HNF1alpha inactivation promotes lipogenesis in human hepatocellular adenoma independently of SREBP-1 and carbohydrate-response element-binding protein (ChREBP) activation.
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.
Rebouissou
Sandra
S
INSERM, U674, Génomique fonctionnelle des tumeurs solides, Paris Cedex, France.
Imbeaud
Sandrine
S
Balabaud
Charles
C
Boulanger
Virginie
V
Bertrand-Michel
Justine
J
Tercé
François
F
Auffray
Charles
C
Bioulac-Sage
Paulette
P
Zucman-Rossi
Jessica
J
D018248:Adenoma, Liver Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D019343:Citric Acid; D005227:Fatty Acids / Q000493:pharmacokinetics; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005943:Gluconeogenesis; D006019:Glycolysis; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D020218:Response Elements / Q000502:physiology*; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D014408:Biomarkers, Tumor; D005227:Fatty Acids; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D019343:Citric Acid