Genetic demonstration of intestinal NPC1L1 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels

Ping Xie, Hongling Zhu, Lin Jia, Yinyan Ma, Weiqing Tang, Youlin Wang, Bingzhong Xue, Hang Shi, Liqing Yu

Research output: Contribution to journalArticle

7 Citations (Scopus)

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/L1IntOnly 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/L1IntOnly mice. Cholesterol feeding induced formation of NPC1L1-positive vesicles beneath this membrane in an ezetimibe-sensitive manner. Compared to DKO mice, DKO/L1IntOnly 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/L1IntOnly 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/L1IntOnly mice. Conclusion: Our findings from DKO/L1IntOnly 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.

Original languageEnglish (US)
Pages (from-to)609-617
Number of pages9
JournalAtherosclerosis
Volume237
Issue number2
DOIs
StatePublished - Dec 1 2014

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Lipoproteins
Cholesterol
Liver
Intestinal Absorption
Apolipoprotein B-48
Anticholesteremic Agents
Membranes
VLDL Lipoproteins
LDL Receptors
Apolipoproteins B
Microvilli
Transgenes
Knockout Mice
LDL Cholesterol
Intestines
Gastrointestinal Tract
Homeostasis
Phenotype
Gene Expression
Ezetimibe

Keywords

  • Apolipoprotein B
  • Cholesterol absorption
  • Chylomicron remnant
  • Fecal neutral sterol excretion
  • Low-density lipoprotein receptor
  • Niemann-Pick-C1-Like 1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Genetic demonstration of intestinal NPC1L1 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels. / Xie, Ping; Zhu, Hongling; Jia, Lin; Ma, Yinyan; Tang, Weiqing; Wang, Youlin; Xue, Bingzhong; Shi, Hang; Yu, Liqing.

In: Atherosclerosis, Vol. 237, No. 2, 01.12.2014, p. 609-617.

Research output: Contribution to journalArticle

Xie, Ping ; Zhu, Hongling ; Jia, Lin ; Ma, Yinyan ; Tang, Weiqing ; Wang, Youlin ; Xue, Bingzhong ; Shi, Hang ; Yu, Liqing. / Genetic demonstration of intestinal NPC1L1 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels. In: Atherosclerosis. 2014 ; Vol. 237, No. 2. pp. 609-617.
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AU - Xie, Ping

AU - Zhu, Hongling

AU - Jia, Lin

AU - Ma, Yinyan

AU - Tang, Weiqing

AU - Wang, Youlin

AU - Xue, Bingzhong

AU - Shi, Hang

AU - Yu, Liqing

PY - 2014/12/1

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AB - 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/L1IntOnly 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/L1IntOnly mice. Cholesterol feeding induced formation of NPC1L1-positive vesicles beneath this membrane in an ezetimibe-sensitive manner. Compared to DKO mice, DKO/L1IntOnly 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/L1IntOnly 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/L1IntOnly mice. Conclusion: Our findings from DKO/L1IntOnly 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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KW - Low-density lipoprotein receptor

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