Cholesterol esterification by ACAT2 is essential for efficient intestinal cholesterol absorption: evidence from thoracic lymph duct cannulation

Nguyen, Tam M.; Sawyer, Janet K.; Kelley, Kathryn L.; Davis, Matthew; Rudel, Lawrence L.

doi:10.1194/jlr.m018820

Cited by 72 publications

(68 citation statements)

References 45 publications

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“…Interestingly, the deletion of G5G8 alone resulted in a smaller but statistically signifi cant 21% decrease in [ (27). Individual animal plots of cholesterol absorption effi ciency (n = 9-10/genotype) at hour 8 of the experiment show limited scatter among individual mice within each genotype ( Fig.…”

Section: Plasma Lipid Analysesmentioning

confidence: 99%

“…Chylomicrons were isolated by ultracentrifugation of whole lymph, and chylomicron particle analyses were performed as described previously ( 27 ). The chylomicron diameter (n = 9-10/ genotype) was measured by dynamic light scattering using the Zetasizer Nano (Malvern Instruments), following the manufacturer's instructions.…”

Section: Chylomicron Isolation and Particle Composition Analysesmentioning

confidence: 99%

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

Nguyen

Sawyer

Kelley

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org Beginning in 1974, the identifi cation of sitosterolemia ( 1 ), a rare recessive disorder characterized by elevated plasma and tissue concentrations of phytosterols, has focused attention on the basic molecular processes that govern how the body normally absorbs animal-derived dietary cholesterol while excluding all other similarly structured plantderived sterols, generally called phytosterols. Phytosterols, including campesterol, stigmasterol, and sitosterol, differ from cholesterol mainly in possessing one or two additional carbons in side chains at C24. The average North American diet contains about equal amounts of cholesterol and phytosterols ( ‫ف‬ 150-400 mg/day) ( 2-5 ), yet <5% of phytosterols are absorbed compared with ‫ف‬ 50% of cholesterol ( 4, 6 ). Thus in healthy individuals, sensitive mechanisms exist that allow the body to distinguish among modestly different sterol structures.In general, different species of sterols have different absorption effi ciencies; the closer the structural similarity to the cholesterol molecule, the higher the percentage absorption ( 4, 7 ). Even mildly hypercholesterolemic patients have serum concentrations of phytosterols that are 500 (campesterol) to 20,000 (sitosterol) times lower than that of cholesterol. Patients with sitosterolemia have increased fractional sterol absorption rates and impaired biliary secretion of neutral sterols, resulting in accumulations of these sterols in the blood and tissues ( 1, 8 ), premature atherosclerosis, and tendon/skin xanthomatosis ( 8, 9 ). Sitosterolemia has been linked to mutations in either adenosine triphosphate-binding cassette transporter G5 or G8 Abstract 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 esterifi cation and have attempted to defi ne the roles of these two factors using gene deletion studies in mice. Male ACAT2 ؊ / ؊ mice, whereas it was up to 6.8% in G5G8؊ / ؊ and DKO mice. G5G8 ؊ / ؊ mice also produced chylomicrons with ‫ف‬ 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 esterifi cation and reduced cholesterol transport efficiency. Intestinal G5G8 appeared to limit the absorption of phytosterols; ACAT2 more effi ciently esterifi ed 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 effi ciency. Abbreviations: ATF-6, activating transcription factor 6; CE, cholesterol ester; DDIT-3, DNA damage-inducible transcript 3; ER, endoplasmic reticulum; FC, free cholesterol; FP, free phytosterol; G5G8, adenosin...

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Section: Plasma Lipid Analysesmentioning

confidence: 99%

Section: Chylomicron Isolation and Particle Composition Analysesmentioning

confidence: 99%

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

Nguyen

Sawyer

Kelley

et al. 2012

Journal of Lipid Research

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“…This prompted us to investigate the effects of genetic depletion of Tgif1 in mice. As mentioned previously, Acat2 is involved in cholesterol esterifi cation for storage and secretion in the lipid core of VLDL and chylomicrons and in intestinal cholesterol absorption ( 6,8,27 ). Genetic depletion of Tgif1 is thus expected to result in increased esterifi ed cholesterol Tgif1 is a homeodomain protein of the TALE superfamily, and loss-of-function mutations have been linked to holoprosencephaly, a developmental disease affecting craniofacial development ( 29 ).…”

Section: Plasma and Hepatic Lipids In Tgif1 Null Micementioning

confidence: 99%

TG-interacting factor 1 acts as a transcriptional repressor of sterol O-acyltransferase 2

Pramfalk

Melhuish

Wotton

et al. 2014

Journal of Lipid Research

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“…Therefore, cholesterol absorption has been studied extensively (1)(2)(3) and reduction in cholesterol absorption is a valid target to lower plasma cholesterol concentrations ( 4 ). Cholesterol absorption involves uptake of free cholesterol by enterocytes from the apical side by a mechanism involving Niemann-Pick C1-like 1 (NPC1L1), conversion to cholesteryl esters by ACAT2 in the endoplasmic reticulum (5)(6)(7)(8), and assembly and secretion with chylomicrons by microsomal triglyceride transfer protein (MTP) (9)(10)(11)(12).…”

mentioning

confidence: 99%

Intestine-specific MTP and global ACAT2 deficiency lowers acute cholesterol absorption with chylomicrons and HDLs

Iqbal

Boutjdir

Rudel

et al. 2014

Journal of Lipid Research

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Cholesterol esterification by ACAT2 is essential for efficient intestinal cholesterol absorption: evidence from thoracic lymph duct cannulation

Cited by 72 publications

References 45 publications

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

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

TG-interacting factor 1 acts as a transcriptional repressor of sterol O-acyltransferase 2

Intestine-specific MTP and global ACAT2 deficiency lowers acute cholesterol absorption with chylomicrons and HDLs

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