Abstract
Biallelic inactivating mutations of the transcription factor 1 gene (TCF1), encoding hepatocyte nuclear factor 1alpha (HNF1alpha) were identified in 50% of hepatocellular adenomas (HCA) phenotypically characterized by a striking steatosis. To understand the molecular basis of this aberrant lipid storage, we performed a microarray transcriptome analysis validated by quantitative reverse transcription-PCR, Western blotting, and lipid profiling. In mutated HCA, we showed a repression of gluconeogenesis coordinated with an activation of glycolysis, citrate shuttle, and fatty acid synthesis predicting elevated rates of lipogenesis. Moreover, the strong down-regulation of liver fatty acid-binding protein suggests that impaired fatty acid trafficking may also contribute to the fatty phenotype. In addition, transcriptional profile analysis of the observed deregulated genes in non-HNF1alpha-mutated HCA as well as in non-tumor livers allowed us to define a specific signature of the HNF1alpha-mutated HCA. In these tumors, lipid composition was dramatically modified according to the transcriptional deregulations identified in the fatty acid synthetic pathway. Surprisingly, lipogenesis activation did not operate through sterol regulatory element-binding protein-1 (SREBP-1) and carbohydrate-response element-binding protein (ChREBP) that were repressed. We conclude that steatosis in HNF1alpha-mutated HCA results mainly from an aberrant promotion of lipogenesis that is linked to HNF1alpha inactivation and that is independent of both SREBP-1 and ChREBP activation. Finally, our findings have potential clinical implications since lipogenesis can be efficiently inhibited by targeted therapies.
Highlights
Hepatocyte nuclear factor 1-␣ (HNF1␣)3 is a transcription factor that controls the expression of liver-specific genes, such as -fibrinogen, ␣1-antitrypsin, and albumin [1]
We identified a repression of gluconeogenesis coordinated with an activation of glycolysis and citrate shuttle predicting an aberrant accumulation of the acetyl-CoA and NADPH lipogenic precursors [12]
These findings provide evidence that de novo lipogenesis activity is increased in HNF1␣-mutated hepatocellular adenomas (HCA), and we showed that it is related to the loss of HNF1␣ activity
Summary
HNF1␣, hepatocyte nuclear factor 1-␣; HNF4␣, hepatocyte nuclear factor 4-␣; ACL, ATP citrate lyase; ChREBP, carbohydrate-response element-binding protein; SREBP-1, sterol regulatory element-binding protein-1; FA, fatty acid; FAS, fatty acid synthase; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids; UFA, unsaturated fatty acids; L-FABP, liver fatty acid-binding protein; G6P, glucose-6-phosphate; GK, glucokinase; HCA, hepatocellular adenomas; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PPAR␥, peroxisome proliferator-activated receptor-␥; PS, phosphatidylserine; PI, phosphatidylinositol; RT, reverse transcription. HNF1␣ Inactivation Promotes Hepatic Lipogenesis at the protein level, and we analyzed the precise composition of accumulated lipids
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