Ping Xie1, Hongling Zhu2, Lin Jia3, Yinyan Ma4, Weiqing Tang2, Youlin Wang2, Bingzhong Xue5, Hang Shi5, Liqing Yu6. 1. Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA; Department of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA; Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China. 2. Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA. 3. Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA; Department of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. 4. Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA; Department of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA; Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA. 5. Department of Biology, Georgia State University, Atlanta, GA 30303, USA. 6. Department of Pathology Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA; Department of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA; Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA. Electronic address: lyu123@umd.edu.
Abstract
OBJECTIVE: The correlation between intestinal cholesterol absorption values and plasma low-density lipoprotein-cholesterol (LDL-C) levels remains controversial. Niemann-Pick-C1-Like 1 (NPC1L1) is essential for intestinal cholesterol absorption, and is the target of ezetimibe, a cholesterol absorption inhibitor. However, studies with NPC1L1 knockout mice or ezetimibe cannot definitively clarify this correlation because NPC1L1 expression is not restricted to intestine in humans and mice. In this study we sought to genetically address this issue. METHODS AND RESULTS: We developed a mouse model that lacks endogenous (NPC1L1) and LDL receptor (LDLR) (DKO), but transgenically expresses human NPC1L1 in gastrointestinal tract only (DKO/L1(IntOnly) mice). Our novel model eliminated potential effects of non-intestinal NPC1L1 on cholesterol homeostasis. We found that human NPC1L1 was localized at the intestinal brush border membrane of DKO/L1(IntOnly) mice. Cholesterol feeding induced formation of NPC1L1-positive vesicles beneath this membrane in an ezetimibe-sensitive manner. Compared to DKO mice, DKO/L1(IntOnly) mice showed significant increases in cholesterol absorption and blood/hepatic/biliary cholesterol. Increased blood cholesterol was restricted to very low-density lipoprotein (VLDL) and LDL fractions, which was associated with increased secretion and plasma levels of apolipoproteins B100 and B48. Additionally, DKO/L1(IntOnly) mice displayed decreased fecal cholesterol excretion and hepatic/intestinal expression of cholesterologenic genes. Ezetimibe treatment virtually reversed all of the transgene-related phenotypes in DKO/L1(IntOnly) mice. CONCLUSION: Our findings from DKO/L1(IntOnly) mice clearly demonstrate that NPC1L1-mediated cholesterol absorption is a major determinant of blood levels of apolipoprotein B-containing atherogenic lipoproteins, at least in mice.
OBJECTIVE: The correlation between intestinal cholesterol absorption values and plasma low-density lipoprotein-cholesterol (LDL-C) levels remains controversial. Niemann-Pick-C1-Like 1 (NPC1L1) is essential for intestinal cholesterol absorption, and is the target of ezetimibe, a cholesterol absorption inhibitor. However, studies with NPC1L1 knockout mice or ezetimibe cannot definitively clarify this correlation because NPC1L1 expression is not restricted to intestine in humans and mice. In this study we sought to genetically address this issue. METHODS AND RESULTS: We developed a mouse model that lacks endogenous (NPC1L1) and LDL receptor (LDLR) (DKO), but transgenically expresses humanNPC1L1 in gastrointestinal tract only (DKO/L1(IntOnly)mice). Our novel model eliminated potential effects of non-intestinal NPC1L1 on cholesterol homeostasis. We found that humanNPC1L1 was localized at the intestinal brush border membrane of DKO/L1(IntOnly)mice. Cholesterol feeding induced formation of NPC1L1-positive vesicles beneath this membrane in an ezetimibe-sensitive manner. Compared to DKO mice, DKO/L1(IntOnly)mice showed significant increases in cholesterol absorption and blood/hepatic/biliary cholesterol. Increased blood cholesterol was restricted to very low-density lipoprotein (VLDL) and LDL fractions, which was associated with increased secretion and plasma levels of apolipoproteins B100 and B48. Additionally, DKO/L1(IntOnly)mice displayed decreased fecal cholesterol excretion and hepatic/intestinal expression of cholesterologenic genes. Ezetimibe treatment virtually reversed all of the transgene-related phenotypes in DKO/L1(IntOnly)mice. CONCLUSION: Our findings from DKO/L1(IntOnly)mice clearly demonstrate that NPC1L1-mediated cholesterol absorption is a major determinant of blood levels of apolipoprotein B-containing atherogenic lipoproteins, at least in mice.
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