Arne Dikkers

Publications (3)19.34 Total impact

• Article: Scavenger receptor BI and ABCG5/G8 differentially impact biliary sterol secretion and reverse cholesterol transport in mice.

  Arne Dikkers, Jan Freak de Boer, Wijtske Annema, Albert K Groen, Uwe J F Tietge
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  ABSTRACT: Biliary lipid secretion plays an important role in gallstone disease and reverse cholesterol transport (RCT). Using Sr-bI/Abcg5 double knockout mice (dko) the present study investigated the differential contribution of two of the most relevant transporters, namely ATP-binding cassette sub-family G member 5 and 8 (ABCG5/G8) and scavenger receptor class B type I (SR-BI) to sterol metabolism and RCT. Plasma cholesterol levels increased in the following order, mainly due to differences in HDL: Abcg5 ko < wild-type < Sr-bI/Abcg5 dko < Sr-bI ko. Liver cholesterol content was elevated in Sr-bI ko only (p<0.05). In Sr-bI/Abcg5 dko plasma plant sterols were highest, while hepatic plant sterols were lower compared with Abcg5 ko (p<0.05). Under baseline conditions, biliary cholesterol secretion rates decreased in the following order: wild-type > Sr-bI ko (-16%) > Abcg5 ko (-75%) > Sr-bI/Abcg5 dko (-94%), all at least p<0.05, while biliary bile acid secretion did not differ between groups. However, under supraphysiological conditions, upon infusion with increasing amounts of the bile salt tauroursodeoxycholic acid, Abcg5 became fully rate-limiting for biliary cholesterol secretion. Additional in vivo macrophage-to-feces RCT studies demonstrated an almost 50% decrease in overall RCT in Sr-bI/Abcg5 dko compared with Abcg5 ko mice (p<0.01). Conclusion: These data demonstrate that (i) SR-BI contributes to ABCG5/8-independent biliary cholesterol secretion under basal conditions, (ii) biliary cholesterol mass secretion under maximal bile salt-stimulated conditions is fully dependent on ABCG5/8, and (iii) Sr-bI contributes to macrophage-to-feces RCT independent of Abcg5/g8. (HEPATOLOGY 2013.).
  Hepatology 02/2013; · 11.66 Impact Factor
• Article: The Neglected Cousin of the Hepatocyte: How Gallbladder Epithelial Cells Might Contribute to Cholesterol Gallstone Formation.

  Arne Dikkers, Uwe J F Tietge
  Digestive Diseases and Sciences 01/2013; · 2.12 Impact Factor
• Source

  Available from: Wijtske Annema

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

  Wijtske Annema, Arne Dikkers, Jan Freark de Boer, Thomas Gautier, Patrick C N Rensen, Daniel J Rader, Uwe J F Tietge
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  ABSTRACT: ApoE plays an important role in lipoprotein metabolism. This study investigated the effects of adenovirus-mediated human apoE overexpression (AdhApoE3) on sterol metabolism and in vivo reverse cholesterol transport (RCT). In wild-type mice, AdhApoE3 resulted in decreased HDL cholesterol levels and a shift toward larger HDL in plasma, whereas hepatic cholesterol content increased (P < 0.05). These effects were dependent on scavenger receptor class B type I (SR-BI) as confirmed using SR-BI-deficient mice. Kinetic studies demonstrated increased plasma HDL cholesteryl ester catabolic rates (P < 0.05) and higher hepatic selective uptake of HDL cholesteryl esters in AdhApoE3-injected wild-type mice (P < 0.01). However, biliary and fecal sterol output as well as in vivo macrophage-to-feces RCT studied with (3)H-cholesterol-loaded mouse macrophage foam cells remained unchanged upon human apoE overexpression. Similar results were obtained using hApoE3 overexpression in human CETP transgenic mice. However, blocking ABCA1-mediated cholesterol efflux from hepatocytes in AdhApoE3-injected mice using probucol increased biliary cholesterol secretion (P < 0.05), fecal neutral sterol excretion (P < 0.05), and in vivo RCT (P < 0.01), specifically within neutral sterols. These combined data demonstrate that systemic apoE overexpression increases i) SR-BI-mediated selective uptake into the liver and ii) ABCA1-mediated efflux of RCT-relevant cholesterol from hepatocytes back to the plasma compartment, thereby resulting in unchanged fecal mass sterol excretion and overall in vivo RCT.
  The Journal of Lipid Research 03/2012; 53(5):929-40. · 5.56 Impact Factor