Regulation of Hepatocyte Nuclear Factor 4α-mediated Transcription

Drug Metab. Pharmacokinet. 23 (1): 2–7 (2008).

Review Regulation of Hepatocyte Nuclear Factor 4a-mediated Transcription Frank J. GONZALEZ* Laboratory of Metabolism, National Cancer Institute, National Instituted of Health, Bethesda, Maryland, USA Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk

Summary: Hepatocyte nuclear factor 4a (HNF4a, NR2A1) is required for development of the liver and for controlling the expression of many genes specifically expressed in the liver and associated with a number of critical metabolic pathways. Among the genes regulated by HNF4a are the xenobiotic-metabolizing cytochromes P450, UDP-glucuronosyltransferases and sulfotransferases thus making this transcription factor critical in the control of drug metabolism. HNF4a, a member of the nuclear receptor superfamily, binds as a homodimer to direct repeat elements upstream of target genes. However, in contrast to many other nuclear receptors, there is no convincing evidence that HNF4a is activated by exogenous ligands, at least in the classic mechanism used by other steroid and metabolic nuclear receptors. X-ray crystallographic studies revealed that HNF4a has a fatty acid embedded in its putative ligand binding site that may not be easily released or displaced by exogenous ligands. HNF4a, as a general rule, controls constitutive expression of many hepatic genes but under certain circumstances can be subjected to regulation by differential co-activator recruitment, by phosphorylation and by interaction with other nuclear receptors. The ability of HNF4a to be regulated offers hope that it could be a drug target. Keywords: Alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase, ACMSD; direct repeat element, DR; CAR, constitutive androstane receptor; forkhead box O1a, FOXO1; glucocorticoid receptor, GR; hepatocyte nuclear factor 4a, HNF4a; maturity onset diabetes of the young 1, MODY-1; phosphoenolpyruvate carboxykinase, PEPCK; glucose-6phosphatase, G-6-Pase; pregnane X receptor, PXR; peroxisome proliferators-activated receptor a, PPARa

Hepatocyte nuclear factor 4a (HNF4a, NR2A1) is a member of the nuclear receptor superfamily but displays properties that are quite distinct from other proteins of this superfamily.1,2) HNF4a was isolated as a protein in rat liver nuclear extracts that bound DNA elements required for transcription of the genes encoding transthyretin and apolipoprotein CIII.1) HNF4a is expressed at high levels in liver, and to a lesser degree in kidney, small intestine, colon, and pancreatic b cells.3,4) HNF4a, a Zn-finger protein, binds as a homodimer to its DNA recognition site, a direct repeat element (AGGTCA) with either a one or two nucleotide spacer (designated DR1 or DR2, respectively). Upon binding to DNA, HNF4a recruits transcriptional co-activators and other accessory proteins and positively regulates the expression of target genes. In the liver where it is localized exclusively in the nucleus, HNF4a regulates constitutive expression of a large number of target genes

encoding enzymes, transporters and even other nuclear receptors, and accounts for, in large part, the liver-specific expression of these genes (Fig. 1). The absence of HNF4a in the adult liver, as a result of conditional targeted gene disruption, results in marked metabolic disregulation and increased mortality.5–9) Among the phenotypes displayed by these mice are elevated serum bile acids that results from lower expression of the bile acid metabolizing enzymes, CYP7A1, CYP8B1,9) bile acid-CoA: amino acid N-acyltransferase and bile acid-CoA ligase,7) and high serum ammonia from the decreased expression of ornithine transcarbamylase.6) These mice also exhibit high hepatic lipids (steatosis) that results from altered expression of fatty acid transporters and fatty acid metabolism. HNF4a is also involved in the constitutive expression of the genes encoding the coagulation factors FXII and XIIIB8) and genes involved in amino acid metabolism such as proline oxidase.10) A more

Received; November 10, 2007, Accepted; December 5, 2007 *To whom correspondence should be addressed: Frank J. GONZALEZ, Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda Maryland, 20892, USA. E-mail: gonzalef＠mail.nih.gov

2

3

Regulation of HNF4a

Fig. 1. Role of HNF4a in control of gene expression in the liver A number of critical metabolic pathways are under constitutive regulation by HNF4a.

complete list of HNF4a target genes can be found at http://www.sladeklab.ucr.edu/hnf43.pdf. Most of these target genes have been determined in rodent model systems with limited in vitro transactivation studies revealing possible human HNF4a target genes. Transfection studies have revealed the presence of HNF4a binding sites upstream of the CYP2D6,11) CYP2A612) and UGT1A913) genes. However recently, adenovirusexpressed HNF4a small interfering RNA (siRNA) has proven to be of value in assessing the role of this transcription factor in control of genes in primary human hepatocytes including several gene encoding human P450s, UDP-glucuronosyltransferases, sulfotransferases and ATP-binding cassette transporters, organic anion transporters and organic cation transporter.14) Studies using mice humanized for potential HNF4a target genes bred with null HNF4a alleles, have revealed a role for HNF4a in the regulation of human target genes such as the CYP2D6.15) HNF4a does not have a ligand, that in the classic sense of nuclear receptor signaling, activates the receptor by altering its conformation allowing the release of co-repressors and binding of co-activators, a mechanism exhibited by a number of other nuclear receptors. Thus, HNF4a is classified as an orphan receptor in a unique family of its own within the nuclear receptor superfamily. However, X-ray structural studies have revealed the presence of a fatty acid in the pocket of the receptor that is associated with ligand binding at the same domain homologous to regions of other bona fide ligand-activated nuclear receptors.16) The endogenous fatty acids did not readily exchange with radiolabeled fatty acids such as palmitic acid, suggesting that the fatty acid is embedded in the binding pocket during folding of the protein upon its translation. While there is some evidence that HNF4a can bind to exogenous fatty acyl-CoA esters,17,18) it is still not clear whether HNF4a trans-activation activity is altered by binding to these or other ligands. Thus, there still remains considerable uncertainty whether HNF4a can be regulated by endogenous or exogenous ligands. This possibility is particularly enticing since HNF4a is involved in regulating genes involved in the control of lipid and cholesterol metabolism. In humans, heterozygous mutation of HNF4a causes maturity onset diabetes of the young 1 (MODY-1). These patients exhibit normal insulin sensitivity and liver and kidney function, but have a defect in glucose-stimulated insulin secretion from

the pancreatic b cells.19) This disorder appears to be due to deficiency in HNF4a signal transduction in the pancreas. Indeed, mice with a targeted disruption of HNF4a in pancreatic b cells exhibit impaired insulin secretion19,20) albeit, in contrast to humans, this is not seen in HNF4a heterozygous mice. Modest differences in liver function as a result of HNF4a haploinsufficiency is also found in MODY-1 patents.21) Of interest, no homozygous mutations of the HNF4a gene have been found in humans in agreement with the neonatal lethality found in embryonic targeted gene disruption;22) these embryos fail to undergo normal gastrulation.23) The embryonic lethality of HNF4a knockout mice is probably due to the requirement for HNF4a in liver development.24) HNF4a is one of the earliest markers associated with the differentiated function of the liver; its expression is coincident with a number of its own target genes, many of which remain expressed in the adult liver. In addition, HNF4a can activate the expression of other transcription factors that in turn control liver-specific target genes. These include HNF1a25) and the pregnane X receptor (PXR).26) Interestingly, in adult liver, HNF4a may not predominate in the control of these genes.26,27) While HNF4a does not appear to be regulated by ligand activation, its critical role in the control of constitutive expression of a large number of hepatic genes requires close examination since altered expression of these genes by metabolic perturbations could have marked physiological effects. There are several mechanisms by which HNF4a transactivation of target genes could be altered as described below.

Nuclear receptor cooperativity In addition to its direct regulation of target genes, HNF4a potentiates the regulation of other genes by nuclear receptors. Studies with the human CYP3A4 gene promoter, which is activated by the nuclear receptors constitutive androstane receptor (CAR) and PXR, indicated that activation by these receptors required a factor specific to liver that was determined to be HNF4a.28) This explains the fact that CYP3A4 is preferentially expressed and induced in liver hepatocytes where it is involved in the metabolism of a large number of clinically used drugs.29) HNF4a may be involved in making the chromatin competent to allow positive activation of the CYP3A4 gene by CAR and PXR. SULT2A1 is also under constitutive control of HNF4a.14,30) However, in contrast to CYP3A4, PXR activation suppressed expression of the human SULT2A1.30) Thus PXR interferes with positive activation of the gene by HNF4a; the mechanism of this interference is still not clear. While HNF4a was found to potentiate the inductive effects of PXR and CAR on the CYP3A4 promoter, other nuclear receptor cooperativity that results in the suppression of gene expression was found with certain gene promoters. Activation of the peroxisome proliferator-activated receptor a (PPARa) results in induction of a number of genes encoding enzymes involved in fatty acid b-oxidation in peroxisomes and mitochondria.31) PPARa is markedly activated under conditions of fast-

4

Frank J. GONZALEZ

ing which serves to promote the metabolism of lipids in order to generate precursors for gluconeogenesis, and energy from ATP and NADH. PPARa also suppresses genes including alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD), a key enzyme in the tryptophannicotinamide adenine dinucleotide pathway. Suppression of ACMSD results in elevated cellular levels of NAD that is needed to accommodate the increased fatty acid oxidation that occurs upon PPARa activation.32) The Acmsd gene was constitutively regulated by HNF4a and upon PPARa activation, expression was decreased coincident with a decrease in cellular content of HNF4a.33) It was proposed that this decrease in HNF4a accounted for the decrease in Acmsd gene expression, however, the mechanism of the decrease is not known. Thus, the expression of both ACMSD and SULT2A1 are attenuated by nuclear receptor activation. The mechanism of this attenuation might be due to phosphorylation of HNF4a. It is interesting to note that HNF4a also regulates the liver-specific expression of human PPARa34) indicating the existence of a transcription factor cascade. Another means by which PPARa can be modulated is through phosphorylation which is known to control cellular levels and signal transduction of other nuclear receptors.35,36) A number of studies have revealed that HNF4a can be phosphorylated by protein kinase A,37) extracellular signal-regulated kinase,38) AMP-activated protein kinase,39,40) and c-Jun NH2-ter-

minal kinase 1,41) Phosphorylation can alter the DNA-binding affinity and trans-activation capacity of HNF4a, can change its intracellular location (i.e., translocation from the nucleus to the cytoplasm) or can trigger degradation of the receptor through the 26S proteasomal pathway (Fig. 2). Phosphorylation at Ser158 can potentiate the binding of co-activators such as PC4 and preferentially activate certain HNF4a target genes.42) Posttranslational modification could also result in other non-transcriptional activities of HNF4a. Phosphorylation at HNF4a Ser78, a residue conserved in other nuclear receptors, by protein kinase C (PKC) was shown to trigger its transport out of the nucleus and degradation resulting in decreased target gene activation.43) It remains an intriguing possibility that this mechanism plays a role in the down regulation of HNF4a found after PPARa activation that gives rise to the lower expression of Acmsd. Whether there are any physiological conditions that increase Ser78 phosphorylation and alter target gene expression and metabolic function, particularly in the liver, is still not clear. One of the most well documented roles for HNF4a in the metabolic control of gene expression was found under conditions of low insulin signaling during fasting.44,45) Glucagon stimulation of a cell surface receptor triggers and increase in cAMP and glucocorticoid ligands for the glucocorticoid receptor (GR). Among the downstream gene targets of the cAMP cascade is PPARg coactivator 1 a (PGC-1a), a coactivator for

Fig. 2. Regulation of HNF4a levels and transcription by phosphorylation and coactivator recruitment Activation of PPARa and PXR suppresses HNF4a-mediated target gene expression. In the case of PPARa, this is the result of lower HNF4a protein levels. One possible mechanism is increased cytoplasmic 26S proteasome degradation possibly as a result of phosphorylation. HNF4a phosphorylation at Ser158 can stimulate recruitment of the coactivator PC4. Elevated PGC-1a can augment expression of HNF4a to increase transcription of PEPCK and G-6-Pase.

5

Regulation of HNF4a

PPARg first identified in brown adipose tissue.46) The PGC-1a gene is directly activated by cAMP response element binding protein, and levels of expression of the coactivator further elevated by synergy with the GR. The elevated cellular levels of PGC-1a then serve as a coactivator of HNF4a-specific activation of target genes such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase) responsible for gluconeogenesis. In the absence of PGC-1a, the control of PEPCK and G-6-Pase gene expression by HNF4a is negligible. Many other HNF4a target genes are not co-activated by PGC-1a. The mechanism of this specificity is not known but may be due to other specific sequences near the HNF4a DR1/2 elements. In addition to HNF4a, PGC-1a also regulates a number of other transcription factors such as forkhead box O1a (FOXO1), GR, PPARa and PPARg in liver and other tissues and is thus a critical component of other important metabolic consequences of the fasting response including fatty acid b-oxidation, ketogenesis, and bile-acid homeostasis.47) PGC-1a was also found to regulate the increase in expression of the nuclear receptor CAR found during the fasting response.48) Similar to PEPCK, this increase was mediated by PGC-1a co-activation of HNF4a that binds to a region upstream of the Car gene. In contrast, others found that PGC-1a mediates the down-regulation of P450s CYP7A1 and CYP8B1, involved in bile acid synthesis, by the PXR activator rifampicin.49) This down-regulation occurs by PXR interference of HNF4a interaction with PGC-1a resulting in lower trans-activation of the CYP7A1 and CYP8B1 promoters. Another transcription factor interaction was recently uncovered involving HNF4a and the zinc finger domain transcription factors GATA4 and GATA6 that bind the consensus (A/T)GATA(A/G) sequence.50) The intergenic region of the genes encoding the ATP-binding cassette half-transporters Abcg5 and Abcg8 genes contains an HNF4a DR1 site flanked by GATA boxes. In this case, activation of these genes requires HNF4a and either GATA4 or GATA6.51) Interestingly, this cooperativity requires both DNA binding and protein-protein interactions between HNF4a and the GATA factors. Another unique transcription factor interaction was uncovered involving HNF4a and the cyclin-dependent kinase inhibitor gene p21/WAF1.52) The p21/WAF1 gene is regulated by the potent transcription factor Sp1 that controls constitutive expression of a number of genes. HNF4a potentiates expression of the p21/WAF1 gene by about three-fold by a mechanism that does not involve direct DNA binding. Interestingly, the oncogene c-Myc was found to bind to HNF4a and suppress expression of p21/WAF1 and more typical HNF4a target genes such as the encoding apolipoprotein CIII. These data indicate that the differentiation factor HNF4a and the proliferation factor c-Myc control the differentiation and proliferative states of hepatocytes.52) In conclusion, a number of studies have revealed that HNF4a not only controls constitutive expression of genes that are largely responsible for the specialized function of the liver, but also participates in metabolic control. However, with the

exception of the studies on PGC-1a, the role of phosphorylation and other nuclear receptor and transcription factor interactions in modulating HNF4a needs to be confirmed by additional in vivo studies using appropriate genetic models.

References 1)

2)

3)

4)

5)

6)

7)

8)

9)

10)

11)

12)

13)

Sladek, F. M., Zhong, W. M., Lai, E. and Darnell, J. E., Jr.: Liverenriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev, 4: 2353–2365 (1990). Schrem, H., Klempnauer, J. and Borlak, J.: Liver-enriched transcription factors in liver function and development. Part I: the hepatocyte nuclear factor network and liver-specific gene expression. Pharmacol Rev, 54: 129–158 (2002). Drewes, T., Senkel, S., Holewa, B. and Ryffel, G. U.: Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes. Mol Cell Biol, 16: 925–931 (1996). Jiang, S., Tanaka, T., Iwanari, H., Hotta, H., Yamashita, H., Kumakura, J., Watanabe, Y., Uchiyama, Y., Aburatani, H., Hamakubo, T., Kodama, T. and Naito, M.: Expression and localization of P1 promoter-driven hepatocyte nuclear factor4alpha (HNF4alpha) isoforms in human and rats. Nucl Recept, 1: 5 (2003). Hayhurst, G. P., Lee, Y. H., Lambert, G., Ward, J. M. and Gonzalez, F. J.: Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol, 21: 1393–1403 (2001). Inoue, Y., Hayhurst, G. P., Inoue, J., Mori, M. and Gonzalez, F. J.: Defective ureagenesis in mice carrying a liver-specific disruption of hepatocyte nuclear factor 4alpha (HNF4alpha ). HNF4alpha regulates ornithine transcarbamylase in vivo. J Biol Chem, 277: 25257–25265 (2002). Inoue, Y., Yu, A. M., Inoue, J. and Gonzalez, F. J.: Hepatocyte nuclear factor 4alpha is a central regulator of bile acid conjugation. J Biol Chem, 279: 2480–2489 (2004). Inoue, Y., Peters, L. L., Yim, S. H., Inoue, J. and Gonzalez, F. J.: Role of hepatocyte nuclear factor 4alpha in control of blood coagulation factor gene expression. J Mol Med, 84: 334–344 (2006). Inoue, Y., Yu, A. M., Yim, S. H., Ma, X., Krausz, K. W., Inoue, J., Xiang, C. C., Brownstein, M. J., Eggertsen, G., Bjorkhem, I. and Gonzalez, F. J.: Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4alpha. J Lipid Res, 47: 215–227 (2006). Kamiya, A., Inoue, Y., Kodama, T. and Gonzalez, F. J.: Hepatocyte nuclear factors 1alpha and 4alpha control expression of proline oxidase in adult liver. FEBS Lett, 578: 63–68 (2004). Cairns, W., Smith, C. A., McLaren, A. W. and Wolf, C. R.: Characterization of the human cytochrome P4502D6 promoter. A potential role for antagonistic interactions between members of the nuclear receptor family. J Biol Chem, 271: 25269–25276 (1996). Pitarque, M., Rodriguez-Antona, C., Oscarson, M. and Ingelman-Sundberg, M.: Transcriptional regulation of the human CYP2A6 gene. J Pharmacol Exp Ther, 313: 814–822 (2005). Barbier, O., Girard, H., Inoue, Y., Duez, H., Villeneuve, L., Kamiya, A., Fruchart, J. C., Guillemette, C., Gonzalez, F. J. and Staels, B.: Hepatic expression of the UGT1A9 gene is governed

6

14)

15)

16)

17)

18)

19)

20)

21)

22)

23)

24) 25)

26)

Frank J. GONZALEZ

by hepatocyte nuclear factor 4alpha. Mol Pharmacol, 67: 241–249 (2005). Kamiyama, Y., Matsubara, T., Yoshinari, K., Nagata, K., Kamimura, H. and Yamazoe, Y.: Role of human hepatocyte nuclear factor 4alpha in the expression of drug-metabolizing enzymes and transporters in human hepatocytes assessed by use of small interfering RNA. Drug Metab Pharmacokinet, 22: 287–298 (2007). Corchero, J., Granvil, C. P., Akiyama, T. E., Hayhurst, G. P., Pimprale, S., Feigenbaum, L., Idle, J. R. and Gonzalez, F. J.: The CYP2D6 humanized mouse: effect of the human CYP2D6 transgene and HNF4alpha on the disposition of debrisoquine in the mouse. Mol Pharmacol, 60: 1260–1267 (2001). Wisely, G. B., Miller, A. B., Davis, R. G., Thornquest, A. D., Jr., Johnson, R., Spitzer, T., Sefler, A., Shearer, B., Moore, J. T., Miller, A. B., Willson, T. M. and Williams, S. P.: Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds fatty acids. Structure, 10: 1225–1234 (2002). Hertz, R., Magenheim, J., Berman, I. and Bar-Tana, J.: Fatty acyl-CoA thioesters are ligands of hepatic nuclear factor-4alpha. Nature, 392: 512–516 (1998). Schroeder, F., Huang, H., Hostetler, H. A., Petrescu, A. D., Hertz, R., Bar-Tana, J. and Kier, A. B.: Stability of fatty acylcoenzyme A thioester ligands of hepatocyte nuclear factor-4alpha and peroxisome proliferator-activated receptor-alpha. Lipids, 40: 559–568 (2005). Gupta, R. K., Vatamaniuk, M. Z., Lee, C. S., Flaschen, R. C., Fulmer, J. T., Matschinsky, F. M., Duncan, S. A. and Kaestner, K. H.: The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest, 115: 1006–1015 (2005). Miura, A., Yamagata, K., Kakei, M., Hatakeyama, H., Takahashi, N., Fukui, K., Nammo, T., Yoneda, K., Inoue, Y., Sladek, F. M., Magnuson, M. A., Kasai, H., Miyagawa, J., Gonzalez, F. J. and Shimomura, I.: Hepatocyte nuclear factor-4alpha is essential for glucose-stimulated insulin secretion by pancreatic beta-cells. J Biol Chem, 281: 5246–5257 (2006). Shih, D. Q., Dansky, H. M., Fleisher, M., Assmann, G., Fajans, S. S. and Stoffel, M.: Genotype/phenotype relationships in HNF4alpha/MODY1: haploinsufficiency is associated with reduced apolipoprotein (AII), apolipoprotein (CIII), lipoprotein(a), and triglyceride levels. Diabetes, 49: 832–837 (2000). Chen, W. S., Manova, K., Weinstein, D. C., Duncan, S. A., Plump, A. S., Prezioso, V. R., Bachvarova, R. F. and Darnell, J. E., Jr.: Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos. Genes Dev, 8: 2466–2477 (1994). Duncan, S. A., Nagy, A. and Chan, W.: Murine gastrulation requires HNF-4 regulated gene expression in the visceral endoderm: tetraploid rescue of Hnf-4(–/–) embryos. Development, 124: 279–287 (1997). Duncan, S. A.: Mechanisms controlling early development of the liver. Mech Dev, 120: 19–33 (2003). Kuo, C. J., Conley, P. B., Chen, L., Sladek, F. M., Darnell, J. E., Jr. and Crabtree, G. R.: A transcriptional hierarchy involved in mammalian cell-type specification. Nature, 355: 457–461 (1992). Kamiya, A., Inoue, Y. and Gonzalez, F. J.: Role of the hepatocyte

27)

28)

29)

30)

31)

32)

33)

34)

35)

36)

37)

38)

39)

nuclear factor 4alpha in control of the pregnane X receptor during fetal liver development. Hepatology, 37: 1375–1384 (2003). Kim, H. J., Lee, S. K., Na, S. Y., Choi, H. S. and Lee, J. W.: Molecular cloning of xSRC–3, a novel transcription coactivator from Xenopus, that is related to AIB1, p/CIP, and TIF2. Mol Endocrinol, 12: 1038–1047 (1998). Tirona, R. G., Lee, W., Leake, B. F., Lan, L. B., Cline, C. B., Lamba, V., Parviz, F., Duncan, S. A., Inoue, Y., Gonzalez, F. J., Schuetz, E. G. and Kim, R. B.: The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nat Med, 9: 220–224 (2003). Bu, H. Z.: A literature review of enzyme kinetic parameters for CYP3A4-mediated metabolic reactions of 113 drugs in human liver microsomes: structure-kinetics relationship assessment. Curr Drug Metab, 7: 231–249 (2006). Fang, H. L., Strom, S. C., Ellis, E., Duanmu, Z., Fu, J., DuniecDmuchowski, Z., Falany, C. N., Falany, J. L., Kocarek, T. A. and Runge-Morris, M.: Positive and negative regulation of human hepatic hydroxysteroid sulfotransferase (SULT2A1) gene transcription by rifampicin: roles of hepatocyte nuclear factor 4alpha and pregnane X receptor. J Pharmacol Exp Ther, 323: 586–598 (2007). Gonzalez, F. J.: Animal models for human risk assessment: the peroxisome proliferator-activated receptor alpha-humanized mouse. Nutr Rev, 65: S2–6 (2007). Shin, M., Sano, K. and Umezawa, C.: Effects of peroxisomeproliferators on the TRP-NAD pathway. Adv Exp Med Biol, 467: 333–340 (1999). Shin, M., Kim, I., Inoue, Y., Kimura, S. and Gonzalez, F. J.: Regulation of mouse hepatic alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase, a key enzyme in the tryptophan-nicotinamide adenine dinucleotide pathway, by hepatocyte nuclear factor 4alpha and peroxisome proliferator-activated receptor alpha. Mol Pharmacol, 70: 1281–1290 (2006). Pineda Torra, I., Jamshidi, Y., Flavell, D. M., Fruchart, J. C. and Staels, B.: Characterization of the human PPARalpha promoter: identification of a functional nuclear receptor response element. Mol Endocrinol, 16: 1013–1028 (2002). Weigel, N. L. and Moore, N. L.: Steroid receptor phosphorylation: a key modulator of multiple receptor functions. Mol Endocrinol, 21: 2311–2319 (2007). Bour, G., Lalevee, S. and Rochette-Egly, C.: Protein kinases and the proteasome join in the combinatorial control of transcription by nuclear retinoic acid receptors. Trends Cell Biol, 17: 302–309 (2007). Viollet, B., Kahn, A. and Raymondjean, M.: Protein kinase Adependent phosphorylation modulates DNA-binding activity of hepatocyte nuclear factor 4. Mol Cell Biol, 17: 4208–4219 (1997). Reddy, S., Yang, W., Taylor, D. G., Shen, X., Oxender, D., Kust, G. and Leff, T.: Mitogen-activated protein kinase regulates transcription of the ApoCIII gene. Involvement of the orphan nuclear receptor HNF4. J Biol Chem, 274: 33050–33056 (1999). Leclerc, I., Lenzner, C., Gourdon, L., Vaulont, S., Kahn, A. and Viollet, B.: Hepatocyte nuclear factor-4alpha involved in type 1 maturity-onset diabetes of the young is a novel target of AMP-ac-

Regulation of HNF4a

40)

41)

42)

43)

44)

45)

46)

tivated protein kinase. Diabetes, 50: 1515–1521 (2001). Hong, Y. H., Varanasi, U. S., Yang, W. and Leff, T.: AMP-activated protein kinase regulates HNF4alpha transcriptional activity by inhibiting dimer formation and decreasing protein stability. J Biol Chem, 278: 27495–27501 (2003). Jahan, A. and Chiang, J. Y.: Cytokine regulation of human sterol 12alpha-hydroxylase (CYP8B1) gene. Am J Physiol Gastrointest Liver Physiol, 288: G685–695 (2005). Guo, H., Gao, C., Mi, Z., Zhang, J. and Kuo, P. C.: Characterization of the PC4 binding domain and its interactions with HNF4alpha. J Biochem (Tokyo), 141: 635–640 (2007). Sun, K., Montana, V., Chellappa, K., Brelivet, Y., Moras, D., Maeda, Y., Parpura, V., Paschal, B. M. and Sladek, F. M.: Phosphorylation of a conserved serine in the deoxyribonucleic acid binding domain of nuclear receptors alters intracellular localization. Mol Endocrinol, 21: 1297–1311 (2007). Rhee, J., Inoue, Y., Yoon, J. C., Puigserver, P., Fan, M., Gonzalez, F. J. and Spiegelman, B. M.: Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis. Proc Natl Acad Sci USA, 100: 4012–4017 (2003). Yoon, J. C., Puigserver, P., Chen, G., Donovan, J., Wu, Z., Rhee, J., Adelmant, G., Stafford, J., Kahn, C. R., Granner, D. K., Newgard, C. B. and Spiegelman, B. M.: Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature, 413: 131–138 (2001). Lin, J., Puigserver, P., Donovan, J., Tarr, P. and Spiegelman, B. M.: Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta ), a novel PGC-1-related transcription coactivator associated with host cell factor. J Biol Chem, 277:

47)

48)

49)

50)

51)

52)

7

1645–1648 (2002). Finck, B. N. and Kelly, D. P.: PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest, 116: 615–622 (2006). Ding, X., Lichti, K., Kim, I., Gonzalez, F. J. and Staudinger, J. L.: Regulation of constitutive androstane receptor and its target genes by fasting, cAMP, hepatocyte nuclear factor alpha, and the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha. J Biol Chem, 281: 26540–26551 (2006). Bhalla, S., Ozalp, C., Fang, S., Xiang, L. and Kemper, J. K.: Ligand-activated pregnane X receptor interferes with HNF-4 signaling by targeting a common coactivator PGC-1alpha. Functional implications in hepatic cholesterol and glucose metabolism. J Biol Chem, 279: 45139–45147 (2004). Arceci, R. J., King, A. A., Simon, M. C., Orkin, S. H. and Wilson, D. B.: Mouse GATA-4: a retinoic acid-inducible GATAbinding transcription factor expressed in endodermally derived tissues and heart. Mol Cell Biol, 13: 2235–2246 (1993). Sumi, K., Tanaka, T., Uchida, A., Magoori, K., Urashima, Y., Ohashi, R., Ohguchi, H., Okamura, M., Kudo, H., Daigo, K., Maejima, T., Kojima, N., Sakakibara, I., Jiang, S., Hasegawa, G., Kim, I., Osborne, T. F., Naito, M., Gonzalez, F. J., Hamakubo, T., Kodama, T. and Sakai, J.: Cooperative interaction between hepatocyte nuclear factor 4 alpha and GATA transcription factors regulates ATP-binding cassette sterol transporters ABCG5 and ABCG8. Mol Cell Biol, 27: 4248–4260 (2007). Hwang-Verslues, W. W. and Sladek, F. M.: Nuclear Receptor alphat 1 Competes with Oncoprotein c-Myc for Control HNF4s of the p21/WAF1 Promoter. Mol Endocrinol, 22: 78–90 (2008).