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PPAR? via HNF4? regulates the expression of genes encoding hepatic amino acid catabolizing enzymes to maintain metabolic homeostasis.

ABSTRACT: The liver is the main organ involved in the metabolism of amino acids (AA), which are oxidized by amino acid catabolizing enzymes (AACE). Peroxisome proliferator-activated receptor-? (PPAR?) stimulates fatty acid ?-oxidation, and there is evidence that it can modulate hepatic AA oxidation during the transition of energy fuels. To understand the role and mechanism of PPAR?'s regulation of AA catabolism, the metabolic and molecular adaptations of Ppara-null mice were studied. The role of PPAR? on AA metabolism was examined by in vitro and in vivo studies. In wild-type and Ppara-null mice, fed increasing concentrations of the dietary protein/carbohydrate ratio, we measured metabolic parameters, and livers were analyzed by microarray analysis, histology and Western blot. Functional enrichment analysis, EMSA and gene reporter assays were performed. Ppara-null mice presented increased expression of AACE in liver affecting AA, lipid and carbohydrate metabolism. Ppara-null mice had increased glucagon/insulin ratio (7.2-fold), higher serum urea (73.1 %), lower body protein content (19.7 %) and decreased several serum AA in response to a high-protein/low-carbohydrate diet. A functional network of differentially expressed genes, suggested that changes in the expression of AACE were regulated by an interrelationship between PPAR? and HNF4?. Our data indicated that the expression of AACE is down-regulated through PPAR? by attenuating HNF4? transcriptional activity as observed in the serine dehydratase gene promoter. PPAR? via HNF4? maintains body protein metabolic homeostasis by down-regulating genes involved in amino acid catabolism for preserving body nitrogen.

SUBMITTER: Contreras AV

PROVIDER: S-EPMC4288992 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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PPARα via HNF4α regulates the expression of genes encoding hepatic amino acid catabolizing enzymes to maintain metabolic homeostasis.

Contreras Alejandra V AV Rangel-Escareño Claudia C Torres Nimbe N Alemán-Escondrillas Gabriela G Ortiz Victor V Noriega Lilia G LG Torre-Villalvazo Ivan I Granados Omar O Velázquez-Villegas Laura A LA Tobon-Cornejo Sandra S González-Hirschfeld Diana D Recillas-Targa Félix F Tejero-Barrera Elizabeth E Gonzalez Frank J FJ Tovar Armando R AR

Genes & nutrition 20150110 2

The liver is the main organ involved in the metabolism of amino acids (AA), which are oxidized by amino acid catabolizing enzymes (AACE). Peroxisome proliferator-activated receptor-α (PPARα) stimulates fatty acid β-oxidation, and there is evidence that it can modulate hepatic AA oxidation during the transition of energy fuels. To understand the role and mechanism of PPARα's regulation of AA catabolism, the metabolic and molecular adaptations of Ppara-null mice were studied. The role of PPARα on ...[more]

PMID: 25576393

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Project description:Although they are expandable in vitro, hepatic progenitors are immature cells and share many immunomarkers with hepatocellular carcinoma, raising potential concerns regarding maltransformation after transplantation. This study investigated the effects of hepatic nuclear factor (HNF) 4α on the proliferation, migration, and maltransformation of hepatic progenitors and determined the feasibility of using these manipulated cells for transplantation.The effects of HNF4α on rat hepatic progenitors (i.e. hepatic oval cells) were analyzed by HNF4α overexpression and HNF4α shRNA. Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice injured by carbon chloride (CCl4) were then transplanted with control, HNF4α-overexpressing or HNF4α-suppressing hepatic oval cells. Finally, the engraftment of these cells in the recipient liver was analyzed.Rat hepatic progenitors (i.e. hepatic oval cells) expressed HNF4α, although less than that in hepatocytes. When HNF4α was overexpressed in these cells, the proliferation and migration of hepatic oval cells were reduced; but when HNF4α was suppressed by shRNA, the proliferation and migration, and even anchorage-independent growth, of these cells were accelerated. RNA microarray and gene functional analysis revealed that suppressing HNF4α not only impaired many biosynthesis and metabolism pathways of hepatocytes but also increased pathways for cancer. When transplanted into CCl4-injured NOD/SCID mice, few HNF4α-suppressing hepatic oval cells localized into the liver, while control cells and HNF4α-overexpressing cells engrafted into the liver and differentiated into albumin-positive hepatocytes. Interestingly, the hepatocytes derived from HNF4α-overexpressing cells were less migrative and expressed less c-Myc than the cells derived from control cells.HNF4α constrains proliferation, migration, and maltransformation of hepatic progenitors, and HNF4α-overexpressing hepatic progenitors serve as an optimal candidate for cell transplantation.

Dataset Information

PPAR? via HNF4? regulates the expression of genes encoding hepatic amino acid catabolizing enzymes to maintain metabolic homeostasis.

Publications

PPARα via HNF4α regulates the expression of genes encoding hepatic amino acid catabolizing enzymes to maintain metabolic homeostasis.

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