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Functional Interaction of Hepatic Nuclear Factor-4 and Peroxisome Proliferator-Activated Receptor- Coactivator 1 in CYP7A1 Regulation Is Inhibited by a Key Lipogenic Activator, Sterol Regulatory Element-Binding Protein-1c

Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

Address all correspondence and requests for reprints to: J. Kim Kemper, Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois 61801. E-mail: jongsook{at}uiuc.edu.

Insulin inhibits transcription of cholesterol 7-hydroxylase (Cyp7a1), a key gene in bile acid synthesis, and the hepatic nuclear factor-4 (HNF-4) site in the promoter was identified as a negative insulin response sequence. Using a fasting/feeding protocol in mice and insulin treatment in HepG2 cells, we explored the inhibition mechanisms. Expression of sterol regulatory element-binding protein-1c (SREBP-1c), an insulin-induced lipogenic factor, inversely correlated with Cyp7a1 expression in mouse liver. Interaction of HNF-4 with its coactivator, peroxisome proliferator-activated receptor- coactivator 1 (PGC-1), was observed in livers of fasted mice and was reduced after feeding. Conversely, HNF-4 interaction with SREBP-1c was increased after feeding. In vitro studies suggested that SREBP-1c competed with PGC-1 for direct interaction with the AF2 domain of HNF-4. Reporter assays showed that SREBP-1c, but not of a SREBP-1c mutant lacking the HNF-4 interacting domain, inhibited HNF-4/PGC-1 transactivation of Cyp7a1. SREBP-1c also inhibited PGC-1-coactivation of estrogen receptor, constitutive androstane receptor, pregnane X receptor, and farnesoid X receptor, implying inhibition of HNF-4 by SREBP-1c could extend to other nuclear receptors. In chromatin immunoprecipitation studies, HNF-4 binding to the promoter was not altered, but PGC-1 was dissociated, SREBP-1c and histone deacetylase-2 (HDAC2) were recruited, and acetylation of histone H3 was decreased upon feeding. Adenovirus-mediated expression of a SREBP-1c dominant-negative mutant, which blocks the interaction of SREBP-1c and HNF-4, partially but significantly reversed the inhibition of Cyp7a1 after feeding. Our data show that SREBP-1c functions as a non-DNA-binding inhibitor and mediates, in part, suppression of Cyp7a1 by blocking functional interaction of HNF-4 and PGC-1. This mechanism may be relevant to known repression of many other HNF-4 target genes upon feeding.

NURSA Molecule Pages Link:

Nuclear Receptors:   SHP  |  FXRα  |  PXR  |  CAR  |  HNF4α  |  ERα

Coregulators:   PGC-1  |  SRC-1  |  GRIP1  |  AIB1

Ligands:   Rifampicin  |  GW4064  |  17β-Estradiol  |  TCPOBOP