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ApoM: gene regulation and effects on HDL metabolism

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The recently discovered apolipoprotein M (apoM) is a plasma protein of the lipocalin family associated with the lipoproteins (mainly high-density lipoproteins, or HDLs). Expression of the apoM gene in the liver is regulated by transcription factors that control key steps in hepatic lipid and glucose metabolism. Although the concentration of plasma apoM correlates with that of cholesterol, apoM was not identified as a risk factor for cardiovascular disease in two prospective studies. In genetically modified mice, however, changes in plasma apoM concentration caused quantitative and qualitative changes in HDLs, and overexpression of the apoM gene reduced atherosclerosis. In conclusion, it seems that apoM plays a part in lipoprotein metabolism; however, the biological impact of apoM in humans remains to be determined.

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ApoM, a unique apolipoprotein in blood

Apolipoprotein M (apoM) is a recently discovered ∼25 kDa lipoprotein-associated plasma protein that is synthesized mainly in the liver and, to a smaller degree, in the kidney [1]. Most human apoM in blood is part of high-density lipoproteins (HDLs), but apoM is also found in other lipoprotein classes, including chylomicrons 1, 2. However, the putative impact of apoM on the metabolism of chylomicron and low-density lipoprotein (LDL) metabolism has not yet been explored. The mean molar plasma

ApoM in the kidney

Liver-derived apoM is mainly secreted to the plasma and integrated in plasma lipoproteins, whereas kidney-derived apoM is probably metabolized in the kidney proximal tubule. Thus, kidney-derived apoM binds the multi-ligand receptor megalin in the proximal tubular epithelium in the kidney (Figure 1). Mice lacking expression of megalin in the proximal tubule secrete apoM in the urine, whereas apoM is normally undetectable in the urine [9]. These data indicate that kidney-derived apoM is secreted

Regulation of apoM gene expression

ApoM gene expression is directly regulated by transcription factors that, among many other factors, control hepatic lipid metabolism: hepatic nuclear factor (HNF)-1α, liver receptor homolog (LRH)-1 and forkhead box A2 (Foxa2) 10, 11, 12 (Figure 2). This might indicate that apoM is linked with lipid and glucose homeostasis.

HNF-1α is a master regulator of hepatic gene expression, and HNF-1α-deficient mice have severe abnormalities in kidney, pancreas and liver function, including defective bile

Role of apoM in murine HDL metabolism

The impact of apoM on cholesterol and lipoprotein metabolism has, so far, been investigated mainly in genetically modified mouse models. Overexpression of apoM in transgenic mice, either with an adenoviral construct or constitutively, increases plasma cholesterol 32, 33. The increase in plasma cholesterol concentration was ∼20% (statistically significant) in mice overexpressing human apoM approximately tenfold, and complete knockout of the apoM gene in mice reduced plasma cholesterol by ∼20%

Effect of apoM on atherosclerosis in mice

Increased plasma concentrations of mouse and human apoM reduced development of early atherosclerotic lesions in the setting of LDL-receptor deficiency 32, 33. Notably, modest apoM overexpression did not affect plasma levels of the atherogenic VLDL and LDL lipoproteins in LDL-receptor-deficient mice, indicating that apoM might have effects on atherosclerosis beyond total plasma lipoprotein levels. Thus, it will be interesting to examine the effect of apoM deficiency on atherosclerosis.

The

Correlation between apoM and cholesterol levels in human plasma

Insight into the effect of apoM in humans stems from studies of isolated apoM-containing HDL and LDL particles isolated by immune-affinity methods and from measuring plasma apoM concentrations because there are no known mutations in the apoM gene that lower or increase apoM expression in humans. Similar to normal HDL, isolated apoM-containing HDL is heterogeneous in size, charge and density [2]. However, apoM-containing HDL is slightly more effective in mobilising cholesterol and slightly more

Concluding remarks

Studies using genetically modified mice have provided novel insight into the regulation and putative roles of apoM in HDL metabolism and atherosclerosis. ApoM is regulated by transcription factors that are also linked with hepatic glucose and lipid metabolism. Even though the biological role of apoM is unsettled, apoM seems to affect pre-β HDL formation. In addition, the recent data from mice with genetically altered apoM expression indicate that apoM has atheroprotective properties. Recent

Future directions

ApoM is a plasma lipoprotein that has been preserved during evolution and is even found in primitive organisms such as fish. There are recent indications that apoM is closely associated with plasma cholesterol in humans and that the apoM gene is regulated by transcription factors that also affect hepatic lipid and glucose metabolism. Because plasma cholesterol levels are important for human cardiovascular disease, it will be pertinent to unravel the mechanism of the association between apoM and

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Cited by (32)

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    ApoM binds primarily to high-density lipoproteins (HDLs) in the plasma (Ren et al., 2015) and is required for prebeta-HDL formation. Studies indicated that ApoM participated in cholesterol efflux to HDL and protected against atherosclerosis (Nielsen et al., 2009; Wolfrum et al., 2005). And the likely roles of ApoM in health and disease has become more diverse after the discovery of sphingosine-1-phosphate as a ligand for ApoM (Borup et al., 2015).

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    Additionally, several Apos including ApoD, ApoF, ApoH, ApoL, ApoM, and ApoO classes, have been discovered and are regarded as atypical apolipoproteins based on their primary structures. The structures of atypical apolipoproteins show no similarity to exchangeable or non-exchangeable apolipoproteins, but they are also components of lipoprotein and are associated with lipid metabolism [7,8]. Apos have been extensively studied in humans (Homo sapiens), and a relationship between specific lipoproteins and cardiovascular disease is apparent [9,10].

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