Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice

Buhman, Kimberly K.; Accad, Michel; Novak, Sabine; Choi, Rebekah S.; Wong, Jinny S.; Hamilton, Robert L.; Turley, Stephen D.; Farese, Robert V.

doi:10.1038/82153

Cited by 333 publications

(292 citation statements)

References 35 publications

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“…It is the predominant enzyme responsible for the synthesis of cholesterol esters and their subsequent secretion with lipoproteins. ACAT2 deficiency results in a considerable decrease in the rate of cholesterol absorption (26). The rate of cholesterol esterification in the presence of these enzymes is notably enhanced by substrate availability, but, as we demonstrated recently, it is inhibited by product accumulation.…”

Section: Cholesterolmentioning

confidence: 73%

“…DGAT1, which is expressed in several tissues (including liver, intestine, and skin), differs from DGAT2 in that defective fat absorption is not seen in DGAT1-KO mice. In recent studies, investigators have found that MGAT2 (29,31) and MGAT3 (30) possess DGAT activity (26,170). Some TAG synthesis also occurs through the dephosphorylation of phosphatidic acid and acylation of the resultant DAG.…”

Section: Triacylglyceridesmentioning

confidence: 99%

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Intestinal lipid absorption

Iqbal¹,

Hussain²

2009

American Journal of Physiology-Endocrinology and Metabolism

651

484

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Our knowledge of the uptake and transport of dietary fat and fat-soluble vitamins has advanced considerably. Researchers have identified several new mechanisms by which lipids are taken up by enterocytes and packaged as chylomicrons for export into the lymphatic system or clarified the actions of mechanisms previously known to participate in these processes. Fatty acids are taken up by enterocytes involving protein-mediated as well as proteinindependent processes. Net cholesterol uptake depends on the competing activities of NPC1L1, ABCG5, and ABCG8 present in the apical membrane. We have considerably more detailed information about the uptake of products of lipid hydrolysis, the active transport systems by which they reach the endoplasmic reticulum, the mechanisms by which they are resynthesized into neutral lipids and utilized within the endoplasmic reticulum to form lipoproteins, and the mechanisms by which lipoproteins are secreted from the basolateral side of the enterocyte. apoB and MTP are known to be central to the efficient assembly and secretion of lipoproteins. In recent studies, investigators found that cholesterol, phospholipids, and vitamin E can also be secreted from enterocytes as components of high-density apoB-free/apoAI-containing lipoproteins. Several of these advances will probably be investigated further for their potential as targets for the development of drugs that can suppress cholesterol absorption, thereby reducing the risk of hypercholesterolemia and cardiovascular disease.intestine; dietary fat; triacylglycerol; cholesterol; phospholipids; fat-soluble vitamins; microsomal triglyceride transfer protein DIETARY FATS CONSIST OF A WIDE ARRAY of polar and nonpolar lipids (32, 33). Triacylglycerol (TAG) is the dominant fat in the diet, contributing 90 -95% of the total energy derived from dietary fat. Dietary fats also include phospholipids (PLs), sterols (e.g., cholesterol), and many other lipids (e.g., fatsoluble vitamins). The predominant PL in the intestinal lumen is phosphatidylcholine (PC), which is derived mostly from bile (10 -20 g/day in humans) but also from the diet (ϳ1-2 g/day). The predominant dietary sterols are cholesterol (mostly of animal origin) and ␤-sitosterol (the major plant sterol). Although ␤-sitosterol accounts for 25% of dietary sterols, it is not absorbed by humans under physiological conditions.Researchers have been investigating the various steps involved in lipid digestion, absorption, and metabolism to identify factors that could serve as targets for the development of drugs capable of reducing the risk of lipid-associated disorders, including dyslipidemias and cardiovascular disease. In so doing, they have explored key aspects of lipid digestion hydrolysis, emulsification, and micelle formation. They have also explored key issues of absorption, e.g., the uptake of the products of lipid hydrolysis by enterocytes (the epithelial cells lining the walls of the intestinal lumen) and their transport to intracellular compartments, where fatty acids and sterols are...

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Section: Cholesterolmentioning

confidence: 73%

Section: Triacylglyceridesmentioning

confidence: 99%

Intestinal lipid absorption

Iqbal¹,

Hussain²

2009

American Journal of Physiology-Endocrinology and Metabolism

651

484

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“…As inferred from our cumulative results, it is highly probable that lack of APO-B48 expression induces the inhibition of intestinal absorption and hepatic bioavailability, which results in contributing considerably less cholesterol to biliary secretion. Studies that underline the importance of chylomicron remnant cholesterol in murine cholelithogenesis are that disturbed hepatic uptake of chylomicron remnants in APO-E-deficient mice 40 and impaired intestinal cholesterol esterification in acyl-CoA: cholesterol acyltransferase 2 knockout mice 41 significantly reduce biliary cholesterol secretion and gallstone formation. More recently, we found that biliary secretion of chylomicron remnant cholesterol is more rapid in gallstone-susceptible C57L mice than in gallstone-resistant AKR mice.…”

Section: Discussionmentioning

confidence: 99%

Reduced susceptibility to cholesterol gallstone formation in mice that do not produce apolipoprotein B48 in the intestine

Wang

2005

Hepatology

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It has been found that polymorphisms in the apolipoprotein (APO)-B gene are associated with cholesterol gallstones in humans. We hypothesized that APO-B plays a major regulatory role in the response of biliary cholesterol secretion to high dietary cholesterol and contributes to cholesterol gallstone formation. In the present study, we investigated whether lack of expression of intestinal Apob48 or Apob100 reduces susceptibility to cholesterol gallstones by decreasing intestinal absorption and biliary secretion of cholesterol in male mice homozygous for an "APO-B48 only" allele (Apob 48/48 ), an "APO-B100 only" allele (Apob 100/100 ), or a wild-type APO-B allele (Apob ؉/؉ ) before and during an 8-week lithogenic diet. We found that cholesterol absorption was significantly decreased as a result of the APO-B48 deficiency in Apob 100/100 mice compared with wild-type and Apob 48/48 mice, regardless of whether chow or the lithogenic diet was administered. Consequently, hepatic cholesterol synthesis was significantly increased in Apob 100/ 100 mice compared with wild-type and Apob 48/48 mice. On chow, the APO-B100 deficiency in S tudies in humans and inbred mice have demonstrated that a complex genetic basis determines the individual and strain predisposition to develop cholesterol gallstones in response to environmental factors. 1 The primary pathophysiological defect involved in cholesterol gallstone formation is increased biliary secretion of cholesterol from the liver, which produces bile supersaturated with cholesterol. 2 Subsequently, biliary cholesterol precipitates as "anhydrous" and monohydrate crystals, which grow and agglomerate toward the formation of macroscopic stones in the gallbladder. Biliary cholesterol is mostly derived from circulating lipoproteins, which originate from the hepatic uptake of plasma high-density lipoprotein (HDL) and chylomicron remnants. [3][4][5][6][7][8] Thus, the potential interrelationship between lipoprotein metabolism-related genes and cholesterol gallstones requires further investigation. In particular, it has been found that polymorphisms in the apolipoprotein (APO)-B gene are associated with cholesterol gallstones in humans. 9-12 Therefore, we hypothesized that APO-B plays a major regulatory role in the response of biliary cholesterol secretion to high dietary cholesterol and contributes to the formation of cholesterol gallstones. APO-B has two different isoforms, APO-B48 and APO-B100, and plays a particularly critical role in the Abbreviations: APO, apolipoprotein; HDL, VLDL, LDL, mRNA, messenger RNA.

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“…The Acat1 −/ − and Acat2 −/− mice (53,54) in C57BL/6 background were received from Sergio Fazio (Nashville, TN) and Shailesh Patel (Charleston, SC), respectively. The 3XTg-AD mice (AD mice) in hybrid 129/C57BL/6 background contain two mutant human transgenes, hAPP harboring Swedish mutation (hAPPswe), and mutant htau (htau P301L ), and contain the knock-in mutant presenilin 1 (PS1 M146V ) (55).…”

Section: Methodsmentioning

confidence: 99%

ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD

Bryleva

Rogers

Chang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

177

193

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Cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative diseases, including the abnormal accumulation of amyloid-β, one of the pathological hallmarks of Alzheimer disease (AD). Acyl-CoA:cholesterol acyltransferases (ACAT1 and ACAT2) are two enzymes that convert free cholesterol to cholesteryl esters. ACAT inhibitors have recently emerged as promising drug candidates for AD therapy. However, how ACAT inhibitors act in the brain has so far remained unclear. Here we show that ACAT1 is the major functional isoenzyme in the mouse brain. ACAT1 gene ablation (A1−) in triple transgenic (i.e., 3XTg-AD) mice leads to more than 60% reduction in full-length human APPswe as well as its proteolytic fragments, and ameliorates cognitive deficits. At 4 months of age, A1− causes a 32% content increase in 24-hydroxycholesterol (24SOH), the major oxysterol in the brain. It also causes a 65% protein content decrease in HMG-CoA reductase (HMGR) and a 28% decrease in sterol synthesis rate in AD mouse brains. In hippocampal neurons, A1− causes an increase in the 24SOH synthesis rate; treating hippocampal neuronal cells with 24SOH causes rapid declines in hAPP and in HMGR protein levels. A model is provided to explain our findings: in neurons, A1− causes increases in cholesterol and 24SOH contents in the endoplasmic reticulum, which cause reductions in hAPP and HMGR protein contents and lead to amelioration of amyloid pathology. Our study supports the potential of ACAT1 as a therapeutic target for treating certain forms of AD.Alzheimer disease | cholesterol esterification | lipid metabolism | oxysterols

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Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice

Cited by 333 publications

References 35 publications

Intestinal lipid absorption

Intestinal lipid absorption

Reduced susceptibility to cholesterol gallstone formation in mice that do not produce apolipoprotein B48 in the intestine

ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD

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