title: Differential impact of hepatic deficiency and total body inhibition of MTP on cholesterol metabolism and RCT in mice.
abstract: Because apoB-containing lipoproteins are pro-atherogenic 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-specific 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 inhibitor-treated and liver-specific 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 clinical benefit of MTP inhibitors; and ii) decreasing hepatic MTP decreases RCT, pointing toward a potential contribution of hepatocyte-derived VLDLs to RCT.
authors: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Arne
authors: A
authors: Dikkers
authors: Wijtske
authors: W
authors: Annema
authors: Jan Freark
authors: JF
authors: de Boer
authors: Jahangir
authors: J
authors: Iqbal
authors: M Mahmood
authors: MM
authors: Hussain
authors: Uwe J F
authors: UJ
authors: Tietge
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000096:biosynthesis; D001562:Benzimidazoles / Q000494:pharmacology; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D005449:Fluorenes / Q000494:pharmacology; D055786:Gene Knockout Techniques; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009928:Organ Specificity; D014280:Triglycerides / Q000097:blood
chemical_list: C424429:9-(4-(2,5-dimethyl-4-(((4'-(trifluoromethyl)(1,1'-biphenyl)-2-yl)carbonyl)amino)-1H-benzimidazol-1-yl)butyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide; D001055:Apolipoproteins B; D001562:Benzimidazoles; D002352:Carrier Proteins; D005449:Fluorenes; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D002784:Cholesterol
keywords: bile; high density lipoprotein; lipoprotein metabolism; liver metabolism; microsomal triglyceride transfer protein; reverse cholesterol transport; transintestinal cholesterol excretion; very low density lipoprotein