Carolina Huaman Samanez

Publications (4)17.17 Total impact

• Article: THE FARNESOID X RECEPTOR INHIBITS THE TRANSCRIPTIONAL ACTIVITY OF THE CARBOHYDRATE RESPONSE ELEMENT BINDING PROTEIN IN HUMAN HEPATOCYTES -- R2.

  Sandrine Caron, Carolina Huaman Samanez, Hélène Dehondt, Maheul Ploton, Olivier Briand, Fleur Lien, Emilie Dorchies, Julie Dumont, Catherine Postic, Bertrand Cariou, Philippe Lefebvre, Bart Staels
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  ABSTRACT: The glucose-activated transcription factor Carbohydrate Response Element Binding Protein (ChREBP) induces the expression of hepatic glycolytic and lipogenic genes. The Farnesoid X Receptor (FXR) is a nuclear bile acid-receptor controlling bile acid, lipid and glucose homeostasis. FXR negatively regulates hepatic glycolysis and lipogenesis in mouse liver. The aim of this study is to determine whether FXR regulates the transcriptional activity of ChREBP in human hepatocytes and to unravel the underlying molecular mechanisms. Agonist-activated FXR inhibits glucose-induced transcription of several glycolytic genes, including Liver-type Pyruvate Kinase (L-PK), in the human hepatocyte IHH and HepaRG cell lines. This inhibition requires the L4L3 region of the L-PK promoter known to bind the transcription factors ChREBP and Hepatocyte Nuclear Factor-4α (HNF4α). FXR interacts directly with ChREBP and HNF4α proteins. Analysis of the protein complex bound to the L4L3 region reveals the presence of ChREBP, HNF4α, FXR and the transcriptional co-activators p300 and CBP at high glucose concentrations. FXR activation does not affect FXR neither HNF4α binding to the L4L3 region, but results in the concomitant release of ChREBP, p300 and CBP and in the recruitment of the transcriptional co-repressor SMRT. Thus, FXR transrepresses the expression of genes involved in glycolysis in human hepatocytes.
  Molecular and cellular biology 03/2013; · 6.06 Impact Factor
• Article: The human hepatocyte cell lines IHH and HepaRG: models to study glucose, lipid and lipoprotein metabolism.

  Carolina Huaman Samanez, Sandrine Caron, Olivier Briand, Hélène Dehondt, Isabelle Duplan, Folkert Kuipers, Nathalie Hennuyer, Véronique Clavey, Bart Staels
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  ABSTRACT: Metabolic diseases reach epidemic proportions. A better knowledge of the associated alterations in the metabolic pathways in the liver is necessary. These studies need in vitro human cell models. Several human hepatoma models are used, but the response of many metabolic pathways to physiological stimuli is often lost. Here, we characterize two human hepatocyte cell lines, IHH and HepaRG, by analysing the expression and regulation of genes involved in glucose and lipid metabolism. Our results show that the glycolysis pathway is activated by glucose and insulin in both lines. Gluconeogenesis gene expression is induced by forskolin in IHH cells and inhibited by insulin in both cell lines. The lipogenic pathway is regulated by insulin in IHH cells. Finally, both cell lines secrete apolipoprotein B-containing lipoproteins, an effect promoted by increasing glucose concentrations. These two human cell lines are thus interesting models to study the regulation of glucose and lipid metabolism.
  Archives of Physiology and Biochemistry 05/2012; 118(3):102-11.
• Article: PNPLA3 is regulated by glucose in human hepatocytes, and its I148M mutant slows down triglyceride hydrolysis.

  Julia Perttilä, Carolina Huaman-Samanez, Sandrine Caron, Kimmo Tanhuanpää, Bart Staels, Hannele Yki-Järvinen, Vesa M Olkkonen
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  ABSTRACT: Liver fat is increased in carriers of the minor G allele in rs738409 (I148M amino acid substitution) in patatin-like phospholipase domain-containing 3 (PNPLA3)/adiponutrin. We studied transcriptional regulation of PNPLA3 in immortalized human hepatocytes (IHH) and human hepatoma cells (HuH7) and the impact of PNPLA3 I148M mutant on hepatocyte triglyceride metabolism. Studies in IHH showed that silencing of the carbohydrate response element-binding protein (ChREBP) abolished induction of PNPLA3 mRNA by glucose. Glucose-dependent binding of ChREBP to a newly identified carbohydrate response element in the PNPLA3 promoter was demonstrated by chromatin immunoprecipitation. Adenoviral overexpression of mouse ChREBP in IHH failed to induce PNPLA3 mRNA. [(3)H]acetate or [(3)H]oleate incorporation with 1-h pulse labeling or 18-h [(3)H]oleate labeling in HuH7 cells showed no effect of PNPLA3 I148M on triglyceride (TG) synthesis in the absence of free fatty acid (FFA) loading. Increased [(3)H]oleate accumulation into triglycerides in I148M-expressing cells was observed after 18 h of labeling in the presence of 200 μM FFA-albumin complexes. This was accompanied by increased PNPLA3 protein levels. The rate of hydrolysis of [(3)H]TG during lipid depletion was decreased significantly by PNPLA3 I148M. Our results suggest that PNPLA3 is regulated in human hepatocytes by glucose via ChREBP. PNPLA3 I148M enhances cellular accumulation of [(3)H]TG in the presence of excess FFA, which is known to stabilize PNPLA3 protein. These data do not exclude an effect of PNPLA3 I148M on hepatocyte lipogenesis but show that the mutant increases the stability of triglycerides.
  AJP Endocrinology and Metabolism 02/2012; 302(9):E1063-9. · 4.75 Impact Factor
• Article: Transcriptional activation of apolipoprotein CIII expression by glucose may contribute to diabetic dyslipidemia.

  Sandrine Caron, An Verrijken, Ilse Mertens, Carolina Huaman Samanez, Gisèle Mautino, Joel T Haas, Daniel Duran-Sandoval, Janne Prawitt, Sven Francque, Emmanuelle Vallez, Anne Muhr-Tailleux, Isabelle Berard, Folkert Kuipers, Jan A Kuivenhoven, Sudha B Biddinger, Marja-Riitta Taskinen, Luc Van Gaal, Bart Staels
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  ABSTRACT: Hypertriglyceridemia and fatty liver are common in patients with type 2 diabetes, but the factors connecting alterations in glucose metabolism with plasma and liver lipid metabolism remain unclear. Apolipoprotein CIII (apoCIII), a regulator of hepatic and plasma triglyceride metabolism, is elevated in type 2 diabetes. In this study, we analyzed whether apoCIII is affected by altered glucose metabolism. Liver-specific insulin receptor-deficient mice display lower hepatic apoCIII mRNA levels than controls, suggesting that factors other than insulin regulate apoCIII in vivo. Glucose induces apoCIII transcription in primary rat hepatocytes and immortalized human hepatocytes via a mechanism involving the transcription factors carbohydrate response element-binding protein and hepatocyte nuclear factor-4α. ApoCIII induction by glucose is blunted by treatment with agonists of farnesoid X receptor and peroxisome proliferator-activated receptor-α but not liver X receptor, ie, nuclear receptors controlling triglyceride metabolism. Moreover, in obese humans, plasma apoCIII protein correlates more closely with plasma fasting glucose and glucose excursion after oral glucose load than with insulin. Glucose induces apoCIII transcription, which may represent a mechanism linking hyperglycemia, hypertriglyceridemia, and cardiovascular disease in type 2 diabetes.
  Arteriosclerosis Thrombosis and Vascular Biology 03/2011; 31(3):513-9. · 6.37 Impact Factor