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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 X Fabp1null (Fabp1/MttpDKO) mice. Here we examine the impact of impaired VLDL secretion in Mttp-LKOmice on HCC incidence and progression in comparison to Fabp1/MttpDKO mice. DEN treated Mttp-LKOmice exhibited steatosis with increased tumor burden compared to floxcontrols, while diethylnitrosamine (DEN)- treated Fabp1/MttpDKO mice exhibited a paradoxical increase in tumor burden and >50% mortality by 50 weeks. Serum HDL cholesterol was elevated in both Mttp-LKOand Fabp1/MttpDKO mice, with increased intratumoral expression of apoA1 and apoE. Lipidomic surveys revealed progressive enrichment in distinct triglyceride species in livers from Mttp-LKOmice with further enrichment in Fabp1/MttpDKO mice. RNAseq revealed mRNA changes suggesting altered monocarboxylic acid utilization and increased aerobic glycolysis, while hepatocytes from Fabp1/MttpDKO mice exhibited increased capacity to utilize glucose and glutamine. These metabolic shifts were accompanied by reduced expression of HNF1a, which correlated with tumor burden. 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.