Blocking very low-density lipoprotein (VLDL) secretion, by microsomal triacylglycerol transfer protein (MTP) inhibition, favors tumor development

COMANZO, CG; VERA, MC; LUCCI, A; FERRETTI, AC; HEIT-BARBINI, FJ; LORENZETTI, F; CEBALLOS, MP; ALVAREZ ML; CARRILLO, MC; QUIROGA, AD

Congreso; SAIB - SAMIGE Joint meeting 2021 on line; 2021

It has been shown that dysregulation in lipid metabolism is a general molecular phenomenon during the progression ofhepatocarcinogenesis. The mechanisms by which lipid accumulation occurs during the cellular hepatocarcinoma developmentare not fully understood. Microsomal triacylglycerol transfer protein (MTP) locates in the lumen of the endoplasmic reticulumand participates in the secretion of lipids from the liver as VLDL. The MTP inhibitor lomitapide binds directly to MTP therebyinhibiting the synthesis of triglyceride-rich VLDL in the liver. The objective of this work was to study the effect of theinhibition of the VLDL secretion on liver tumor development. Adult male C57BL/6 mice were subjected to a model ofchemical hepatocarcinogenesis. Animals were randomly divided into two groups. One group (Control) received vehicle(methylcellulose, gastric probe) and another group received 5 mg/kg bw/day lomitapide (gastric probe) for 3 weeks. At theend of the treatment, mice were sacrificed, livers were excised and weighed and tumors counted from the liver ́s surface. Aftertreatment, lomitapide-treated mice showed increased liver/body weights ratio (2-fold) and more tumors (2-fold) than controlmice. As expected, plasma levels of triacylglycerol and ApoB-100 were decreased (-40% and -60%, respectively) inlomitapide-treated mice compared to control mice. Liver histology analysis showed no differences between groups on tissueand tumor architecture; however, lomitapide-treated mice presented less remaining normal liver parenchyma. Conclusion:these studies demonstrate that inhibition of lipid secretion from the liver could lead to increased tumor development, and MTPmay be participating in tumor growth, and represent the first steps in the evaluation of the role of MTP in cancer developm