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

COMANZO, CARLA G.; VERA, MARINA C.; LUCCI ALVARO; HEIT BARBINI, FRANCISCO J.; LORENZETTI, FLORENCIA; FERRETTI, ANABELA CECILIA; CEBALLOS, MARÍA PAULA; ALVAREZ, MARÍA DE L.; CARRILLO, MARÍA CRISTINA; QUIROGA, ARIEL D.

Congreso; LVII reunión de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular - SAIB; 2021

It has been shown that dysregulation in lipid metabolism is a general molecular phenomenon during the progression of hepatocarcinogenesis. The mechanisms by which lipid accumulation occurs during the cellular hepatocarcinoma development are not fully understood. Microsomal triacylglycerol transfer protein (MTP) locates in the lumen of the endoplasmic reticulum and participates in the secretion of lipids from the liver as VLDL. The MTP inhibitor lomitapide binds directly to MTP thereby inhibiting the synthesis of triglyceride-rich VLDL in the liver. The objective of this work was to study the effect of the inhibition of the VLDL secretion on liver tumor development. Adult male C57BL/6 mice were subjected to a model of chemical 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 the end of the treatment, mice were sacrificed, livers were excised and weighed and tumors counted from the liver´s surface. After treatment, lomitapide-treated mice showed increased liver/body weights ratio (2-fold) and more tumors (2-fold) than control mice. As expected, plasma levels of triacylglycerol and ApoB-100 were decreased (-40% and -60%, respectively) in lomitapide-treated mice compared to control mice. Liver histology analysis showed no differences between groups on tissue and 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 MTP may be participating in tumor growth, and represent the first steps in the evaluation of the role of MTP in cancer development.