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

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-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 inhibitortreated 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.-Dikkers, A., W. Annema, J. F. de Boer, J. Iqbal, M. M. Hussain, and U. J. F. Tietge. Differential impact of hepatic deficiency and total body inhibition of MTP on cholesterol metabolism and RCT in mice. J. Lipid Res. 2014. 55: 816-825. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.