ApoE promotes hepatic selective uptake but not RCT due to increased ABCA1-mediated cholesterol efflux to plasma

Annema, Wijtske; Dikkers, Arne; Boer, Jan Freark de; Gautier, Thomas; Rensen, Patrick C.N.; Rader, Daniel J.; Tietge, Uwe J. F.

doi:10.1194/jlr.m020743

Cited by 24 publications

(18 citation statements)

References 48 publications

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“…Apolipoprotein E in serum‐free medium has been demonstrated to mediate ABCA1‐dependent cholesterol efflux and assembly of HDL particles, particularly through its C‐terminal lipid‐binding domain 31. Systemic overexpression of human APOE was also shown to increase ABCA1‐mediated CEC from mice hepatocytes 32. This is in contrast with a recent study with apolipoprotein E knockout mice apolipoprotein B–depleted serum samples, which exhibit a marked reduction of CEC from cAMP‐stimulated J774 macrophages 33.…”

Section: Discussioncontrasting

confidence: 57%

Variants at the APOE/C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High‐Density Lipoprotein Cholesterol

Low‐Kam

Rhainds

et al. 2018

JAHA

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BackgroundMacrophage cholesterol efflux to high‐density lipoproteins (HDLs) is the first step of reverse cholesterol transport. The cholesterol efflux capacity (CEC) of HDL particles is a protective risk factor for coronary artery disease independent of HDL cholesterol levels. Using a genome‐wide association study approach, we aimed to identify pathways that regulate CEC in humans.Methods and ResultsWe measured CEC in 5293 French Canadians. We tested the genetic association between 4 CEC measures and genotypes at >9 million common autosomal DNA sequence variants. These analyses yielded 10 genome‐wide significant signals (P<6.25×10−9) representing 7 loci. Five of these loci harbor genes with important roles in lipid biology (CETP,LIPC,LPL,APOA1/C3/A4/A5, and APOE /C1/C2/C4). Except for the APOE/C1/C2/C4 variant (rs141622900, P nonadjusted=1.0×10−11; P adjusted=8.8×10−9), the association signals disappear when correcting for HDL cholesterol and triglyceride levels. The additional 2 significant signals were near the PPP1CB/PLB1 and RBFOX3/ENPP7 genes. In secondary analyses, we considered candidate functional variants for 58 genes implicated in HDL biology, as well as 239 variants associated with blood lipid levels and/or coronary artery disease risk by genome‐wide association study. These analyses identified 27 significant CEC associations, implicating 5 additional loci (GCKR,LIPG,PLTP,PPARA, and TRIB1).ConclusionsOur genome‐wide association study identified common genetic variation at the APOE/C1/C2/C4 locus as a major determinant of CEC that acts largely independently of HDL cholesterol. We predict that HDL‐based therapies aiming at increasing CEC will be modulated by changes in the expression of apolipoproteins in this gene cluster.

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Section: Discussioncontrasting

confidence: 57%

Variants at the APOE/C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High‐Density Lipoprotein Cholesterol

Low‐Kam

Rhainds

et al. 2018

JAHA

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“…HDL cholesterol taken up into the liver can then follow different metabolic routes. In hepatocytes, it can either be i ) used for conversion into bile acids ( 21 ), ii ) secreted directly into the bile ( 21 ), iii ) resecreted within newly formed HDL particles via the action of ABCA1 ( 22,23 ), or iv ) resecreted as part of VLDLs ( 24 ). The fi nal step of RCT is the excretion of sterols, either bile acids or cholesterol, from the body via the feces, and several studies have indicated that inhibiting intestinal sterol uptake increases RCT (25)(26)(27).…”

Section: Analysis Of Hepatic Gene Expression By Real-time Pcrmentioning

confidence: 99%

“…Liver tissue was homogenized and lipids were extracted according to the general procedure of Bligh and Dyer and redissolved in water containing 2% Triton X-100 (Sigma-Aldrich, Steinheim, Germany) ( 22 ). Total cholesterol, free cholesterol, and triglycerides were assayed as described above.…”

Section: Analysis Of Liver Lipid Compositionmentioning

confidence: 99%

“…Feces were collected over a 48 h period, dried, weighed, and ground. Aliquots were separated into neutral sterol and bile acid fractions ( 22 ), and radioactivity was determined by liquid scintillation counting. Counts were expressed relative to the administered dose.…”

Section: In Vivo Macrophage-to-feces Rct Studiesmentioning

confidence: 99%

“…Fecal samples were dried, weighed, and ground. Neutral sterol and bile acid composition was determined in a 50 mg fecal aliquot by gas liquid chromatography using a published protocol ( 22 ).…”

Section: Analysis Of Fecal Neutral Sterol and Bile Acid Secretionmentioning

confidence: 99%

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Differential impact of hepatic deficiency and total body inhibition of MTP on cholesterol metabolism and RCT in mice

Dikkers

Annema

Boer

et al. 2014

Journal of Lipid Research

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Cholesterol within apoB-containing lipoproteins is a major risk factor for the development of atherosclerotic CVD ( 1, 2 ). Plasma levels of apoB-containing lipoproteins are determined by hepatic production in the form of VLDLs and intestinal production of chylomicrons, in which cholesterol absorbed from the diet is packaged ( 3-5 ). For the assembly of both forms of apoB-containing lipoproteins, microsomal triglyceride transfer protein (MTP) expression is essential ( 4, 5 ). This is exemplifi ed by reduced secretion of apoBcontaining lipoproteins and the subsequent accumulation of hepatic triglycerides when MTP is absent in rodent models ( 6-9 ) or in human abetalipoproteinemia, a genetic disease characterized by MTP defi ciency ( 10 ). On the other hand, overexpression of MTP increases secretion of apoBcontaining lipoproteins ( 11, 12 ). Deletion of MTP, specifically in the intestine, was shown to reduce plasma cholesterol levels by about 45-50% ( 13, 14 ), illustrating the contribution of the intestine to systemic lipoprotein metabolism. The key role of MTP in determining circulating levels of apoB-containing lipoproteins and their importance for atherosclerotic CVD resulted in the development of systemically active pharmacological inhibitors that have recently entered phase 3 clinical trials ( 15, 16 ). Although a variable increase in hepatic triglyceride content was noticed, MTP inhibitors seem to have a reasonable safety profi le and thus Abstract Because apoB-containing lipoproteins are proatherogenic and their secretion by liver and intestine largely depends on microsomal triglyceride transfer protein (MTP) activity, MTP inhibition strategies are actively pursued. How decreasing the secretion of apoB-containing lipoproteins affects intracellular rerouting of cholesterol is unclear. Therefore, the aim of the present study was to determine the effects of reducing either systemic or liver-specifi c MTP activity on cholesterol metabolism and reverse cholesterol transport (RCT) using a pharmacological MTP inhibitor or a genetic model, respectively. Plasma total cholesterol and triglyceride levels were decreased in both MTP inhibitortreated and liver-specifi c MTP knockout (L-Mttp ؊ / ؊ ) mice (each P < 0.001). With both inhibition approaches, hepatic cholesterol as well as triglyceride content was consistently increased (each P < 0.001), while biliary cholesterol and bile acid secretion remained unchanged. A small but significant decrease in fecal bile acid excretion was observed in inhibitor-treated mice ( P < 0.05), whereas fecal neutral sterol excretion was substantially increased by 75% ( P < 0.001), conceivably due to decreased intestinal absorption. In contrast, in L-Mttp ؊ / ؊ mice both fecal neutral sterol and bile acid excretion remained unchanged. However, while total RCT increased in inhibitor-treated mice ( P < 0.01), it surprisingly decreased in L-Mttp ؊ / ؊ mice ( P < 0.05). These data demonstrate that: i ) pharmacological MTP inhibition increases RCT, an effect that might provide additional cli...

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miR‐33 controls the expression of biliary transporters, and mediates statin‐ and diet‐induced hepatotoxicity

et al. 2012

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Bile secretion is essential for whole body sterol homeostasis. Loss-of-function mutations in specific canalicular transporters in the hepatocyte disrupt bile flow and result in cholestasis. We show that two of these transporters, ABCB11 and ATP8B1, are functional targets of miR-33, a micro-RNA that is expressed from within an intron of SREBP-2. Consequently, manipulation of miR-33 levels in vivo with adenovirus or with antisense oligonucleotides results in changes in bile secretion and bile recovery from the gallbladder. Using radiolabelled cholesterol, we show that systemic silencing of miR-33 leads to increased sterols in bile and enhanced reverse cholesterol transport in vivo. Finally, we report that simvastatin causes, in a dose-dependent manner, profound hepatotoxicity and lethality in mice fed a lithogenic diet. These latter results are reminiscent of the recurrent cholestasis found in some patients prescribed statins. Importantly, pretreatment of mice with anti-miR-33 oligonucleotides rescues the hepatotoxic phenotype. Therefore, we conclude that miR-33 mediates some of the undesired, hepatotoxic effects of statins.

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ApoE promotes hepatic selective uptake but not RCT due to increased ABCA1-mediated cholesterol efflux to plasma

Cited by 24 publications

References 48 publications

Variants at the APOE/C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High‐Density Lipoprotein Cholesterol

Variants at the APOE/C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High‐Density Lipoprotein Cholesterol

Differential impact of hepatic deficiency and total body inhibition of MTP on cholesterol metabolism and RCT in mice

miR‐33 controls the expression of biliary transporters, and mediates statin‐ and diet‐induced hepatotoxicity

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