Phospholipid transfer activity of microsomal triglyceride transfer protein produces apolipoprotein B and reduces hepatosteatosis while maintaining low plasma lipids in mice

Abstract

SUMMARY Microsomal triglyceride transfer protein (MTP), essential for apoB-lipoprotein biosynthesis, evolved as a phospholipid transfer protein and acquired triglyceride transfer activity during a transition from invertebrates to vertebrates. But it is unknown whether MTP directly transfers lipids onto apoB in vivo and, if it does, whether both neutral and polar lipid transfer activities of MTP are critical for lipoprotein assembly. The molecular bases for differences in lipid transfer activities with respect to distinct domains in dMTP and hMTP are not obvious because both proteins have very similar primary, secondary and tertiary structures. We used an in vivo approach to delineate physiological significance of these distinct lipid transfer activities by expressing Drosophila (transfers phospholipids) and human MTP (transfers phospholipids and triglycerides) orthologs using adenoviruses in liver-specific MTP deficient (L-MTP−/−) mice that have low plasma and high hepatic lipids. Both orthologs improved plasma lipids but plasma triglycerides were lower in dMTP mice due to lower hepatic triglyceride and apoB production. Hepatosteatosis in L-MTP−/− mice was ameliorated to similar levels by both. Attenuation of hepatosteatosis upon dMTP expression pertained to enhanced β-oxidation with no changes in lipogenesis. Phospholipid transfer activity of MTP promoted biogenesis of both apoB48 and apoB100-containing VLDL in addition to a phospholipid-rich apoB48-containing HDL-size particle. Triglyceride transfer activity augmented the biosynthesis of triglyceride-rich lipoproteins by increasing the formation of these particles in the lumen of the endoplasmic reticulum. Based on these findings, we posit that the selective inhibition of MTP triglyceride transfer activity might reduce hyperlipidemia while protecting liver from excess lipid accumulation.

Hepatic Mttp deletion reverses gallstone susceptibility in L-Fabp knockout mice

“…The observation that biliary phospholipid secretion was unaltered in the setting of hepatic Mttp deletion should not be construed as implying that there is no effect of hepatic Mttp on hepatic phospholipid metabolism. Indeed, Hussain and colleagues defi ned both neutral and polar lipid transfer activities of Mttp based on the properties of human versus Drosophila proteins and have demonstrated distinct effects on whole body lipid metabolism and in the apical secretion of hepatic VLDLs ( 27 ). However, those studies did not address the question of whether canalicular phospholipid secretion is altered following adenoviral Mttp expression.…”

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

“…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 inhepatocyte-specifi c albumin promoter (Jackson Laboratory, Bar Harbor, ME; all on the C57BL/6J background) ( 28 ). Littermate controls not expressing Cre were used for all experiments.…”

Microsomal triacylglycerol transfer protein (MTP) is required to expand tracheal lumen in Drosophila in a cell-autonomous manner

“…MTP protein function has so far almost exclusively been studied in the context of apoB family lipoprotein assembly and secretion, both in mammals and in Drosophila (Khatun et al, 2012;Hussain et al, 2003a;Sellers et al, 2003;Palm et al, 2012). Here we present results suggesting a function for this protein in a developmental process, in shaping the lumen of unicellular tubes in the Drosophila tracheal system.…”

“…MTP could be involved in the regulation of cellular trafficking through the lipidation of these unknown proteins. Alternatively, as MTP was found to be able to recruit phospolipids to specific locations within ER membranes (Khatun et al, 2012) and to transfer phospholipids between (C,C9, arrows). Also, parts of the main branch are not completely filled with gas (arrowheads in D,D9).…”