Elevated hepatocyte levels of the Forkhead box A2 (HNF-3β) transcription factor cause postnatal steatosis and mitochondrial damage

Douglas E. Hughes, Donna Beer Stolz, Songtao Yu, Yongjun Tan, Janardan K. Reddy, Simon C. Watkins, Anna Mae Diehl, Robert H. Costa*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


The Forkhead box (Fox) transcription factor Foxa2 (HNF-3β) and related family members Foxa1 (HNF-3α) and Foxa3 (HNF-3γ) act in concert with other hepatocyte nuclear factors (HNF) to coordinately regulate liver-specific gene expression. To circumvent the hepatic functional redundancy of the Foxa proteins, we used the T-77 transgenic (TG) mouse line in which the -3-kb transthyretin (TTR) promoter functioned to increase hepatocyte expression of the Foxa2 cDNA. Adult TG mice exhibited reduced hepatic glycogen and progressive liver injury, but maintained normal serum levels of glucose, insulin, and glucagon. In this study, we further characterized the postnatal liver defect in TTR-FoxA2 TG mice. The postnatal TG mice displayed significant reduction in serum glucose levels and in hepatocyte glycogen storage without increased serum levels of ketone bodies and free fatty acid suggesting that they are not undergoing a starvation response. We show that TG liver developed a substantial transient steatosis, which reached a maximum at postnatal day 5 and is associated with increased expression of hepatic genes involved in fatty acid and triglyceride synthesis, lipid β-oxidation, and amino acid biosynthesis. Furthermore, transmission electron microscopy analysis of postnatal TG liver revealed extensive mitochondrial membrane damage, which is likely due to reactive oxygen species generated from lipid β-oxidation. In conclusion, our model proposes that in response to reduction in hepatocyte glycogen storage, the TTR-Foxa2 TG mice survive by maintaining sufficient serum levels of glucose through gluconeogenesis using deaminated amino acids with dicarboxylate products of peroxisomal lipid β-oxidation shuttled through the tricarboxylic acid cycle.

Original languageEnglish (US)
Pages (from-to)1414-1424
Number of pages11
Issue number6
StatePublished - Jun 1 2003

ASJC Scopus subject areas

  • Hepatology


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