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.

Apolipoprotein M promotes mobilization of cellular cholesterol in vivo.

OBJECTIVE: The HDL associated apolipoprotein M (apoM) protects against experimental atherosclerosis but the mechanism is unknown. ApoM increases prebeta-HDL formation. We explored whether plasma apoM affects mobilization of cholesterol from peripheral cells in mice. METHODS AND RESULTS: ApoM-enriched HDL from apoM-transgenic mice increased the in vitro efflux of 3H-cholesterol from macrophages by 24 +/- 3% (p < 0.05) as compared with HDL from wild type (WT) mice, thus confirming previous findings. However, apoM-free HDL was not poorer than that of WT HDL to mobilize 3H-cholesterol. 3H-cholesterol-labeled foam cells were implanted in the peritoneal cavity of apoM-/-, WT and apoM-transgenic mice to assess the mobilization of cholesterol from foam cells in vivo and subsequent excretion into feces. The results showed a statistically non-significant trend towards increased mobilization of cellular cholesterol to plasma with increasing plasma apoM. However, the apoM-genotype did not affect the excretion of 3H-cholesterol in feces. Nevertheless, when apoM-/-, apoM-transgenic and WT mice received a constant intravenous infusion of 13C2-cholesterol/intralipid for 5 h, the rate of enrichment of blood free cholesterol with free 13C2-cholesterol was significantly lower (consistent with an increase in flux of unlabeled free cholesterol into the plasma) in the apoM-transgenic (3.0 +/- 0.9 per thousand/h) as compared to WT (5.7 +/- 0.9 per thousand/h, p < 0.05) and apoM-/- (6.5 +/- 0.6 per thousand/h, p < 0.01) mice. CONCLUSION: The present data indicate that the plasma apoM levels modulate the ability of plasma to mobilize cellular cholesterol, whereas apoM has no major effect on the excretion of cholesterol into feces.

Apolipoprotein M binds oxidized phospholipids and increases the antioxidant effect of HDL.

OBJECTIVE: Oxidation of LDL plays a key role in the development of atherosclerosis. HDL may, in part, protect against atherosclerosis by inhibiting LDL oxidation. Overexpression of HDL-associated apolipoprotein M (apoM) protects mice against atherosclerosis through a not yet clarified mechanism. Being a lipocalin, apoM contains a binding pocket for small lipophilic molecules. Here, we report that apoM likely serves as an antioxidant in HDL by binding oxidized phospholipids, thus enhancing the antioxidant potential of HDL. METHODS AND RESULTS: HDL was isolated from wild type mice, apoM-deficient mice, and two lines of apoM-Tg mice with ∼2-fold and ∼10-fold increased plasma apoM, respectively. Increasing amounts of HDL-associated apoM were associated with an increase in the resistance of HDL to oxidation with Cu(2+) or 2,2'-azobis 2-methyl-propanimidamide, dihydrochloride (AAPH) and to an increased ability of HDL to protect human LDL against oxidation. Oxidized phospholipids, but not native phospholipids, quenched the intrinsic fluorescence of recombinant human apoM and the quenching could be competed with myristic acid suggesting selective binding of oxidized phospholipid in the lipocalin-binding pocket of apoM. CONCLUSIONS: The results suggest that apoM can bind oxidized phospholipids and that it increases the antioxidant effect of HDL. This new mechanism may explain at least part of the antiatherogenic potential of apoM.