Effect Of Total Sphingomyelin Synthase Activity On Low Density Lipoprotein Catabolism

Objective: Sphingomyelin (SM) and cholesterol are two key lipid partners on cell membrane and on lipoproteins. Many studies have indicated the influence of cholesterol on SM metabolism. This study examined the influence of SM biosynthesis on cholesterol metabolism. Approach and Results: Inducible global Sms1 KO/global Sms2 KO mice were prepared to evaluate the effect of whole-body SM biosynthesis deficiency on lipoprotein metabolism. Tissue cholesterol, SM, ceramide, glucosylceramide levels were measured. TG production rate and LDL catabolism were measured. Lipid rafts were isolated and LDL receptor mass and function were evaluated. Also, the effect of exogenous sphingolipids on hepatocytes were investigated. We found that total SMS depletion significantly reduced plasma SM levels. Also, the total deficiency significantly induced plasma cholesterol, apoB, and apoE levels. Importantly, total SMS deficiency, but not SMS2 deficiency, dramatically decreased LDL receptor in the liver and attenuated LDL uptake through the receptor. Further, we found that total SMS deficiency greatly reduced LDL receptor in the rafts which contained significantly lower SM and significantly higher glucosylceramide as well as cholesterol. Furthermore, we treated primary hepatocytes and Huh7 cells (a human hepatoma cell line) with SM or ceramide or glucosylceramide, we found that only SM could up-regulate LDL receptor levels in the dose-dependent fashion. Conclusions: Whole body SM biosynthesis plays an important role in LDL-cholesterol catabolism. The total SMS deficiency, but not SMS2 deficiency, reduces LDL uptake and causes LDL-cholesterol accumulation in the circulation. Given the fact that serum SM level is a risk factor for cardiovascular diseases, inhibiting SMS2 but not SMS1 should be the desirable approach.