Dietary Shift Leads to Venous Thrombosis-Induced Congestive Liver Failure in CBS-Deficient Mice

Abstract

Cystathionine beta-synthase (CBS) deficiency is an inborn error of metabolism that results in a large increase in plasma total homocysteine (tHcy) and a significant risk of venous thrombosis. Although a mouse model of CBS deficiency (Tg-I278T Cbs^−/−) has several phenotypes in common with human patients, it has not been shown to have elevated thrombosis risk. Here, we describe a novel phenotype in which 40% of Tg-I278T Cbs^−/− mice die of liver failure due to hepatic vein thrombosis shortly after being shifted from a low methionine diet (LMD) to a regular diet (RD). Importantly, no deaths or thromboses occur if the mice are continuously maintained on RD or LMD for extended periods of time. RNAseq analysis of the livers of Tg-I278T Cbs^−/− mice that were shifted to RD for 3 days after spending 1 week on LMD (RD3D) shows significant differences in many transcripts involved in coagulation and fibrinolysis, key processes involved in thrombosis. Interestingly, the liver gene expression profile and serum amino acid profiles of both Tg-I278T Cbs^−/− and Tg-I278T Cbs^+/− mice maintained continuously on RD are also significantly different from RD3D mice. Since the only difference between RD and RD3D mice is their previous exposure to an LMD diet, this shows that the liver transcriptional profile is affected not only by the current diet but also by the animals' previous dietary history. Overall, our findings indicate that there is a strong gene-diet interaction between the Cbs genotype and dietary methionine and that this interaction may help explain the thrombosis phenotype in human CBS deficient patients.