Hepatocyte Nuclear Factor-4 (cid:1) Regulates the Human Apolipoprotein AV Gene: Identification of a Novel Response Element and Involvement in the Control by Peroxisome Proliferator-Activated Receptor- (cid:2) Coactivator-1 (cid:1) , AMP-Activated Protein Kinase, and Mitogen-Activated Protein Kinase

The recently discovered apolipoprotein AV (apoAV) gene has been reported to be a key player in mod-ulating plasma triglyceride levels. Here we identify the hepatocyte nuclear factor-4 (cid:1) (HNF-4 (cid:1) ) as a novel regulator of human apoAV gene. Inhibition of HNF-4 (cid:1) expression by small interfering RNA resulted in down-regulation of apoAV. Deletion, mutagenesis, and binding assays revealed that HNF-4 (cid:1) directly regulates human apoAV promoter through DR1 [a direct repeat separated by one nucleotide (nt)], and via a novel element for HNF-4 (cid:1) consisting of an inverted repeat separated by 8 nt (IR8). In addition, we show that the coactivator peroxisome proliferator-activated receptor- (cid:2) coactivator-1 (cid:1) was capable of stimulating the HNF-4 (cid:1) -dependent transactivation of apoAV promoter. Furthermore, analyses in human hepatic cells demonstrated that AMP-activated protein kinase (AMPK) and the MAPK signaling pathway regulate human apoAV expression and suggested that this regulation may be mediated, at least in part, by changes in HNF-4 (cid:1)

[1]  E. Park,et al.  Peroxisomal Proliferator-activated Receptor-γ Coactivator-1α (PGC-1α) Enhances the Thyroid Hormone Induction of Carnitine Palmitoyltransferase I (CPT-Iα)* , 2004, Journal of Biological Chemistry.

[2]  R. Sato,et al.  Bile Acid Reduces the Secretion of Very Low Density Lipoprotein by Repressing Microsomal Triglyceride Transfer Protein Gene Expression Mediated by Hepatocyte Nuclear Factor-4* , 2004, Journal of Biological Chemistry.

[3]  L. Pennacchio,et al.  The Liver X Receptor Ligand T0901317 Down-regulates APOA5 Gene Expression through Activation of SREBP-1c* , 2004, Journal of Biological Chemistry.

[4]  P. Duchateau,et al.  Apolipoproteins A-IV and A-V are acute-phase proteins in mouse HDL. , 2004, Atherosclerosis.

[5]  K. V. van Dijk,et al.  ApoAV Reduces Plasma Triglycerides by Inhibiting Very Low Density Lipoprotein-Triglyceride (VLDL-TG) Production and Stimulating Lipoprotein Lipase-mediated VLDL-TG Hydrolysis* , 2004, Journal of Biological Chemistry.

[6]  L. Pennacchio,et al.  Analysis of Apolipoprotein A5, C3, and Plasma Triglyceride Concentrations in Genetically Engineered Mice , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[7]  S. Shoelson,et al.  Structural Basis for HNF-4α Activation by Ligand and Coactivator Binding* , 2004, Journal of Biological Chemistry.

[8]  Sander M Houten,et al.  Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. , 2004, The Journal of clinical investigation.

[9]  Nicola J. Rinaldi,et al.  Control of Pancreas and Liver Gene Expression by HNF Transcription Factors , 2004, Science.

[10]  P. Edwards,et al.  Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) regulates triglyceride metabolism by activation of the nuclear receptor FXR , 2004 .

[11]  T. Osborne,et al.  PGC-1α Activates CYP7A1 and Bile Acid Biosynthesis* , 2003, Journal of Biological Chemistry.

[12]  X. Adiconis,et al.  The APOA5 locus is a strong determinant of plasma triglyceride concentrations across ethnic groups in Singapore Published, JLR Papers in Press, September 1, 2003. DOI 10.1194/jlr.M300251-JLR200 , 2003, Journal of Lipid Research.

[13]  F. Gonzalez,et al.  Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression. , 2003, Gastroenterology.

[14]  Yu Hong,et al.  AMP-activated Protein Kinase Regulates HNF4α Transcriptional Activity by Inhibiting Dimer Formation and Decreasing Protein Stability* , 2003, Journal of Biological Chemistry.

[15]  X. Prieur,et al.  The Human Apolipoprotein AV Gene Is Regulated by Peroxisome Proliferator-activated Receptor-α and Contains a Novel Farnesoid X-activated Receptor Response Element* , 2003, Journal of Biological Chemistry.

[16]  F. Gonzalez,et al.  Role of the hepatocyte nuclear factor 4α in control of the pregnane X receptor during fetal liver development , 2003, Hepatology.

[17]  L. Pennacchio,et al.  Apolipoprotein A5, a Crucial Determinant of Plasma Triglyceride Levels, Is Highly Responsive to Peroxisome Proliferator-activated Receptor α Activators* , 2003, The Journal of Biological Chemistry.

[18]  P. Puigserver,et al.  Regulation of hepatic fasting response by PPARγ coactivator-1α (PGC-1): Requirement for hepatocyte nuclear factor 4α in gluconeogenesis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Jonathan C. Cohen,et al.  Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels. , 2002, Human molecular genetics.

[20]  F. Gonzalez,et al.  The Coactivator PGC-1 Is Involved in the Regulation of the Liver Carnitine Palmitoyltransferase I Gene Expression by cAMP in Combination with HNF4α and cAMP-response Element-binding Protein (CREB)* , 2002, The Journal of Biological Chemistry.

[21]  R. Chamuleau,et al.  Adenoviral overexpression of apolipoprotein A-V reduces serum levels of triglycerides and cholesterol in mice. , 2002, Biochemical and biophysical research communications.

[22]  J. Bar-Tana,et al.  Ligand Specificity and Conformational Dependence of the Hepatic Nuclear Factor-4α (HNF-4α)* , 2002, The Journal of Biological Chemistry.

[23]  H. Moriwaki,et al.  Analysis of Gene Expression Profile Induced by Hepatocyte Nuclear Factor 4α in Hepatoma Cells Using an Oligonucleotide Microarray* , 2002, The Journal of Biological Chemistry.

[24]  F. Sladek,et al.  Competitive Cofactor Recruitment by Orphan Receptor Hepatocyte Nuclear Factor 4α1: Modulation by the F Domain , 2002, Molecular and Cellular Biology.

[25]  F. Sladek,et al.  Lipopolysaccharide results in a marked decrease in hepatocyte nuclear factor 4α in rat liver , 2001 .

[26]  Jonathan C. Cohen,et al.  An Apolipoprotein Influencing Triglycerides in Humans and Mice Revealed by Comparative Sequencing , 2001, Science.

[27]  Guillaume Adelmant,et al.  Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1 , 2001, Nature.

[28]  B. Viollet,et al.  Hepatocyte Nuclear Factor-4α Involved in Type 1 Maturity-Onset Diabetes of the Young Is a Novel Target of AMP-Activated Protein Kinase , 2001 .

[29]  D. Kardassis,et al.  Transcriptional regulatory mechanisms of the human apolipoprotein genes in vitro and in vivo , 2001, Current opinion in lipidology.

[30]  T. Leff.  AMP-activated protein kinase regulates gene expression by direct phosphorylation of nuclear proteins. , 2001, Biochemical Society transactions.

[31]  Jerrold M. Ward,et al.  Hepatocyte Nuclear Factor 4α (Nuclear Receptor 2A1) Is Essential for Maintenance of Hepatic Gene Expression and Lipid Homeostasis , 2001, Molecular and Cellular Biology.

[32]  P. Cullen.  Evidence that triglycerides are an independent coronary heart disease risk factor. , 2000, The American journal of cardiology.

[33]  F. Cohen,et al.  Analysis of protein dimerization and ligand binding of orphan receptor HNF4alpha. , 2000, Journal of molecular biology.

[34]  M. Stoffel,et al.  Genotype/phenotype relationships in HNF-4alpha/MODY1: haploinsufficiency is associated with reduced apolipoprotein (AII), apolipoprotein (CIII), lipoprotein(a), and triglyceride levels. , 2000, Diabetes.

[35]  Rick B. Vega,et al.  The Coactivator PGC-1 Cooperates with Peroxisome Proliferator-Activated Receptor α in Transcriptional Control of Nuclear Genes Encoding Mitochondrial Fatty Acid Oxidation Enzymes , 2000, Molecular and Cellular Biology.

[36]  S. Duncan,et al.  Mammalian hepatocyte differentiation requires the transcription factor HNF-4alpha. , 2000, Genes & development.

[37]  L. Groop,et al.  Mutation in the HNF-4alpha gene affects insulin secretion and triglyceride metabolism. , 1999, Diabetes.

[38]  K. Mehta,et al.  Differential Roles of Extracellular Signal-regulated Kinase-1/2 and p38MAPK in Interleukin-1β- and Tumor Necrosis Factor-α-induced Low Density Lipoprotein Receptor Expression in HepG2 Cells* , 1998, The Journal of Biological Chemistry.

[39]  M. Briggs,et al.  DNA binding and transcription activation specificity of hepatocyte nuclear factor 4. , 1998, Nucleic acids research.

[40]  H. Nakshatri,et al.  Multiple parameters determine the specificity of transcriptional response by nuclear receptors HNF-4, ARP-1, PPAR, RAR and RXR through common response elements. , 1998, Nucleic acids research.

[41]  F. Hegardt,et al.  The hepatocyte nuclear factor 4 (HNF-4) represses the mitochondrial HMG-CoA synthase gene. , 1998, Biochemical and biophysical research communications.

[42]  A. Kumar,et al.  Phorbol ester-induced low density lipoprotein receptor gene expression in HepG2 cells involves protein kinase C-mediated p42/44 MAP kinase activation. , 1997, Journal of lipid research.

[43]  M. Briggs,et al.  Utilization of Recombinant Adenovirus and Dominant Negative Mutants to Characterize Hepatocyte Nuclear Factor 4-regulated Apolipoprotein AI and CIII Expression* , 1997, The Journal of Biological Chemistry.

[44]  N. Wong,et al.  Hepatocyte nuclear factor 4 inhibits the activity of site A from the rat apolipoprotein AI gene. , 1997, Biochemistry.

[45]  S. Malik,et al.  Control of Apolipoprotein AI Gene Expression through Synergistic Interactions between Hepatocyte Nuclear Factors 3 and 4* , 1996, The Journal of Biological Chemistry.

[46]  G. Ryffel,et al.  Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes , 1996, Molecular and cellular biology.

[47]  F. Sladek,et al.  Exclusive homodimerization of the orphan receptor hepatocyte nuclear factor 4 defines a new subclass of nuclear receptors , 1995, Molecular and cellular biology.

[48]  A. Bridges,et al.  A synthetic inhibitor of the mitogen-activated protein kinase cascade. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[49]  D. Hardie,et al.  5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? , 1995, European journal of biochemistry.

[50]  G. Gil-Gómez,et al.  Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids. , 1994, The Journal of biological chemistry.

[51]  D. Moore,et al.  A pleiotropic element in the medium-chain acyl coenzyme A dehydrogenase gene promoter mediates transcriptional regulation by multiple nuclear receptor transcription factors and defines novel receptor-DNA binding motifs , 1994, Molecular and cellular biology.

[52]  N. Wong,et al.  HNF-4 increases activity of the rat Apo A1 gene. , 1993, Nucleic acids research.

[53]  G. Ginsburg,et al.  Antagonism between apolipoprotein AI regulatory protein 1, Ear3/COUP-TF, and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells , 1992, Molecular and cellular biology.

[54]  N. Andrews,et al.  A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. , 1991, Nucleic acids research.

[55]  J. Darnell,et al.  Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. , 1990, Genes & development.

[56]  J. Bar-Tana,et al.  Ligand specificity and conformational dependence of the hepatic nuclear factor-4alpha (HNF-4alpha ). , 2002, The Journal of biological chemistry.

[57]  P. Reitsma,et al.  Apolipoprotein A-V A NOVEL APOLIPOPROTEIN ASSOCIATED WITH AN EARLY PHASE OF LIVER REGENERATION* , 2001 .

[58]  古田 浩人.  Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1) , 1999 .

[59]  M. Stoffel,et al.  Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1) , 1996, Nature.