Liver-Specific Hepatocyte Nuclear Factor-4α Deficiency: Greater Impact on Gene Expression in Male than in Female Mouse Liver

Hepatocyte nuclear factor (HNF)-4α is a liver-enriched transcription factor that regulates numerous liver-expressed genes including several sex-specific cytochrome P450 genes. Presently, a liver-specific HNF4α-deficient mouse model was used to characterize the impact of liver HNF4α deficiency on a global scale using 41,174 feature microarrays. A total of 4994 HNF4α-dependent genes were identified, of which about 1000 fewer genes responded to the loss of HNF4α in female liver as compared with male liver. Sex differences in the impact of liver HNF4α deficiency were even more dramatic when genes showing sex-specific expression were examined. Thus, 372 of the 646 sex-specific genes characterized by a dependence on HNF4α responded to the loss of HNF4α in males only, as compared with only 61 genes that responded in females only. Moreover, in male liver, 78% of 508 male-specific genes were down-regulated and 42% of 356 female-specific genes were up-regulated in response to the loss of HNF4α, with sex specificity lost for 90% of sex-specific genes. This response to HNF4α deficiency is similar to the response of male mice deficient in the GH-activated transcription factor signal transducer and activator of transcription 5b (STAT5b), where 90% of male-specific genes were down-regulated and 61% of female-specific genes were up-regulated, suggesting these two factors cooperatively regulate liver sex specificity by mechanisms that are primarily active in males. Finally, 203 of 648 genes previously shown to bind HNF4α near the transcription start site in mouse hepatocytes were affected by HNF4α deficiency in mouse liver, with the HNF4α-bound gene set showing a 5-fold enrichment for genes positively regulated by HNF4α. Thus, a substantial fraction of the HNF4α-dependent genes reported here are likely to be direct targets of HNF4α.