Ontogenesis and Modulation of Intestinal Unesterified Cholesterol Sequestration in a Mouse Model of Niemann–Pick C1 Disease

Adam M. Lopez, Charina M Ramirez, Anna M. Taylor, Ryan D. Jones, Joyce Repa, Stephen D Turley

Research output: Contribution to journalArticle

Abstract

Background: Mutations in the NPC1 gene result in sequestration of unesterified cholesterol (UC) and glycosphingolipids in most tissues leading to multi-organ disease, especially in the brain, liver, lungs, and spleen. Various data from NPC1-deficient mice suggest the small intestine (SI) is comparatively less affected, even in late stage disease. Methods: Using the Npc1nih mouse model, we measured SI weights and total cholesterol (TC) levels in Npc1−/− versus Npc1+/+ mice as a function of age, and then after prolonged ezetimibe-induced inhibition of cholesterol absorption. Next, we determined intestinal levels of UC and esterified cholesterol (EC), and cholesterol synthesis rates in Npc1−/− and Npc1+/+ mice, with and without the cholesterol-esterifying enzyme SOAT2, following a once-only subcutaneous injection with 2-hydroxypropyl-β-cyclodextrin (2HPβCD). Results: By ~ 42 days of age, intestinal TC levels averaged ~ 2.1-fold more (mostly UC) in the Npc1−/− versus Npc1+/+ mice with no further increase thereafter. Chronic ezetimibe treatment lowered intestinal TC levels in the Npc1−/− mice by only ~ 16%. In Npc1−/− mice given 2HPβCD 24 h earlier, UC levels fell, EC levels increased (although less so in mice lacking SOAT2), and cholesterol synthesis was suppressed equally in the Npc1−/−:Soat2+/+ and Npc1−/−:Soat2−/− mice. Conclusions: The low and static levels of intestinal UC sequestration in Npc1−/− mice likely reflect the continual sloughing of cells from the mucosa. This sequestration is blunted by about the same extent following a single acute treatment with 2HPβCD as it is by a prolonged ezetimibe-induced block of cholesterol absorption.

Original languageEnglish (US)
JournalDigestive Diseases and Sciences
DOIs
StatePublished - Jan 1 2019

Fingerprint

Cholesterol
Cyclodextrins
Small Intestine
Sterol O-Acyltransferase
Glycosphingolipids
Subcutaneous Injections
Mucous Membrane
Spleen
Weights and Measures
Lung
Mutation
Liver
Brain
Therapeutics

Keywords

  • 2-Hydroxypropyl-β-cyclodextrin
  • Biliary cholesterol
  • Ezetimibe
  • Fecal sterol excretion
  • Lysosomal cholesterol storage disease
  • Small intestine

ASJC Scopus subject areas

  • Physiology
  • Gastroenterology

Cite this

@article{1ba4fcae108e47d5bacb680e2aac7693,
title = "Ontogenesis and Modulation of Intestinal Unesterified Cholesterol Sequestration in a Mouse Model of Niemann–Pick C1 Disease",
abstract = "Background: Mutations in the NPC1 gene result in sequestration of unesterified cholesterol (UC) and glycosphingolipids in most tissues leading to multi-organ disease, especially in the brain, liver, lungs, and spleen. Various data from NPC1-deficient mice suggest the small intestine (SI) is comparatively less affected, even in late stage disease. Methods: Using the Npc1nih mouse model, we measured SI weights and total cholesterol (TC) levels in Npc1−/− versus Npc1+/+ mice as a function of age, and then after prolonged ezetimibe-induced inhibition of cholesterol absorption. Next, we determined intestinal levels of UC and esterified cholesterol (EC), and cholesterol synthesis rates in Npc1−/− and Npc1+/+ mice, with and without the cholesterol-esterifying enzyme SOAT2, following a once-only subcutaneous injection with 2-hydroxypropyl-β-cyclodextrin (2HPβCD). Results: By ~ 42 days of age, intestinal TC levels averaged ~ 2.1-fold more (mostly UC) in the Npc1−/− versus Npc1+/+ mice with no further increase thereafter. Chronic ezetimibe treatment lowered intestinal TC levels in the Npc1−/− mice by only ~ 16{\%}. In Npc1−/− mice given 2HPβCD 24 h earlier, UC levels fell, EC levels increased (although less so in mice lacking SOAT2), and cholesterol synthesis was suppressed equally in the Npc1−/−:Soat2+/+ and Npc1−/−:Soat2−/− mice. Conclusions: The low and static levels of intestinal UC sequestration in Npc1−/− mice likely reflect the continual sloughing of cells from the mucosa. This sequestration is blunted by about the same extent following a single acute treatment with 2HPβCD as it is by a prolonged ezetimibe-induced block of cholesterol absorption.",
keywords = "2-Hydroxypropyl-β-cyclodextrin, Biliary cholesterol, Ezetimibe, Fecal sterol excretion, Lysosomal cholesterol storage disease, Small intestine",
author = "Lopez, {Adam M.} and Ramirez, {Charina M} and Taylor, {Anna M.} and Jones, {Ryan D.} and Joyce Repa and Turley, {Stephen D}",
year = "2019",
month = "1",
day = "1",
doi = "10.1007/s10620-019-05736-x",
language = "English (US)",
journal = "Digestive Diseases and Sciences",
issn = "0163-2116",
publisher = "Springer New York",

}

TY - JOUR

T1 - Ontogenesis and Modulation of Intestinal Unesterified Cholesterol Sequestration in a Mouse Model of Niemann–Pick C1 Disease

AU - Lopez, Adam M.

AU - Ramirez, Charina M

AU - Taylor, Anna M.

AU - Jones, Ryan D.

AU - Repa, Joyce

AU - Turley, Stephen D

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Mutations in the NPC1 gene result in sequestration of unesterified cholesterol (UC) and glycosphingolipids in most tissues leading to multi-organ disease, especially in the brain, liver, lungs, and spleen. Various data from NPC1-deficient mice suggest the small intestine (SI) is comparatively less affected, even in late stage disease. Methods: Using the Npc1nih mouse model, we measured SI weights and total cholesterol (TC) levels in Npc1−/− versus Npc1+/+ mice as a function of age, and then after prolonged ezetimibe-induced inhibition of cholesterol absorption. Next, we determined intestinal levels of UC and esterified cholesterol (EC), and cholesterol synthesis rates in Npc1−/− and Npc1+/+ mice, with and without the cholesterol-esterifying enzyme SOAT2, following a once-only subcutaneous injection with 2-hydroxypropyl-β-cyclodextrin (2HPβCD). Results: By ~ 42 days of age, intestinal TC levels averaged ~ 2.1-fold more (mostly UC) in the Npc1−/− versus Npc1+/+ mice with no further increase thereafter. Chronic ezetimibe treatment lowered intestinal TC levels in the Npc1−/− mice by only ~ 16%. In Npc1−/− mice given 2HPβCD 24 h earlier, UC levels fell, EC levels increased (although less so in mice lacking SOAT2), and cholesterol synthesis was suppressed equally in the Npc1−/−:Soat2+/+ and Npc1−/−:Soat2−/− mice. Conclusions: The low and static levels of intestinal UC sequestration in Npc1−/− mice likely reflect the continual sloughing of cells from the mucosa. This sequestration is blunted by about the same extent following a single acute treatment with 2HPβCD as it is by a prolonged ezetimibe-induced block of cholesterol absorption.

AB - Background: Mutations in the NPC1 gene result in sequestration of unesterified cholesterol (UC) and glycosphingolipids in most tissues leading to multi-organ disease, especially in the brain, liver, lungs, and spleen. Various data from NPC1-deficient mice suggest the small intestine (SI) is comparatively less affected, even in late stage disease. Methods: Using the Npc1nih mouse model, we measured SI weights and total cholesterol (TC) levels in Npc1−/− versus Npc1+/+ mice as a function of age, and then after prolonged ezetimibe-induced inhibition of cholesterol absorption. Next, we determined intestinal levels of UC and esterified cholesterol (EC), and cholesterol synthesis rates in Npc1−/− and Npc1+/+ mice, with and without the cholesterol-esterifying enzyme SOAT2, following a once-only subcutaneous injection with 2-hydroxypropyl-β-cyclodextrin (2HPβCD). Results: By ~ 42 days of age, intestinal TC levels averaged ~ 2.1-fold more (mostly UC) in the Npc1−/− versus Npc1+/+ mice with no further increase thereafter. Chronic ezetimibe treatment lowered intestinal TC levels in the Npc1−/− mice by only ~ 16%. In Npc1−/− mice given 2HPβCD 24 h earlier, UC levels fell, EC levels increased (although less so in mice lacking SOAT2), and cholesterol synthesis was suppressed equally in the Npc1−/−:Soat2+/+ and Npc1−/−:Soat2−/− mice. Conclusions: The low and static levels of intestinal UC sequestration in Npc1−/− mice likely reflect the continual sloughing of cells from the mucosa. This sequestration is blunted by about the same extent following a single acute treatment with 2HPβCD as it is by a prolonged ezetimibe-induced block of cholesterol absorption.

KW - 2-Hydroxypropyl-β-cyclodextrin

KW - Biliary cholesterol

KW - Ezetimibe

KW - Fecal sterol excretion

KW - Lysosomal cholesterol storage disease

KW - Small intestine

UR - http://www.scopus.com/inward/record.url?scp=85068970120&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068970120&partnerID=8YFLogxK

U2 - 10.1007/s10620-019-05736-x

DO - 10.1007/s10620-019-05736-x

M3 - Article

C2 - 31312996

AN - SCOPUS:85068970120

JO - Digestive Diseases and Sciences

JF - Digestive Diseases and Sciences

SN - 0163-2116

ER -