Abstract
Niemann-Pick C1-Like 1 (NPC1L1) is a cholesterol importer and target of ezetimibe, a cholesterol absorption inhibitor used clinically for dyslipidemia. Recent studies demonstrated that NPC1L1 regulates the intestinal absorption of several fat-soluble nutrients, in addition to cholesterol. The study was conducted to reveal new physiological roles of NPC1L1 by identifying novel dietary substrate(s). Very low-density lipoprotein and low-density lipoprotein (VLDL/LDL) are increased in Western diet (WD)-fed mice in an NPC1L1-dependent manner, so we comprehensively analyzed the NPC1L1-dependent VLDL/LDL components. Apolipoprotein M (apoM), a binding protein of sphingosine-1-phosphate (S1P: a lipid mediator), and S1P were NPC1L1-dependently increased in VLDL/LDL by WD feeding. S1P is metabolized from sphingomyelin (SM) and SM is abundant in WD, so we focused on intestinal SM absorption. In vivo studies with Npc1l1 knockout mice and in vitro studies with NPC1L1-overexpressing cells revealed that SM is a physiological substrate of NPC1L1. These results suggest a scenario in which dietary SM is absorbed by NPC1L1 in the intestine, followed by SM conversion to S1P and, after several steps, S1P is exported into the blood as the apoM-bound form in VLDL/LDL. Our findings provide insight into the functions of NPC1L1 for a better understanding of sphingolipids and S1P homeostasis.
Highlights
Sphingolipids constitute a class of lipids that are essential components of membranes in eukaryotes.In addition to their primary roles in membrane formation, some bioactive sphingolipids and their metabolites (e.g., sphingomyelin (SM) and sphingosine-1-phosphate (S1P)) have attracted attention as important regulators of multiple cellular behaviors and responses, including cell proliferation, cell death, and immune responses [1]
These results suggest a scenario in which dietary SM is absorbed by Niemann-Pick C1-Like 1 (NPC1L1) in the intestine, followed by SM conversion to S1P and, after several steps, S1P is exported into the blood as the apolipoprotein M (apoM)-bound form in very low-density lipoprotein (VLDL)/low-density lipoprotein (LDL)
Consistent with our previous studies [10], VLDL/LDL-cholesterol (Figure 1A), and triglyceride (Figure 1B) after long-term Western diet (WD) feeding were higher in Npc1l1WT mice than in both Npc1l1KO and ezetimibe-administered Npc1l1WT mice, whereas only a minimal difference in high-density lipoprotein (HDL) lipids was observed. Such an NPC1L1-dependent increase in VLDL/LDL lipids was observed even after short-term WD feeding. These results indicate that NPC1L1 controls VLDL/LDL lipids in WD-fed mice
Summary
Sphingolipids constitute a class of lipids that are essential components of membranes in eukaryotes. In addition to their primary roles in membrane formation, some bioactive sphingolipids and their metabolites (e.g., sphingomyelin (SM) and sphingosine-1-phosphate (S1P)) have attracted attention as important regulators of multiple cellular behaviors and responses, including cell proliferation, cell death, and immune responses [1]. Numerous studies have demonstrated that changes in the dietary intake of sphingolipids influence the progression and/or onset of several lifestyle-related diseases, cancer, and inflammation, indicating that dietary sphingolipids are physiologically important [2,3]. Our recent studies demonstrated that NPC1L1 is involved in intestinal absorption of fat-soluble vitamins, such as vitamin E and vitamin K1 , in addition to Nutrients 2020, 12, 2641; doi:10.3390/nu12092641 www.mdpi.com/journal/nutrients
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