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

Arne Dikkers,Wijtske Annema,Jan Freark De Boer,Jahangir Iqbal,M Mahmood Hussain,Uwej.F Tietge

doi:10.1194/jlr.m042986

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.

Highlights

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
For the assembly of both forms of apoB-containing lipoproteins, microsomal triglyceride transfer protein (MTP) expression is essential [4, 5]. This is exemplified by reduced secretion of apoBcontaining lipoproteins and the subsequent accumulation of hepatic triglycerides when MTP is absent in rodent models [6,7,8,9] or in human abetalipoproteinemia, a genetic disease characterized by MTP deficiency [10]
This study investigated the consequences of differentially lowering MTP activity systemically with a pharmacological inhibitor or genetically in the liver only on cholesterol metabolism, with a specific focus on reverse cholesterol transport (RCT)

Summary

Introduction

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. 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. For the assembly of both forms of apoB-containing lipoproteins, microsomal triglyceride transfer protein (MTP) expression is essential [4, 5] This is exemplified by reduced secretion of apoBcontaining lipoproteins and the subsequent accumulation of hepatic triglycerides when MTP is absent in rodent models [6,7,8,9] or in human abetalipoproteinemia, a genetic disease characterized by MTP deficiency [10].

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