Attenuation of obesity-induced hyperlipidemia reduces tumor growth.

Accumulating evidence suggests that hyperlipidemia is associated with obesity and cancer mortality in humans. We tested the hypotheses that inhibition of microsomal triglyceride transfer protein (MTP) would attenuate obesity-induced hyperlipidemia and reduce tumor growth by treating BCR-ABL B cell tumor-bearing hyperlipidemic obese ob/ob obese mice with a MTP inhibitor. MTP inhibition in tumor-bearing mice reduced concentrations of plasma apoB100 5-fold together with a corresponding decrease in VLDL triacylglycerol (TG) and cholesterol. Inhibition of MTP decreased tumor volume by 50%. MTP inhibitor did not alter tumor cell viability in vitro, suggesting that the in vivo tumor shrinkage effect was related to altered circulating lipids. Tumor volume reduction occurred without change in the protein expression of LDLR, FASN and HMGCR in the tumor, suggesting a lack of compensatory mechanisms in response to decreased hyperlipidemia. Expression of genes encoding GLUT4 and PEPCK was increased 6- and 10-fold, respectively, but no change in the expression of genes encoding regulatory enzymes of glycolysis was observed, suggesting that the tumors were not dependent on or switching to carbohydrates for energy requirement to support their growth. No change of proliferative signaling PI3K/AKT and ERK pathways after MTP inhibition was observed in the tumors. In conclusion, MTP inhibition decreased dyslipidemia and tumor growth in obese, insulin resistant mice. Therefore, decreasing VLDL secretion could be further explored as an adjuvant therapeutic intervention together with standard care to reduce tumor growth in obese patients.