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Insulin Regulates Retinol Dehydrogenase Expression and All-trans-retinoic Acid Biosynthesis through FoxO1*

  • Kristin M. Obrochta
    Affiliations
    Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, University of California, Berkeley, California 94720
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  • Charles R. Krois
    Affiliations
    Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, University of California, Berkeley, California 94720
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  • Benito Campos
    Footnotes
    Affiliations
    Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, University of California, Berkeley, California 94720
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  • Joseph L. Napoli
    Correspondence
    To whom correspondence should be addressed. Tel.: 510-642-5202; Fax: 510-642-0535;
    Affiliations
    Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, University of California, Berkeley, California 94720
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  • Author Footnotes
    * This work was supported, in whole or in part, by National Institutes of Health Grants DK090522 and AA017927 (to J. L. N.).
    1 Present address: Dept. of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
Open AccessPublished:January 27, 2015DOI:https://doi.org/10.1074/jbc.M114.609313
      All-trans-retinoic acid (atRA), an autacoid derived from retinol (vitamin A), regulates energy balance and reduces adiposity. We show that energy status regulates atRA biosynthesis at the rate-limiting step, catalyzed by retinol dehydrogenases (RDH). Six h after re-feeding, Rdh1 expression decreased 80–90% in liver and brown adipose tissue and Rdh10 expression was decreased 45–63% in liver, pancreas, and kidney, all relative to mice fasted 16 h. atRA in the liver was decreased 44% 3 h after reduced Rdh expression. Oral gavage with glucose or injection with insulin decreased Rdh1 and Rdh10 mRNA 50% or greater in mouse liver. Removing serum from the medium of the human hepatoma cell line HepG2 increased Rdh10 and Rdh16 (human Rdh1 ortholog) mRNA expression 2–3-fold by 4 h, by increasing transcription and stabilizing mRNA. Insulin decreased Rdh10 and Rdh16 mRNA in HepG2 cells incubated in serum-free medium by inhibiting transcription and destabilizing mRNA. Insulin action required PI3K and Akt, which suppress FoxO1. Serum removal increased atRA biosynthesis 4-fold from retinol in HepG2 cells, whereas dominant-negative FoxO1 prevented the increase. Thus, energy status via insulin and FoxO1 regulate Rdh expression and atRA biosynthesis. These results reveal mechanisms for regulating atRA biosynthesis and the opposing effects of atRA and insulin on gluconeogenesis, and also suggest an interaction between atRA and insulin signaling related diseases, such as type II diabetes and cancer.

      Introduction

      A wide scope of biological processes, including embryonic development, cell differentiation and proliferation, immune function, neurogenesis, and energy metabolism, depend on the vitamin A (retinol) metabolite all-trans-retinoic acid (atRA)
      The abbreviations used are: atRA
      all-trans-retinoic acid
      ActD
      actinomycin D
      CHX
      cycloheximide
      dnFoxO1
      dominant-negative FoxO
      FoxO1
      forkhead box other 1
      RDH
      retinol dehydrogenase
      DHRS3
      dehydrogenase reductase 3
      mTORC1
      mammalian target of rapamycin complex 1
      Glc-6-P
      glucose-6-phosphatase
      G6pc
      glucose-6-phosphatase
      qPCR
      quantitative PCR.
      (
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      ). atRA functions through nuclear hormone receptors RARα, -β, and -γ and peroxisome proliferator-activated receptor δ, which affect transcription and translation (
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      ). Genes regulated by atRA through nuclear receptors include: Pck1, which expresses phosphoenolpyruvate carboxykinase, the enzyme that catalyzes the committed step in gluconeogenesis (
      • Sugiyama T.
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      Structural requirements of the glucocorticoid and retinoic acid response units in the phosphoenolpyruvate carboxykinase gene promoter.
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      Induction of uncoupling protein-1 in mouse embryonic fibroblast-derived adipocytes by retinoic acid.
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      The one-two punch: retinoic acid suppresses obesity both by promoting energy expenditure and by inhibiting adipogenesis.
      ). Despite the impact of atRA on energy balance, little is known about whether energy balance might regulate atRA homeostasis.
      Two successive dehydrogenations produce atRA from retinol (
      • Napoli J.L.
      Physiological insights into all-trans-retinoic acid biosynthesis.
      ). During limited or normal vitamin A nutriture, retinol dehydrogenases (RDH) of the short-chain dehydrogenase/reductase gene family catalyze the first and rate-limiting reaction to produce all-trans-retinal. Retinal dehydrogenases, of the aldehyde dehydrogenase gene family, catalyze the second reaction to produce atRA. Multiple isoforms of retinoid-metabolizing enzymes occur in both families, often in the same cell types, but these enzymes differ in subcellular expression loci, and can show differential cell expression patterns. RDH1 and RDH10 are the most characterized RDH in the path of atRA biosynthesis: both are expressed early in embryogenesis and throughout life in multiple tissues, and both contribute to atRA biosynthesis from retinol in intact cells in the presence of retinal dehydrogenases (
      • Zhang M.
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      ). Dehydrogenase reductase 3 (DHRS3) functions as a retinal reductase, which interacts with RDH10 to control retinoid homeostasis (
      • Adams M.K.
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      • Wu L.
      • Kedishvili N.Y.
      The retinaldehyde reductase activity of DHRS3 is reciprocally activated by retinol dehydrogenase 10 to control retinoid homeostasis.
      ). Rdh1-null mice are born in Mendelian frequency, but experience increased weight and adiposity, which is prevented by feeding copious vitamin A (
      • Zhang M.
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      • Kane M.A.
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      Altered vitamin A homeostasis and increased size and adiposity in the rdh1-null mouse.
      ). In contrast, most Rdh10-null mice die by embryonic day 12.5, but can be rescued by maternal administration of retinoids (
      • Rhinn M.
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      Involvement of retinol dehydrogenase 10 in embryonic patterning and rescue of its loss of function by maternal retinaldehyde treatment.
      ). Notably, like Rdh1-null mice, Rdh10-null mice do not exhibit total atRA deficiency, suggesting complementary actions of the two and/or occurrence of additional RDH.
      Liver exerts a central function in maintaining whole body metabolic homeostasis (
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      ). During feeding, liver catalyzes increased energy storage by generating glycogen and triacylglycerol. During fasting, liver generates glucose and ketone bodies from gluconeogenesis, glycogenolysis, and fatty acid oxidation. Glucose, insulin, and glucagon control the balance between energy storage during feeding and production of fuels during fasting.
      A combination of portal vein glucose, insulin, and neuronal signal(s) causes liver to transition from catabolic to anabolic metabolism (
      • Moore M.C.
      • Coate K.C.
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      • An Z.
      • Cherrington A.D.
      Regulation of hepatic glucose uptake and storage in vivo.
      ). Insulin binding to its cell surface receptors activates two canonical pathways in hepatocytes: the mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K). The mitogen-activated protein kinase pathway includes extracellular-signal regulated kinase (ERK) signaling and regulates transcription involved in differentiation, growth, and survival (
      • Tobe K.
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      ). The PI3K pathway activates Akt (PKB) to mediate metabolic transitions, including promotion of glycogen and lipid synthesis, and suppression of gluconeogenesis. Effectors downstream of PI3K/Akt include: glycogen synthase kinase-3 (GSK-3), which regulates glycogen synthesis; mammalian target of rapamycin complex 1 (mTORC1), which regulates protein synthesis; BCL2-associated agonist of cell death (BAD), which regulates cell survival; and forkhead box other (FoxO), which regulates transcription of genes required for gluconeogenesis, including glucose-6-phosphatase (Glc-6-P) (
      • Siddle K.
      Signalling by insulin and IGF receptors: supporting acts and new players.
      ,
      • Vander Kooi B.T.
      • Streeper R.S.
      • Svitek C.A.
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      • Powell D.R.
      • O'Brien R.M.
      The three insulin response sequences in the glucose-6-phosphatase catalytic subunit gene promoter are functionally distinct.
      ).
      This report compares Rdh1 and Rdh10 expression in tissues of fasted versus re-fed mice, and focuses on atRA in liver. Liver served as the focus of this study because of its central contributions to both energy and retinoid homeostasis. We found that insulin, via inactivating FoxO1, represses Rdh1 and Rdh10 expression, with an associated decrease in atRA biosynthesis. These observations are consistent with the recent analysis that FoxO1 may link gluconeogenesis to retinoid homeostasis (
      • Shin D.-J.
      • Joshi P.
      • Hong S.-H.
      • Mosure K.
      • Shin D.-G.
      • Osborne T.F.
      Genome-wide analysis of FoxO1 binding in hepatic chromatin: potential involvement of FoxO1 in linking retinoid signaling to hepatic gluconeogenesis.
      ). Our results provide direct evidence showing that energy status regulates atRA biosynthesis, and provides new insight into the relationship between atRA biosynthesis and its regulation of energy balance.

      DISCUSSION

      A vitamin A-deficient diet results in glycogen deficiency because of impaired gluconeogenesis, caused by low Pck1 expression (
      • Wolf G.
      • Wagle S.R.
      • Lane M.D.
      • Johnson B.C.
      Studies on the function of vitamin A in metabolism by the use of radioactive metabolic intermediates.
      ,
      • Lucas P.C.
      • O'Brien R.M.
      • Mitchell J.A.
      • Davis C.M.
      • Imai E.
      • Forman B.M.
      • Samuels H.H.
      • Granner D.K.
      A retinoic acid response element is part of a pleiotropic domain in the phosphoenolpyruvate carboxykinase gene.
      • Scott D.K.
      • Mitchell J.A.
      • Granner D.K.
      Identification and charaterization of the second retinoic acid response element in the phosphoenolpyruvate carboxykinase gene promoter.
      ). Stimulation of gluconeogenesis is mediated directly by the vitamin A metabolite atRA through RA receptor response elements in the key gluconeogenic gene Pck1 (
      • Wolf G.
      • Wagle S.R.
      • Lane M.D.
      • Johnson B.C.
      Studies on the function of vitamin A in metabolism by the use of radioactive metabolic intermediates.
      ,
      • Lucas P.C.
      • O'Brien R.M.
      • Mitchell J.A.
      • Davis C.M.
      • Imai E.
      • Forman B.M.
      • Samuels H.H.
      • Granner D.K.
      A retinoic acid response element is part of a pleiotropic domain in the phosphoenolpyruvate carboxykinase gene.
      ). Here we demonstrate reciprocal regulation by energy status of Rdh mRNA and atRA concentrations via insulin effects on FoxO1. Fasting-induced coordinate induction of both Rdh and Pck1 by FoxO1 stimulates gluconeogenesis (Fig. 8). In the fed state, insulin repression of FoxO1 suppresses gluconeogenesis via repressing both Rdh and Pck1. Although serum factor(s) other than insulin control Rdh expression and mRNA stability, we focused on insulin because of its critical role in regulating gluconeogenesis (
      • Shin D.-J.
      • Odom D.P.
      • Scribner K.B.
      • Ghoshal S.
      • McGrane M.M.
      Retinoid regulation of the phosphoenolpyruvate carboxykinase gene in liver.
      ,
      • Kido Y.
      • Nakae J.
      • Accili D.
      Clinical review 125: the insulin receptor and its cellular targets.
      ).
      Figure thumbnail gr8
      FIGURE 8Regulation of Rdh expression by insulin signaling. Both atRA and FoxO1 induce Pck1 transcription to increase gluconeogenesis. FoxO1 induces atRA biosynthesis by inducing Rdh mRNA. Insulin suppresses FoxO1 activity, thereby suppressing gluconeogenesis and atRA biosynthesis through decreasing Rdh transcription and mRNA stability. Activation of PI3K/Akt represents a molecular indicator of cancer, implicating decreased atRA.
      Tissue-specific changes in Rdh10 and Rdh1 expression during fasting and re-feeding are consistent with a complex contribution of atRA to regulating intermediary metabolism. Epididymal white adipose tissue and pancreata do not express Rdh1 (data not shown), but express Rdh10. The non-responsiveness of Rdh10 in epididymal white adipose tissue to changes in energy balance allows several interpretations, including the presence of another Rdh that responds to changes in energy status, or feeding versus fasting does not modify atRA epididymal white adipose tissue concentrations in adult mice. These possibilities are the subjects of ongoing studies. The decrease in Rdh10 expression in pancreas during re-feeding is consistent with the requirement for retinoids in pancreatic development (
      • Martín M.
      • Gallego-Llamas J.
      • Ribes V.
      • Kedinger M.
      • Niederreither K.
      • Chambon P.
      • Dollé P.
      • Gradwohl G.
      Dorsal pancreas agenesis in retinoic acid-deficient Raldh2 mutant mice.
      ,
      • Pérez R.J.
      • Benoit Y.D.
      • Gudas L.J.
      Deletion of retinoic acid receptor β (RARβ) impairs pancreatic endocrine differentiation.
      ) and function (
      • Chertow B.S.
      • Blaner W.S.
      • Baranetsky N.G.
      • Sivitz W.I.
      • Cordle M.B.
      • Thompson D.
      • Meda P.
      Effects of vitamin A deficiency and repletion on rat insulin secretion in vivo and in vitro from isolated islets.
      ,
      • Zhao S.
      • Li R.
      • Li Y.
      • Chen W.
      • Zhang Y.
      • Chen G.
      Roles of vitamin A status and retinoids in glucose and fatty acid metabolism.
      ), and also a subject of ongoing studies. Suppression of Rdh1 in liver by re-feeding, and Rdh10 in liver and kidney, relate insulin action with atRA signaling in two gluconeogenic tissues. Decreased Dhrs3 expression in liver of re-fed versus fasted mice is consistent with a mutually activating interaction of Rdh10 and Dhrs3 (
      • Adams M.K.
      • Belyaeva O.V.
      • Wu L.
      • Kedishvili N.Y.
      The retinaldehyde reductase activity of DHRS3 is reciprocally activated by retinol dehydrogenase 10 to control retinoid homeostasis.
      ), and the reduction in atRA biosynthesis. Evidently, energy metabolism affects Rdh expression in multiple tissues to regulate retinoid signaling effects as feedback to regulation of energy disposition by atRA.
      Oral dosing has a singular effect on glucose uptake and insulin action in liver (
      • Moore M.C.
      • Coate K.C.
      • Winnick J.J.
      • An Z.
      • Cherrington A.D.
      Regulation of hepatic glucose uptake and storage in vivo.
      ). Glucose delivery by the portal vein combined with insulin, and an as yet unidentified neuronal signal, increases net hepatic glucose uptake compared with peripheral delivery, with a concomitant impact on insulin-regulated processes (
      • Ishida T.
      • Chap Z.
      • Chou J.
      • Lewis R.
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      Differential effects of oral, peripheral intravenous, and intraportal glucose on hepatic glucose uptake and insulin and glucagon extraction in conscious dogs.
      ,
      • Myers S.R.
      • Biggers D.W.
      • Neal D.W.
      • Cherrington A.D.
      Intraportal glucose delivery enhances the effects of hepatic glucose load on net hepatic glucose uptake in vivo.
      ). A comparison of oral glucose dosing to infusion via the portal vein revealed similar enhancement in hepatic glucose uptake relative to peripheral presentation, which excludes a contribution from a gut-secreted factor, such as Glp-1 (
      • Bergman R.N.
      • Beir J.R.
      • Hourigan P.M.
      Intraportal glucose infusion matched to oral glucose absorption: lack of evidence for “gut factor” involvement in hepatic glucose storage.
      ). Yet, secretion of Glp-1 upon feeding contributes to reduced glucose production in liver by augmenting glucose-stimulated insulin secretion from pancreas (
      • Ohlsson L.
      • Kohan A.B.
      • Tso P.
      • Ahrén B.
      GLP-1 released to the mesenteric lymph duct in mice: effects of glucose and fat.
      ). Our data of oral but not peripheral glucose dosing reducing Rdh mRNA are consistent with these observations and support the physiological significance of the observation.
      Reduced Rdh expression preceded the reduction in liver atRA, and was accompanied by a lower rate of atRA biosynthesis in HepG2 cells, consistent with a cause and effect relationship. atRA homeostasis autoregulates via induction of both catabolic cytochromes P-450 and the retinyl ester-forming lecithin:retinol acyltransferase (
      • Yamamoto Y.
      • Zolfaghari R.
      • Ross A.C.
      Regulation of CYP26 (cytochrome P450RAI) mRNA expression and retinoic acid metabolism by retinoids and dietary vitamin A in liver of mice and rats.
      ,
      • Ross A.C.
      • Cifelli C.J.
      • Zolfaghari R.
      • Li N.-Q.
      Multiple cytochrome P-450 genes are concomitantly regulated by vitamin A under steady-state conditions and by retinoic acid during hepatic first-pass metabolism.
      • Matsuura T.
      • Ross A.C.
      Regulation of hepatic lecithin:retinol acyltransferase activity by retinoic acid.
      ). The former decreases atRA itself, whereas the latter decreases the amount of retinol available to support atRA biosynthesis. Changes in lecithin:retinol acyltransferase and cytochrome P-450 may have buffered atRA differences in the re-fed relative to the fasted liver. The 2-fold decrease in liver atRA resulting from insulin action seems remarkable in the context of this impetus to sustain atRA homeostasis.
      FoxO (forkhead box “Other”) proteins constitute a subgroup of a family of evolutionarily conserved transcription factors that mediate insulin signaling in mammals, but also mediate metabolism and longevity in primitive organisms such as Caenorhabditis elegans and Drosophila (
      • Kousteni S.
      FoxO1, the transcriptional chief of staff of energy metabolism.
      ,
      • Barthel A.
      • Schmoll D.
      • Unterman T.G.
      FoxO proteins in insulin action and metabolism.
      ). FoxO proteins contribute to metabolic regulation through effects in liver, muscle, adipose tissue, and pancreas. Of these, FoxO1 stimulates a committed step in hepatic gluconeogenesis, catalyzed by phosphoenolpyruvate carboxykinase (PCK1), and also the last step catalyzed by glucose-6-phosphatase (Glc-6-P) (
      • Vander Kooi B.T.
      • Streeper R.S.
      • Svitek C.A.
      • Oeser J.K.
      • Powell D.R.
      • O'Brien R.M.
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      ,
      • Nakae J.
      • Kitamura T.
      • Silver D.L.
      • Accili D.
      The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression.
      ,
      • Hall R.K.
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      • O'Brien R.
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      ,
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      • Depinho R.A.
      • Accili D.
      Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver.
      ). Haploinsufficiency of FoxO1 restores insulin sensitivity in insulin-resistant mice (
      • Nakae J.
      • Biggs 3rd, W.H.
      • Kitamura T.
      • Cavenee W.K.
      • Wright C.V.
      • Arden K.C.
      • Accili D.
      Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1.
      ). A constitutively active gain-of-function FoxO1 mutant targeted to liver and pancreas manifests a diabetic phenotype (
      • Nakae J.
      • Biggs 3rd, W.H.
      • Kitamura T.
      • Cavenee W.K.
      • Wright C.V.
      • Arden K.C.
      • Accili D.
      Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1.
      ). Liver-specific inactivation results in decreased serum glucose at birth, and upon fasting in adult mice from impaired glycogenolysis and gluconeogenesis (
      • Matsumoto M.
      • Pocai A.
      • Rossetti L.
      • Depinho R.A.
      • Accili D.
      Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver.
      ). A liver-specific FoxO1-null mouse crossed with an insulin receptor-null mouse has reduced glucose production and lacks the neonatal diabetes and hepatosteatosis that occur in insulin receptor-null mice (
      • Matsumoto M.
      • Pocai A.
      • Rossetti L.
      • Depinho R.A.
      • Accili D.
      Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver.
      ). Liver-specific FoxO1-null mice treated with the β-cell toxin streptozotocin, have elevated VLDL secretion, cholesterol, and plasma-free fatty acids (
      • Haeusler R.A.
      • Han S.
      • Accili D.
      Hepatic FoxO1 ablation exacerbates lipid abnormalities during hyperglycemia.
      ).
      Insulin-stimulated phosphorylation of FoxO1 by Akt causes nuclear export, resulting in ubiquitination-mediated proteasomal degradation (
      • Matsuzaki H.
      • Daitoku H.
      • Hatta M.
      • Tanaka K.
      • Fukamizu A.
      Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation.
      ), and down-regulation of target gene transcription (
      • Nakae J.
      • Park B.C.
      • Accili D.
      Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway.
      ). Indeed, we confirmed the ability of insulin to cause nuclear export of FoxO1 in HepG2 cells (Fig. 4D). FoxO1 activity is also stimulated by deacetylation, catalyzed by sirtuin1 (
      • Schwer B.
      • Verdin E.
      Conserved metabolic regulatory functions of sirtuins.
      ). Inhibition of sirtuin1 in HepG2 cells with Ex-527 incubated in serum-free medium did not affect RDH10 expression (data not shown), indicating that acetylation is not involved in regulation of RDH10, at least under the conditions tested.
      Recent insight into the functions of insulin receptor substrates IRS1 and IRS2 indicate that both coordinate responses to insulin via FoxO1 (
      • Dong X.C.
      • Copps K.D.
      • Guo S.
      • Li Y.
      • Kollipara R.
      • DePinho R.A.
      • White M.F.
      Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation.
      ,
      • Kubota N.
      • Kubota T.
      • Itoh S.
      • Kumagai H.
      • Kozono H.
      • Takamoto I.
      • Mineyama T.
      • Ogata H.
      • Tokuyama K.
      • Ohsugi M.
      • Sasako T.
      • Moroi M.
      • Sugi K.
      • Kakuta S.
      • Iwakura Y.
      • Noda T.
      • Ohnishi S.
      • Nagai R.
      • Tobe K.
      • Terauchi Y.
      • Ueki K.
      • Kadowaki T.
      Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding.
      ). During the re-fed state, insulin activates IRS1 to suppress FoxO1 and allow an increase in glucokinase and sterol regulatory element-binding transcription factor 1 (SREBF1, a.k.a. SREBP1) expression that promotes glycolysis and lipid biosynthesis, respectfully. In contrast, insulin inhibits IRS2. Because IRS2 stimulates gluconeogenesis by inducing PCK1 and G6PC in liver through FoxO1, the relatively low levels of insulin in the fasted state allow IRS2 to induce gluconeogenesis. Based on these insights, the higher insulin levels in the re-fed state would function through IRS1 to suppress RDH expression, whereas the lower insulin levels in the fasted state would allow IRS2 to induce RDH expression.
      The actions of insulin and serum both prevented transcription and destabilized RDH mRNA. The effects differed in degree, and resulted in different levels of mRNA, but did not totally eliminate RDH mRNA. In both serum-free medium and insulin-containing serum-free medium, the amounts of RDH mRNA after 24 h remained 2–3-fold higher compared with serum-containing medium, because the initial concentrations were 2–3-fold higher. Destabilization of RDH mRNA by insulin depended on active PI3K, Akt, and inhibition of FoxO1. The reduction but not elimination of RDH mRNA by insulin and serum is compatible with the continued presence and biosynthesis of atRA, and a need for RDH to modulate basal gluconeogenesis and/or its other multiple functions, whether related or unrelated to energy balance, such as regulating proliferation (
      • Rossi E.
      • Picozzi P.
      • Bodega B.
      • Lavazza C.
      • Carlo-Stella C.
      • Marozzi A.
      • Ginelli E.
      Forced expression of RDH10 gene retards growth of HepG2 cells.
      ).
      FoxO1 binding sites have been identified in promoters of genes associated with retinoid metabolism, including dehydrogenase/reductase SDR family member 9 (Dhrs9), cellular retinol-binding protein type 1 (encoded by Rbp1), and Rdh8, but not in Rdh1 or Rdh10 (
      • Shin D.-J.
      • Joshi P.
      • Hong S.-H.
      • Mosure K.
      • Shin D.-G.
      • Osborne T.F.
      Genome-wide analysis of FoxO1 binding in hepatic chromatin: potential involvement of FoxO1 in linking retinoid signaling to hepatic gluconeogenesis.
      ). To address the impact of FoxO1-regulated expression of retinoid genes, atRA target genes Pck1 and Pdk4 were measured in cells with FoxO1 knocked down. Induction of both genes in response to atRA or to its precursor, retinol, were blunted. The dose (20 μm) of atRA used, however, exceeded those found in tissues by 400–4000-fold, and those used in vitro by 20-fold. Nevertheless, these results are also consistent with FoxO1 linking retinoid metabolism and hepatic gluconeogenesis. Multiple putative FoxO/A binding sites were found in the 5′-untranslated region of Rdh10 (Encyclopedia of DNA Elements Consortium, ENCODE; University of California Southern California genome browser). Future work will determine whether these or other sites are true response elements.
      Regulation by insulin signaling prompts the question whether abnormal RDH expression associates with human disease. For example, impaired insulin secretion and insulin resistance during diabetes predicts elevated RDH expression and atRA synthesis (
      • Lin H.V.
      • Accili D.
      Hormonal regulation of hepatic glucose production in health and disease.
      ). Conversely, enhancement of insulin signaling through PI3K/Akt from loss of phosphatase and tensin homolog deleted on chromosome 10 in cancer implicates decreased RDH (
      • Vogelstein B.
      • Papadopoulos N.
      • Velculescu V.E.
      • Zhou S.
      • Diaz Jr., L.A.
      • Kinzler K.W.
      Cancer genome landscapes.
      ). Reduced RDH expression would decrease atRA biosynthesis, which could affect tumor differentiation and/or aggressiveness. Various cancers show alterations in the atRA signaling pathway, such as loss of atRA receptors (
      • Chakravarti N.
      • Lotan R.
      • Diwan A.H.
      • Warneke C.L.
      • Johnson M.M.
      • Prieto V.G.
      Decreased expression of retinoid receptors in melanoma: entailment in tumorigenesis and prognosis.
      ,
      • Tanabe K.
      • Utsunomiya H.
      • Tamura M.
      • Niikura H.
      • Takano T.
      • Yoshinaga K.
      • Nagase S.
      • Suzuki T.
      • Ito K.
      • Matsumoto M.
      • Hayashi S.
      • Yaegashi N.
      Expression of retinoic acid receptors in human endometrial carcinoma.
      ) and down-regulation of atRA chaperons (
      • Calmon M.F.
      • Rodrigues R.V.
      • Kaneto C.M.
      • Moura R.P.
      • Silva S.D.
      • Mota L.D.
      • Pinheiro D.G.
      • Torres C.
      • de Carvalho A.F.
      • Cury P.M.
      • Nunes F.D.
      • Nishimoto I.N.
      • Soares F.A.
      • da Silva A.M.
      • Kowalski L.P.
      • Brentani H.
      • Zanelli C.F.
      • Silva Jr., W.A.
      • Rahal P.
      • Tajara E.H.
      • Carraro D.M.
      • Camargo A.A.
      • Valentini S.R.
      Epigenetic silencing of CRABP2 and MX1 in head and neck tumors.
      ,
      • Campos B.
      • Warta R.
      • Chaisaingmongkol J.
      • Geiselhart L.
      • Popanda O.
      • Hartmann C.
      • von Deimling A.
      • Unterberg A.
      • Plass C.
      • Schmezer P.
      • Herold-Mende C.
      Epigenetically mediated downregulation of the differentiation-promoting chaperon protein CRABP2 in astrocytic gliomas.
      ). atRA biosynthesis is impaired in breast cancer cell lines relative to normal cells (
      • Mira-Y-Lopez R.
      • Zheng W.L.
      • Kuppumbatti Y.S.
      • Rexer B.
      • Jing Y.
      • Ong D.E.
      Retinol conversion to retinoic acid is impaired in breast cancer cell lines relative to normal cells.
      ). Reduced atRA synthesis in the Rbp1-null mouse is consistent with increased mammary tumors, and suggests consequences of the epigenetic silencing of Rbp1 in 25% of human breast cancers (
      • Pierzchalski K.
      • Yu J.
      • Norman V.
      • Kane M.A.
      CrbpI regulates mammary retinoic acid homeostasis and the mammary microenvironment.
      ). In contrast, overexpression of RDH10 in HepG2 cells reduces proliferation (
      • Rossi E.
      • Picozzi P.
      • Bodega B.
      • Lavazza C.
      • Carlo-Stella C.
      • Marozzi A.
      • Ginelli E.
      Forced expression of RDH10 gene retards growth of HepG2 cells.
      ).
      In summary, despite the importance of atRA in vertebrate physiology, little is known about regulation of the rate-limiting enzymes (Rdh) that catalyze its biosynthesis. This report reveals a reciprocal interaction in which energy status regulates atRA biosynthesis through insulin that would attenuate energy balance regulation by atRA. These data predict altered atRA concentrations in diseases characterized by dysfunctional insulin signaling, including diabetes and cancer.

      Acknowledgments

      We are grateful to Domenico Accili for a gift of the dominant-negative adenovirus construct (Δ256).

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