity (i.e., a phenotype similar to that induced by cold exposure or ß3-adrenergic stimulation). Moreover, the data suggest that the phenotype of apoM-deficient mice is S1P dependent and reflects diminished S1P1 stimulation. The results reveal a link between the apoM/S1P axis and energy metabolism.

Apolipoprotein M in lipid metabolism and cardiometabolic diseases.

PURPOSE: This review will address recent findings on apolipoprotein M (apoM) and its ligand sphingosine-1-phosphate (S1P) in lipid metabolism and inflammatory diseases. RECENT FINDINGS: ApoM's likely role(s) in health and disease has become more diverse after the discovery that apoM functions as a chaperone for S1P. Hence, apoM has recently been implicated in lipid metabolism, diabetes and rheumatoid arthritis through in-vivo, in-vitro and genetic association studies. It remains to be established to which degree such associations with apoM can be attributed to its ability to bind S1P. SUMMARY: The apoM/S1P axis and its implications in atherosclerosis and lipid metabolism have been thoroughly studied. Owing to the discovery of the apoM/S1P axis, the scope of apoM research has broadened. ApoM and S1P have been implicated in lipid metabolism, that is by modulating HDL particles. Also, the importance in regulating endothelial function is being investigated. Furthermore, both apoM and S1P have been linked to diabetes and glucose and insulin metabolism. Finally, genetic variations in the apoM gene are associated with lipid disturbances, diabetes and rheumatoid arthritis. These findings suggest not only diverse effects of apoM, but also the important question of whether apoM mainly acts as a S1P carrier, if apoM carries other substances with biological effects as well, or whether the apoM protein has effects on its own.