Impaired hepatic VLDL secretion promotes tumorigenesis and is accelerated with Fabp1 deletion

Am J Pathol. 2024 Feb 26:S0002-9440(24)00074-9. doi: 10.1016/j.ajpath.2024.02.005. Online ahead of print.ABSTRACTGenetic 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 Fabp1 null (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. Serum HDL cholesterol was elevated in both Mttp-LKO and Fabp1/Mttp DKO mice, with increased intratumoral expression of apoA1 and apoE. Lipidomic surveys revealed progressive enrichment in distinct triglyceride species in livers from Mttp-LKO mice with further enrichment in Fabp1/Mttp DKO mice. RNAseq 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. These metabolic shifts were accompanied by reduced expression of HNF1a, which correlated with tumor burden. Taken together, these findings demonstra...
Source: The American Journal of Pathology - Category: Pathology Authors: Source Type: research