Hypomorphic sialidase expression decreases serum cholesterol by downregulation of VLDL production in mice

Lipoprotein metabolism is an important contributing factor in the development and progression of atherosclerosis. Plasma lipoproteins and their receptors are heavily glycosylated and sialylated, and levels of sialic acids modulate their biological functions. Sialylation is controlled by the activities of sialyltranferases and sialidases. To address the impact of sialidase (neu1) activity on lipoprotein metabolism, we have generated a mouse model with a hypomorphic neu1 allele (B6.SM) that displays reduced sialidase expression and sialidase activity. The objectives of this study are to determine the impact of sialidase on the rate of hepatic lipoprotein secretion and lipoprotein uptake. Our results indicate that hepatic levels of cholesterol and triglycerides are significantly higher in B6.SM mice compared with C57Bl/6 mice; however, VLDL-triglyceride production rate is lower. In addition, B6.SM mice show significantly lower levels of hepatic microsomal triglyceride transfer protein (MTP) and active sterol-regulatory element binding protein (SREBP)-2 but higher levels of diglyceride acyltransferase (DGAT)2; these are all indicative of increased hepatic lipid storage. Rescue of sialidase activity in hypomorphic sialidase mice using helper-dependent adenovirus resulted in increased VLDL production and an increase in MTP levels. Furthermore, hypomorphic sialidase expression results in stabilization of hepatic LDL receptor (LDLR) protein expression, which enhances LDL uptake. These findings provide novel evidence for a central role of sialidase in the cross talk between the uptake and production of lipoproteins. Lipoprotein metabolism is an important contributing factor in the development and progression of atherosclerosis. Plasma lipoproteins and their receptors are heavily glycosylated and sialylated, and levels of sialic acids modulate their biological functions. Sialylation is controlled by the activities of sialyltranferases and sialidases. To address the impact of sialidase (neu1) activity on lipoprotein metabolism, we have generated a mouse model with a hypomorphic neu1 allele (B6.SM) that displays reduced sialidase expression and sialidase activity. The objectives of this study are to determine the impact of sialidase on the rate of hepatic lipoprotein secretion and lipoprotein uptake. Our results indicate that hepatic levels of cholesterol and triglycerides are significantly higher in B6.SM mice compared with C57Bl/6 mice; however, VLDL-triglyceride production rate is lower. In addition, B6.SM mice show significantly lower levels of hepatic microsomal triglyceride transfer protein (MTP) and active sterol-regulatory element binding protein (SREBP)-2 but higher levels of diglyceride acyltransferase (DGAT)2; these are all indicative of increased hepatic lipid storage. Rescue of sialidase activity in hypomorphic sialidase mice using helper-dependent adenovirus resulted in increased VLDL production and an increase in MTP levels. Furthermore, hypomorphic sialidase expression results in stabilization of hepatic LDL receptor (LDLR) protein expression, which enhances LDL uptake. These findings provide novel evidence for a central role of sialidase in the cross talk between the uptake and production of lipoproteins. diglyceride acyltransferase endoplasmic reticulum fast-protein liquid chromatography inverted terminal repeat LDL receptor microsomal triglyceride transfer protein proprotein convertase subtilisin/kexin type 9 sterol-regulatory element binding protein triglyceride Atherosclerosis is a chronic inflammation of the arteries caused by subendothelial accumulation of modified lipoproteins and their interactions with components of the vasculature and immune cells (1Hegele R.A. Plasma lipoproteins: genetic influences and clinical implications.Nat. Rev. Genet. 2009; 10: 109-121Crossref PubMed Scopus (326) Google Scholar). This complex and multifactorial disease is the leading preventable cause of death in the modern world due to complications involved with plaque formation and rupture, which lead to coronary heart disease, myocardial infarctions, and strokes (2Glass C.K. Witztum J.L. Atherosclerosis: the road ahead.Cell. 2001; 104: 503-516Abstract Full Text Full Text PDF PubMed Scopus (2636) Google Scholar). Neu1 sialidase belongs to a family of hydrolytic enzymes that cleave terminal sialyl linkages of glycoproteins, glycolipids, and oligosaccharides (3Reuter G. Gabius H.J. Sialic acids structure-analysis-metabolism-occurrence-recognition.Biol. Chem. Hoppe Seyler. 1996; 377: 325-342Crossref PubMed Google Scholar). While the role of the enzyme in the lysosome is well defined, its functional consequences on the cell surface, including its role in cell-surface receptor recognition, catabolism, tumorigenicity, and antigen masking, are still being explored (4Collard J.G. Schijven J.F. Bikker A. La R.G. 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P. in lipoproteins enhances the adhesion of human cells to endothelial PubMed Scopus Google Scholar). their roles in lipid metabolism and disease the functional of sialic acids on these have significantly To the of sialidase on lipoprotein and cholesterol metabolism in we to and mice with hypomorphic sialidase of sialidase in the mouse in the M. in the Lett. PubMed Scopus Google Potier M. for activity on mouse on PubMed Scopus Google Scholar), and these have sialylation of and an immune of cell activity by cells.J. Immunol. Google Scholar). and have that the sialidase M. Cloning and of a sialidase from the murine levels of and a acid are for reduced sialidase activity in mice the 1997; PubMed Scopus Google Scholar), and we have a in the mouse lysosomal sialidase which results in reduced sialidase gene in the This a binding for a in reduced gene expression M. A. S.A. in the neu1 an and results in a mouse model of sialidase Genet. 2009; PubMed Scopus Google Scholar). however, in a of genes T. M. M. A. mouse the of a in the receptor PubMed Google G. A.V. Zhang C. J.M. et that and in and 2009; PubMed Scopus Google Scholar), of the consequences of have this from the mice by a C57Bl/6 genetic a hypomorphic sialidase which reduced sialidase protein levels and activity. In this we on the effect of hypomorphic sialidase (neu1) expression on the regulation of lipoprotein metabolism in the that hypomorphic sialidase expression cholesterol levels by modulating hepatic VLDL production as well as hepatic lipid This study to sialidase as an important in lipoprotein metabolism and as a potential for such as and atherosclerosis. 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