Lomitapide does not affect liver tumor development in mice on a High-fat diet

COMANZO, CARLA G; VERA, MARINA C; OVIEDO BUSTOS L; PALMA NICOLÁS FRANCISCO; FERRETTI, ANABELA C; CEBALLOS, MARÍA PAULA; ALVAREZ, MARÍA DE L.; QUIROGA, ARIEL D

rosario

Congreso; LIX Reunión anual de SAIB; 2023

Dysregulation in lipid metabolism is a general molecular phenomenon during the progression ofhepatocarcinogenesis. It has been shown that lipid accumulation occurs during liver cancerdevelopment; however this mechanism is not fully understood. Microsomal triacylglycerol transferprotein (MTP) locates in the lumen of the endoplasmic reticulum and participates in the secretion of lipids from the liver as VLDL. MTP inhibitor lomitapide binds directly to MTP thereby inhibiting thesynthesis of triglyceride-rich VLDL in the liver. In a previous work, we demonstrated that mice subjected to a chemical model of hepatocarcinogenesis, and treated with lomitapide, presented with increased liver/body weight ratio (2-fold) and with more tumors (2-fold) than control mice. The objective of the present work was to study the effect of the inhibition of VLDL secretion on liver tumor development in mice with dyslipidemia. Two-week old C57BL/6 male mice were subjected to a model of chemical hepatocarcinogenesis and kept on a chow diet. At week 16, mice were changed to a 60% fat diet (high fat diet – HFD). At week 29, mice were randomly divided into two groups. Control group received a vehicle (methylcellulose, gastric probe), and the other group received 5 mg/kg bw/day lomitapide (gastric probe) for 3 weeks. At week 32, mice were euthanized, livers were excised and weighed and tumors counted from the surface of the liver. There were no differences on body weight of lomitapide-treated mice compared to control mice. HFD induced an increase in plasma triacylglycerol (TG) and total cholesterol levels; as expected, plasma levels of TG and cholesterol were decreased (-25%, and -20%, respectively) in lomitapide-treated mice compared to control mice. Lomitapide-treated mice showed no differences on liver/body weights ratio or number of tumors compared to control mice. Conclusion: Lomitapide administration did not present disadvantages regarding tumor growth in a model with metabolic alterations, unlike what we had observed in a model of chemical hepatocarcinogenesis with chow diet. These studies demonstrate that metabolic context could significantly change the effect of a treatment in a given disease.