Impaired VLDL secretion following Mttp deletion promotes tumorigenesis and is accelerated by Fabp1 deletion

Genetic polymorphisms that impair VLDL secretion are linked to hepatic steatosis, fibrosis and hepatocellular cancer (HCC). Liver-specific deletion of microsomal triglyceride transfer protein (Mttp-LKO) impairs VLDL assembly, promoting hepatic steatosis and fibrosis, which are attenuated in Mttp-LKO mice with germline Fabp1 deletion (Fabp1/Mttp DKO) mice. Here we examine the impact of impaired VLDL secretion in Mttp-LKO mice on HCC incidence and progression in comparison to Fabp1/Mttp DKO mice. DEN treated Mttp-LKO mice exhibited steatosis with increased tumor burden compared to flox controls, while diethylnitrosamine (DEN)- treated Fabp1/Mttp DKO mice exhibited a paradoxical increase in tumor burden and >50% mortality by 50 weeks. Lipidomic surveys revealed progressive enrichment in distinct triglyceride species in livers from Mttp-LKO mice with further enrichment in Fabp1/Mttp DKO mice. RNAseq analysis performed on liver tissue at 6 months revealed mRNA changes suggesting altered monocarboxylic acid utilization and increased aerobic glycolysis, while hepatocytes from Fabp1/Mttp DKO mice exhibited increased capacity to utilize glucose and glutamine. Taken together, these findings demonstrate that hepatic tumorigenesis is increased in mice with impaired VLDL secretion and further accelerated via pathways including altered fatty acid compartmentalization and shifts in hepatic energy utilization. Study was performed on whole liver RNA isolated from 3 genotypes of mice:Mttp fl/fl mice (CON), mice with liver specific deletion of Mttp (MttpLKO) and MttpLKO mice with germline deletion of Fabp1 (Fabp1 Mttp DKO) All mice were C57BL/6J congenic male mice injected with DEN at P14d and sacrificed at 6 months of age Each sample represents pooled RNA from 3 mice of same genotype. 3 pools of RNA were analyzed for each genotype for a total of 9 samples.