ACAT2 and ABCG5/G8 are both required for efficient cholesterol absorption in mice: evidence from thoracic lymph duct cannulation[S]

The metabolic fate of newly absorbed cholesterol and phytosterol is orchestrated through adenosine triphosphate-binding cassette transporter G5 and G8 heterodimer (G5G8), and acyl CoA:cholesterol acyltransferase 2 (ACAT2). We hypothesized that intestinal G5G8 limits sterol absorption by reducing sub...

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Main Authors: Tam M. Nguyen, Janet K. Sawyer, Kathryn L. Kelley, Matthew A. Davis, Carol R. Kent, Lawrence L. Rudel
Format: Article
Language:English
Published: Elsevier 2012-08-01
Series:Journal of Lipid Research
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S0022227520418632
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spelling doaj-9d152265ab7c409db50f6256e0300da42021-04-28T06:05:29ZengElsevierJournal of Lipid Research0022-22752012-08-0153815981609ACAT2 and ABCG5/G8 are both required for efficient cholesterol absorption in mice: evidence from thoracic lymph duct cannulation[S]Tam M. Nguyen0Janet K. Sawyer1Kathryn L. Kelley2Matthew A. Davis3Carol R. Kent4Lawrence L. Rudel5Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157To whom correspondence should be addressed. e-mail: lrudel@wakehealth.edu.; To whom correspondence should be addressed. e-mail: lrudel@wakehealth.edu.; Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157The metabolic fate of newly absorbed cholesterol and phytosterol is orchestrated through adenosine triphosphate-binding cassette transporter G5 and G8 heterodimer (G5G8), and acyl CoA:cholesterol acyltransferase 2 (ACAT2). We hypothesized that intestinal G5G8 limits sterol absorption by reducing substrate availability for ACAT2 esterification and have attempted to define the roles of these two factors using gene deletion studies in mice. Male ACAT2−/−, G5G8−/−, ACAT2−/−G5G8−/− (DKO), and wild-type (WT) control mice were fed a diet with 20% of energy as palm oil and 0.2% (w/w) cholesterol. Sterol absorption efficiency was directly measured by monitoring the appearance of [3H]sitosterol and [14C]cholesterol tracers in lymph after thoracic lymph duct cannulation. The average percentage (± SEM) absorption of [14C]cholesterol after 8 h of lymph collection was 40.55 ± 0.76%, 19.41 ± 1.52%, 32.13 ± 1.60%, and 21.27 ± 1.35% for WT, ACAT2−/−, G5G8−/−, and DKO mice, respectively. [3H]sitosterol absorption was <2% in WT and ACAT2−/− mice, whereas it was up to 6.8% in G5G8−/− and DKO mice. G5G8−/− mice also produced chylomicrons with ∼70% less cholesterol ester mass than WT mice. In contrast to expectations, the data demonstrated that the absence of G5G8 led to decreased intestinal cholesterol esterification and reduced cholesterol transport efficiency. Intestinal G5G8 appeared to limit the absorption of phytosterols; ACAT2 more efficiently esterified cholesterol than phytosterols. The data indicate that handling of sterols by the intestine involves both G5G8 and ACAT2 but that an additional factor (possibly Niemann-Pick C1-like 1) may be key in determining absorption efficiency.http://www.sciencedirect.com/science/article/pii/S0022227520418632chylomicronscholesterol esterificationintestinal cholesterol absorptionphytosterol absorptionsitosterolemia
collection DOAJ
language English
format Article
sources DOAJ
author Tam M. Nguyen
Janet K. Sawyer
Kathryn L. Kelley
Matthew A. Davis
Carol R. Kent
Lawrence L. Rudel
spellingShingle Tam M. Nguyen
Janet K. Sawyer
Kathryn L. Kelley
Matthew A. Davis
Carol R. Kent
Lawrence L. Rudel
ACAT2 and ABCG5/G8 are both required for efficient cholesterol absorption in mice: evidence from thoracic lymph duct cannulation[S]
Journal of Lipid Research
chylomicrons
cholesterol esterification
intestinal cholesterol absorption
phytosterol absorption
sitosterolemia
author_facet Tam M. Nguyen
Janet K. Sawyer
Kathryn L. Kelley
Matthew A. Davis
Carol R. Kent
Lawrence L. Rudel
author_sort Tam M. Nguyen
title ACAT2 and ABCG5/G8 are both required for efficient cholesterol absorption in mice: evidence from thoracic lymph duct cannulation[S]
title_short ACAT2 and ABCG5/G8 are both required for efficient cholesterol absorption in mice: evidence from thoracic lymph duct cannulation[S]
title_full ACAT2 and ABCG5/G8 are both required for efficient cholesterol absorption in mice: evidence from thoracic lymph duct cannulation[S]
title_fullStr ACAT2 and ABCG5/G8 are both required for efficient cholesterol absorption in mice: evidence from thoracic lymph duct cannulation[S]
title_full_unstemmed ACAT2 and ABCG5/G8 are both required for efficient cholesterol absorption in mice: evidence from thoracic lymph duct cannulation[S]
title_sort acat2 and abcg5/g8 are both required for efficient cholesterol absorption in mice: evidence from thoracic lymph duct cannulation[s]
publisher Elsevier
series Journal of Lipid Research
issn 0022-2275
publishDate 2012-08-01
description The metabolic fate of newly absorbed cholesterol and phytosterol is orchestrated through adenosine triphosphate-binding cassette transporter G5 and G8 heterodimer (G5G8), and acyl CoA:cholesterol acyltransferase 2 (ACAT2). We hypothesized that intestinal G5G8 limits sterol absorption by reducing substrate availability for ACAT2 esterification and have attempted to define the roles of these two factors using gene deletion studies in mice. Male ACAT2−/−, G5G8−/−, ACAT2−/−G5G8−/− (DKO), and wild-type (WT) control mice were fed a diet with 20% of energy as palm oil and 0.2% (w/w) cholesterol. Sterol absorption efficiency was directly measured by monitoring the appearance of [3H]sitosterol and [14C]cholesterol tracers in lymph after thoracic lymph duct cannulation. The average percentage (± SEM) absorption of [14C]cholesterol after 8 h of lymph collection was 40.55 ± 0.76%, 19.41 ± 1.52%, 32.13 ± 1.60%, and 21.27 ± 1.35% for WT, ACAT2−/−, G5G8−/−, and DKO mice, respectively. [3H]sitosterol absorption was <2% in WT and ACAT2−/− mice, whereas it was up to 6.8% in G5G8−/− and DKO mice. G5G8−/− mice also produced chylomicrons with ∼70% less cholesterol ester mass than WT mice. In contrast to expectations, the data demonstrated that the absence of G5G8 led to decreased intestinal cholesterol esterification and reduced cholesterol transport efficiency. Intestinal G5G8 appeared to limit the absorption of phytosterols; ACAT2 more efficiently esterified cholesterol than phytosterols. The data indicate that handling of sterols by the intestine involves both G5G8 and ACAT2 but that an additional factor (possibly Niemann-Pick C1-like 1) may be key in determining absorption efficiency.
topic chylomicrons
cholesterol esterification
intestinal cholesterol absorption
phytosterol absorption
sitosterolemia
url http://www.sciencedirect.com/science/article/pii/S0022227520418632
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