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

Christoffersen, Christina; Federspiel, Christine K.; Borup, Anna; Christensen, Peter Holdt; Madsen, Andreas Nygaard; Heine, Markus; Nielsen, Carsten H.; Kjær, Andreas; Holst, Birgitte; Heeren, Joerg; Nielsen, Lars Bo

doi:10.1016/j.celrep.2017.12.029

Cited by 53 publications

(45 citation statements)

References 61 publications

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“…In addition, it was shown that ApoM deficiency protects against diet-induced obesity and improves glucose tolerance. However, in the present study, female ApoM-knockout mice were used 4 . Previous studies have shown that estrogen upregulates the expression of ApoM through estrogen receptor a 20 .…”

Section: Discussionmentioning

confidence: 99%

“…HDL in type 2 diabetes patients loses the ability to maintain proper endothelial function, possibly as a result of the loss of S1P, and might contribute to the development of diabetic complications 3 . Christoffersen et al 4 showed that ApoM deficiency protects against diet-induced obesity and improves glucose tolerance. Furthermore, we reported that plasma ApoM was decreased by 70% in diabetic mice, ApoM messenger ribonucleic acid (mRNA) levels in the liver were decreased by 40%, and ApoM mRNA levels in the liver and kidneys were increased by the injection of exogenous insulin 5 .…”

Section: Introductionmentioning

confidence: 99%

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Apolipoprotein M overexpression through adeno‐associated virus gene transfer improves insulin secretion and insulin sensitivity in Goto‐Kakizaki rats

Zhang

Yao

et al. 2020

J of Diabetes Invest

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Aims/Objective The development of type 2 diabetes is a result of insulin resistance in various tissues, including skeletal muscle and liver. Apolipoprotein M (ApoM) plays an important role in the function of high‐density lipoprotein, and also affects hepatic lipid and glucose metabolism. In this study, we aimed to investigate whether ApoM overexpression modulates glucose metabolism and improves insulin sensitivity. Materials and Methods The Goto‐Kakizaki (GK) rats were transfected with adeno‐associated virus (AAV) encoding rat ApoM gene or control blank. The oral glucose tolerance test (OGTT) and hyperinsulinemic‐euglycemic clamp (HEC) experiment were used to assess the insulin sensitivity of GK rats. Results The results show that ApoM messenger ribonucleic acid and protein were significantly overexpressed in the pancreatic tissues. Overexpression of ApoM decreased fasting blood glucose and random blood glucose, improved glucose tolerance, and increased bodyweight and insulin levels in GK rats. The glucose infusion rate of rats in the AAV encoding rat ApoM gene group during HEC test was 1.04‐, 1.23‐ and 1.95‐fold higher than that in the AAV control blank group at 1–3 weeks after injection of AAV, respectively. A Wes‐ProteinSimple assay and quantification was carried out to assess phosphorylated protein kinase B/protein kinase B protein levels in the muscle tissues of ApoM‐overexpressing GK rats, and they were found to be higher than those of the control group at the seventh week after AAV injection. Conclusions ApoM overexpression through adeno‐associated virus gene transfer might improve insulin secretion and insulin sensitivity in GK rats.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Apolipoprotein M overexpression through adeno‐associated virus gene transfer improves insulin secretion and insulin sensitivity in Goto‐Kakizaki rats

Zhang

Yao

et al. 2020

J of Diabetes Invest

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“…A recentstudy demonstrated that lack of ApoM in mice increases the amount of brown adipose tissue (BAT), accelerates clearance of postprandial triglycerides, and protects against diet-induced obesity. Moreover, ApoM-de cient mice phenotype is S1Pdependent and re ects diminished S1P1 stimulation [22]. In genetically modi ed mice, changes in plasma ApoM concentration resulted in quantitative and qualitative changes in HDLs, while its overexpression reduced atherosclerosis [6].…”

Section: Discussionmentioning

confidence: 99%

Integrated bioinformatics analysis of apolipoprotein M in thyroid cancer

Wei¹,

Yu²,

Zhang³

et al. 2019

Preprint

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Background Throid cancer is one of the most common cancer worldwide and its mechanism of development remains elusive.Apolipoprotein M (ApoM) is associated with lipid metabolism, inflammation and atherosclerosis, but the prognostic value of apoM in thyroid cancer has not been well studied.Methods In this study, transcriptional expression, survival, gene ontology and networks of apoM in patients with thyroid cancer were analyzed using integrated bioinformatics tools including UALCAN, GEO, LinkedOmics, GeneMANIA, STRING, CircNET and KOBAS.Results Results indicated that ApoM is decreased in thyroid cancer tissues and is therefore negatively associated with malignant clinicopathological parameters. However, Kaplan-Meier analyses showed that ApoM expression is not an independent and significant prognostic factor for overall survival in thyroid cancer. LinkedOmicsConclusions These results indicate that integrated bioinformatics analysis provide valuable information on apoM expression and potential regulatory networks in thyroid cancer. This information will be crucial in understanding the role of apoM in thyroid carcinogenesis.

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“…Together with the novel data in this manuscript, these findings suggest that there are at least two independent mechanisms by which hepatic FoxOs regulate HDL composition. S1P is a signaling molecule, and it is been reported that S1P can induce differential effects, depending on its chaperone, either ApoM or albumin 16,[20][21][22][23] . The molecular mechanisms for the differential effects between ApoM-and albumin-bound S1P remain under investigation.…”

Section: Discussionmentioning

confidence: 99%

“…In plasma, around 65% of S1P is carried by HDL-bound ApoM and the remainder is found in the lipoprotein depleted (LPD) fraction, presumably associated to albumin 16,19 . Importantly, S1P induces differential effects depending on whether it is associated with ApoM or albumin 20,21 . This is exemplified by the ability of the HDL-ApoM-S1P complex to enhance endothelial function 16,[22][23][24] .…”

Section: Introductionmentioning

confidence: 99%

Hepatic FoxOs induce apolipoprotein M and are required for sphingosine-1-phosphate to bind high density lipoproteins

Izquierdo

Shanmugarajah

Lee

et al. 2019

Preprint

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The authors declare no conflicts of interest.Abbreviations: AAV=adeno-associated virus, ApoM=apolipoprotein M, DIO=diet induced obese, FPLC=fast protein liquid chromatography, HDL=high density lipoprotein, HFD=high fat diet, LC-MS/MS=liquid chromatography-mass spectrometry, LDL=low density lipoprotein, LPD=lipoprotein depleted, S1P=sphingosine-1-phosphate, Tbg=thyroxin binding globulin, VLDL=very low density lipoprotein, WTD=western type diet ABSTRACTThe FoxO family of transcription factors play an important role in mediating insulin action on glucose, lipid, and lipoprotein metabolism. Liver-specific triple FoxO knockout mice (L-FoxO1,3,4) have defects in expression of genes related to glucose production, bile acid synthesis, and high density lipoprotein (HDL)-cholesterol uptake. We have now identified Apolipoprotein M (Apom) as a novel transcriptional target of liver FoxO. ApoM is a liver-secreted apolipoprotein that is bound to HDL in the circulation, and it serves as a chaperone for the bioactive lipid, sphingosine-1-phosphate (S1P). Several recent studies have demonstrated that S1P bound to ApoM induces unique effects, compared to S1P bound to albumin. We now show that liver FoxOs are required for ApoM mRNA and protein expression, and that ApoM is a transcriptional target of FoxOs. Moreover, while total plasma S1P levels are similar between control and L-FoxO1,3,4 mice, S1P is nearly absent from HDL in L-FoxO1,3,4 mice, and is instead increased in the lipoprotein depleted fraction. We also observed that leptin receptor deficient db/db mice have low hepatic Apom mRNA, and low levels of ApoM and S1P in HDL, without changes in total plasma S1P. These data demonstrate that FoxO transcription factors are novel regulators of the ApoM-S1P pathway, and indicate a potential link between hepatic insulin action and HDL function. METHODS Mice and diets.All experiments were approved by the Columbia University Institutional Animal Care and Use Committee. L-FoxO1,3,4 mice have been previously described 5,9 . Males at least 12 weeks old were studied, except in studies of 2-day-old pups, which were of mixed sex. For the acute FoxO depletion experiments, adult Foxo1 fl/fl , Foxo3 fl/fl , and Foxo4 fl/Y control mice were transduced with adeno-associated virus (serotype 8) expressing Cre recombinase driven by the hepatocyte-specific Tbg promoter (AAV8.Tbg. Cre) or control virus (AAV.GFP). Mice were injected intravenously with 1×10 11 virus particles/mouse, 4 weeks prior to euthanasia. AAV8.Tbg.Cre was a gift ). For the adenovirus experiments, adult male mice were injected intravenously with murine ApoM adenovirus (Welgen) 0.5 × 10 9 virus particles/gram of body weight, 8 days prior to euthanasia. For the db/db studies, male db/db and db/+ mice were purchased from Jackson Laboratory and were studied when they were 12, 13 or 25 weeks old. For the diet induced obesity studies, male C57BL/6J mice were purchased from Jackson Laboratory when they were 6 weeks old. Mice were fed either a standard chow diet (Purina) or a high fat diet ...

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

Cited by 53 publications

References 61 publications

Apolipoprotein M overexpression through adeno‐associated virus gene transfer improves insulin secretion and insulin sensitivity in Goto‐Kakizaki rats

Apolipoprotein M overexpression through adeno‐associated virus gene transfer improves insulin secretion and insulin sensitivity in Goto‐Kakizaki rats

Integrated bioinformatics analysis of apolipoprotein M in thyroid cancer

Hepatic FoxOs induce apolipoprotein M and are required for sphingosine-1-phosphate to bind high density lipoproteins

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