Niemann-pick C1-deficient mice lacking sterol O-acyltransferase 2 have less hepatic cholesterol entrapment and improved liver function

Adam M. Lopez, Ryan D. Jones, Joyce J. Repa, Stephen D. Turley

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Abstract

Cholesteryl esters are generated at multiple sites in the body by sterol O-acyltransferase (SOAT) 1 or SOAT2 in various cell types and lecithin cholesterol acyltransferase in plasma. Esterified cholesterol and triacylglycerol contained in lipoproteins cleared from the circulation via receptormediated or bulk-phase endocytosis are hydrolyzed by lysosomal acid lipase within the late endosomal/lysosomal (E/L) compartment. Then, through the successive actions of Niemann-Pick C (NPC) 2 and NPC 1, unesterified cholesterol (UC) is exported from the E/L compartment to the cytosol. Mutations in either NPC1 or NPC2 lead to continuing entrapment of UC in all organs, resulting in multisystem disease, which includes hepatic dysfunction and in some cases liver failure. These studies investigated primarily whether elimination of SOAT2 in NPC1-deficient mice impacted hepatic UC sequestration, inflammation, and transaminase activities. Measurements were made in 7-wkold mice fed a low-cholesterol chow diet or one enriched with cholesterol starting 2 wk before study. In the chow-fed mice, NPC1: SOAT2 double knockouts, compared with their littermates lacking only NPC1, had 20% less liver mass, 28% lower hepatic UC concentrations, and plasma alanine aminotransferase and aspartate aminotransferase activities that were decreased by 48% and 36%, respectively. mRNA expression levels for several markers of inflammation were all significantly lower in the NPC1 mutants lacking SOAT2. The existence of a new class of potent and selective SOAT2 inhibitors provides an opportunity for exploring if suppression of this enzyme could potentially become an adjunctive therapy for liver disease in NPC1 deficiency. NEW & NOTEWORTHY In Niemann-Pick type C1 (NPC1) disease, the entrapment of unesterified cholesterol (UC) in the endosomal/ lysosomal compartment of all cells causes multiorgan disease, including neurodegeneration, pulmonary dysfunction, and liver failure. Some of this sequestered UC entered cells initially in the esterified form. When sterol O-acyltransferase 2, a cholesterol esterifying enzyme present in enterocytes and hepatocytes, is eliminated in NPC1-deficient mice, there is a reduction in their hepatomegaly, hepatic UC content, and cellular injury.

Original languageEnglish (US)
Pages (from-to)G454-G463
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume315
Issue number4
DOIs
StatePublished - Oct 1 2018

Fingerprint

Cholesterol
Liver
Liver Failure
Type C Niemann-Pick Disease
sterol O-acyltransferase 2
Sterol O-Acyltransferase
Inflammation
Sterol Esterase
Phosphatidylcholine-Sterol O-Acyltransferase
Hepatomegaly
Enterocytes
Cholesterol Esters
Aspartate Aminotransferases
Endocytosis
Transaminases
Alanine Transaminase
Cytosol
Lipoproteins
Liver Diseases
Hepatocytes

Keywords

  • Esterified cholesterol
  • Hepatomegaly
  • Lysosomal storage disease
  • Transaminase activity
  • Unesterified cholesterol

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

@article{1f1111961d73489eaf0b7eb48756a063,
title = "Niemann-pick C1-deficient mice lacking sterol O-acyltransferase 2 have less hepatic cholesterol entrapment and improved liver function",
abstract = "Cholesteryl esters are generated at multiple sites in the body by sterol O-acyltransferase (SOAT) 1 or SOAT2 in various cell types and lecithin cholesterol acyltransferase in plasma. Esterified cholesterol and triacylglycerol contained in lipoproteins cleared from the circulation via receptormediated or bulk-phase endocytosis are hydrolyzed by lysosomal acid lipase within the late endosomal/lysosomal (E/L) compartment. Then, through the successive actions of Niemann-Pick C (NPC) 2 and NPC 1, unesterified cholesterol (UC) is exported from the E/L compartment to the cytosol. Mutations in either NPC1 or NPC2 lead to continuing entrapment of UC in all organs, resulting in multisystem disease, which includes hepatic dysfunction and in some cases liver failure. These studies investigated primarily whether elimination of SOAT2 in NPC1-deficient mice impacted hepatic UC sequestration, inflammation, and transaminase activities. Measurements were made in 7-wkold mice fed a low-cholesterol chow diet or one enriched with cholesterol starting 2 wk before study. In the chow-fed mice, NPC1: SOAT2 double knockouts, compared with their littermates lacking only NPC1, had 20{\%} less liver mass, 28{\%} lower hepatic UC concentrations, and plasma alanine aminotransferase and aspartate aminotransferase activities that were decreased by 48{\%} and 36{\%}, respectively. mRNA expression levels for several markers of inflammation were all significantly lower in the NPC1 mutants lacking SOAT2. The existence of a new class of potent and selective SOAT2 inhibitors provides an opportunity for exploring if suppression of this enzyme could potentially become an adjunctive therapy for liver disease in NPC1 deficiency. NEW & NOTEWORTHY In Niemann-Pick type C1 (NPC1) disease, the entrapment of unesterified cholesterol (UC) in the endosomal/ lysosomal compartment of all cells causes multiorgan disease, including neurodegeneration, pulmonary dysfunction, and liver failure. Some of this sequestered UC entered cells initially in the esterified form. When sterol O-acyltransferase 2, a cholesterol esterifying enzyme present in enterocytes and hepatocytes, is eliminated in NPC1-deficient mice, there is a reduction in their hepatomegaly, hepatic UC content, and cellular injury.",
keywords = "Esterified cholesterol, Hepatomegaly, Lysosomal storage disease, Transaminase activity, Unesterified cholesterol",
author = "Lopez, {Adam M.} and Jones, {Ryan D.} and Repa, {Joyce J.} and Turley, {Stephen D.}",
year = "2018",
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TY - JOUR

T1 - Niemann-pick C1-deficient mice lacking sterol O-acyltransferase 2 have less hepatic cholesterol entrapment and improved liver function

AU - Lopez, Adam M.

AU - Jones, Ryan D.

AU - Repa, Joyce J.

AU - Turley, Stephen D.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Cholesteryl esters are generated at multiple sites in the body by sterol O-acyltransferase (SOAT) 1 or SOAT2 in various cell types and lecithin cholesterol acyltransferase in plasma. Esterified cholesterol and triacylglycerol contained in lipoproteins cleared from the circulation via receptormediated or bulk-phase endocytosis are hydrolyzed by lysosomal acid lipase within the late endosomal/lysosomal (E/L) compartment. Then, through the successive actions of Niemann-Pick C (NPC) 2 and NPC 1, unesterified cholesterol (UC) is exported from the E/L compartment to the cytosol. Mutations in either NPC1 or NPC2 lead to continuing entrapment of UC in all organs, resulting in multisystem disease, which includes hepatic dysfunction and in some cases liver failure. These studies investigated primarily whether elimination of SOAT2 in NPC1-deficient mice impacted hepatic UC sequestration, inflammation, and transaminase activities. Measurements were made in 7-wkold mice fed a low-cholesterol chow diet or one enriched with cholesterol starting 2 wk before study. In the chow-fed mice, NPC1: SOAT2 double knockouts, compared with their littermates lacking only NPC1, had 20% less liver mass, 28% lower hepatic UC concentrations, and plasma alanine aminotransferase and aspartate aminotransferase activities that were decreased by 48% and 36%, respectively. mRNA expression levels for several markers of inflammation were all significantly lower in the NPC1 mutants lacking SOAT2. The existence of a new class of potent and selective SOAT2 inhibitors provides an opportunity for exploring if suppression of this enzyme could potentially become an adjunctive therapy for liver disease in NPC1 deficiency. NEW & NOTEWORTHY In Niemann-Pick type C1 (NPC1) disease, the entrapment of unesterified cholesterol (UC) in the endosomal/ lysosomal compartment of all cells causes multiorgan disease, including neurodegeneration, pulmonary dysfunction, and liver failure. Some of this sequestered UC entered cells initially in the esterified form. When sterol O-acyltransferase 2, a cholesterol esterifying enzyme present in enterocytes and hepatocytes, is eliminated in NPC1-deficient mice, there is a reduction in their hepatomegaly, hepatic UC content, and cellular injury.

AB - Cholesteryl esters are generated at multiple sites in the body by sterol O-acyltransferase (SOAT) 1 or SOAT2 in various cell types and lecithin cholesterol acyltransferase in plasma. Esterified cholesterol and triacylglycerol contained in lipoproteins cleared from the circulation via receptormediated or bulk-phase endocytosis are hydrolyzed by lysosomal acid lipase within the late endosomal/lysosomal (E/L) compartment. Then, through the successive actions of Niemann-Pick C (NPC) 2 and NPC 1, unesterified cholesterol (UC) is exported from the E/L compartment to the cytosol. Mutations in either NPC1 or NPC2 lead to continuing entrapment of UC in all organs, resulting in multisystem disease, which includes hepatic dysfunction and in some cases liver failure. These studies investigated primarily whether elimination of SOAT2 in NPC1-deficient mice impacted hepatic UC sequestration, inflammation, and transaminase activities. Measurements were made in 7-wkold mice fed a low-cholesterol chow diet or one enriched with cholesterol starting 2 wk before study. In the chow-fed mice, NPC1: SOAT2 double knockouts, compared with their littermates lacking only NPC1, had 20% less liver mass, 28% lower hepatic UC concentrations, and plasma alanine aminotransferase and aspartate aminotransferase activities that were decreased by 48% and 36%, respectively. mRNA expression levels for several markers of inflammation were all significantly lower in the NPC1 mutants lacking SOAT2. The existence of a new class of potent and selective SOAT2 inhibitors provides an opportunity for exploring if suppression of this enzyme could potentially become an adjunctive therapy for liver disease in NPC1 deficiency. NEW & NOTEWORTHY In Niemann-Pick type C1 (NPC1) disease, the entrapment of unesterified cholesterol (UC) in the endosomal/ lysosomal compartment of all cells causes multiorgan disease, including neurodegeneration, pulmonary dysfunction, and liver failure. Some of this sequestered UC entered cells initially in the esterified form. When sterol O-acyltransferase 2, a cholesterol esterifying enzyme present in enterocytes and hepatocytes, is eliminated in NPC1-deficient mice, there is a reduction in their hepatomegaly, hepatic UC content, and cellular injury.

KW - Esterified cholesterol

KW - Hepatomegaly

KW - Lysosomal storage disease

KW - Transaminase activity

KW - Unesterified cholesterol

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VL - 315

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JO - American Journal of Physiology - Heart and Circulatory Physiology

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