LOMITAPIDE DOES NOT AFFECT LIVER TUMOR DEVELOPMENT IN MICE ON A HIGH-FAT DIET

COMANZO, CG; QUIROGA, AD

Congreso; Sociedad Argentina de Investigaciones en Bioquímica y Biología Molecular; 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 oflipids 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 subjectedto a chemical model of hepatocarcinogenesis, and treated with lomitapide, presented with increasedliver/body weight ratio (2-fold) and with more tumors (2-fold) than control mice. The objective of thepresent work was to study the effect of the inhibition of VLDL secretion on liver tumor development inmice with dyslipidemia. Two-week old C57BL/6 male mice were subjected to a model of chemicalhepatocarcinogenesis and kept on a chow diet. At week 16, mice were changed to a 60% fat diet (highfat diet – HFD). At week 29, mice were randomly divided into two groups. Control group received avehicle (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 andtumors counted from the surface of the liver. There were no differences on body weight oflomitapide-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 tumorscompared to control mice. Conclusion: Lomitapide administration did not present disadvantagesregarding tumor growth in a model with metabolic alterations, unlike what we had observed in a modelof chemical hepatocarcinogenesis with chow diet. These studies demonstrate that metabolic contextcould significantly change the effect of a treatment in a given disease.