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Fructose-Induced Increases in Expression of Intestinal Fructolytic and Gluconeogenic Genes Are Regulated by GLUT5 and KHK

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Fructose-Induced Increases in Expression of Intestinal Fructolytic and Gluconeogenic Genes Are Regulated by GLUT5 and KHK Fructose-induced increases in expression of intestinal fructolytic and gluconeogenic genes are regulated by GLUT5 and KHK. Chirag Patel, Véronique Douard, Shiyan Yu, Phuntila Tharabenjasin, Nan Gao, Ronaldo P Ferraris To cite this version: Chirag Patel, Véronique Douard, Shiyan Yu, Phuntila Tharabenjasin, Nan Gao, et al.. Fructose- induced increases in expression of intestinal fructolytic and gluconeogenic genes are regulated by GLUT5 and KHK.. AJP - Regulatory, Integrative and Comparative Physiology, American Physio- logical Society, 2015, 309 (5), pp.R499-509. 10.1152/ajpregu.00128.2015. hal-01607831 HAL Id: hal-01607831 https://hal.archives-ouvertes.fr/hal-01607831 Submitted on 28 May 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Copyright Am J Physiol Regul Integr Comp Physiol 309: R499–R509, 2015. First published June 17, 2015; doi:10.1152/ajpregu.00128.2015. Fructose-induced increases in expression of intestinal fructolytic and gluconeogenic genes are regulated by GLUT5 and KHK Chirag Patel,1 Veronique Douard,1 Shiyan Yu,2 Phuntila Tharabenjasin,1 Nan Gao,2 and Ronaldo P. Ferraris1 1Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, New Jersey; and 2Department of Biological Sciences, School of Arts and Sciences, Rutgers University, Newark, New Jersey Submitted 30 March 2015; accepted in final form 16 June 2015 Patel C, Douard V, Yu S, Tharabenjasin P, Gao N, Ferraris blood fructose is directly dependent on intestinal processing of RP. Fructose-induced increases in expression of intestinal fructolytic dietary fructose. and gluconeogenic genes are regulated by GLUT5 and KHK. Am J In the small intestine, glucose transporter protein, member 5 Downloaded from Physiol Regul Integr Comp Physiol 309: R499–R509, 2015. First (GLUT5) is the primary fructose transporter responsible for the published June 17, 2015; doi:10.1152/ajpregu.00128.2015.—Marked absorption of fructose into the cytosol. Unlike the intestinal increases in fructose consumption have been tightly linked to meta- bolic diseases. One-third of ingested fructose is metabolized in the glucose transporter sodium-dependent glucose transporter pro- small intestine, but the underlying mechanisms regulating expression tein 1 (SGLT1), which is sodium dependent, GLUT5 transports ϭ of fructose-metabolizing enzymes are not known. We used genetic fructose (Km 6–14 mM) across the apical membrane down mouse models to test the hypothesis that fructose absorption via a chemical gradient (5). Fructose transport in the blood from glucose transporter protein, member 5 (GLUT5), metabolism via the cytosol is mediated by GLUT2 (7). Although the liver is the http://ajpregu.physiology.org/ ketohexokinase (KHK), as well as GLUT5 trafficking to the apical primary organ that metabolizes most of the ingested fructose, membrane via the Ras-related protein in brain 11a (Rab11a)-depen- the small intestine strongly expresses all fructose-metabolizing dent endosomes are required for the regulation of intestinal fructolytic enzymes and is responsible for the catabolism of 10–30% of and gluconeogenic enzymes. Fructose feeding increased the intestinal ingested fructose (3, 19, 34). Fructolysis is initiated by keto- mRNA and protein expression of these enzymes in the small intestine hexokinase (KHK, fructokinase), which converts fructose and of adult wild-type (WT) mice compared with those gavage fed with lysine or glucose. Fructose did not increase expression of these ATP into fructose 1-phosphate and ADP, respectively. KHK has two isoforms, KHK-A and KHK-C. KHK-C has a 10-fold enzymes in the GLUT5 knockout (KO) mice. Blocking intracellular ϭ fructose metabolism by KHK ablation also prevented fructose-in- higher affinity for fructose (Km 0.8 mM) and is mainly duced upregulation. Glycolytic hexokinase I expression was similar responsible for its metabolism (1). Aldolase-B cleaves fructose between WT and GLUT5- or KHK-KO mice and did not vary with 1-phosphate into three-carbon intermediates, dihydroxyacetone by 10.220.33.2 on August 30, 2017 feeding solution. Gavage feeding with the fructose-specific metabolite phosphate and glyceraldehyde, and the latter is then converted glyceraldehyde did not increase enzyme expression, suggesting that by triokinase into glyceraldehyde 3-phosphate, which then signaling occurs before the hydrolysis of fructose to three-carbon joins the glycolysis pathway. Because fructolysis bypasses compounds. Impeding GLUT5 trafficking to the apical membrane feedback regulation controlling glycolysis upstream of glycer- using intestinal epithelial cell-specific Rab11a-KO mice impaired aldehyde 3-phosphate, fructose catabolism results in the rapid fructose-induced upregulation. KHK expression was uniformly dis- accumulation of several metabolic intermediates (49) that are tributed along the villus but was localized mainly in the basal region of the cytosol of enterocytes. The feedforward upregulation of fruc- thought to play a crucial role in the development of metabolic tolytic and gluconeogenic enzymes specifically requires GLUT5 and disease. KHK, aldolase-B, and triokinase mediate most of KHK and may proactively enhance the intestine’s ability to process fructolysis (20). Other enzymes do not contribute significantly anticipated increases in dietary fructose concentrations. to fructose metabolism due to their relatively much higher Km for fructose: hexokinase IV or glucokinase (Ͼ100 mM), fruc- fructolysis; glyceraldehyde; gluconeogenesis; glucose transporter pro- tose dehydrogenase (5 mM), fructose-3-phosphokinase (30 tein, member 5; ketohexokinase; Ras-related protein in brain 11a; mice; small intestine mM), and sorbitol dehydrogenase (100 mM) (15). The consti- tutive glycolytic hexokinase I has a Km (ϳ2 mM) for fructose that is ϳ50-fold or more greater than for glucose (20). Thus, a THE FRUCTOSE CONCENTRATION in human diets has increased deficiency of KHK and aldolase-B is responsible for major almost 100-fold in the last 200 years (16, 33), and the current genetic disorders like essential fructosuria and fructose intol- high rates of fructose intake are now linked to the development erance, respectively (18). of the metabolic syndrome of insulin resistance, dyslipidemia, KHK-C is strongly expressed in mouse and rat enterocytes, hypertension, and obesity (32, 47). Chronic consumption of hepatocytes, and renal proximal tubule cells (15, 50), whereas high-fructose diets increases portal blood fructose concentra- KHK-A is expressed in many other tissues, but levels are tions, leading to fatty liver and perturbed liver function, as well vanishingly low. Like those of GLUT5 and GLUT2 (16), the as systemic blood fructose levels, leading to pathologies in intestinal- and hepatic-specific activities of KHK, aldolase-B, peripheral organ systems (16). The rate of increase in portal and triokinase increase with dietary fructose (29). Expression of GLUT5 and other fructose-responsive genes is typically regulated by luminal and not endocrine signals (45). Address for reprint requests and other correspondence: Ronaldo P. Ferraris, Dept. of Pharmacology & Physiology, New Jersey Medical School, 185 South GLUT5 plays a vital role in regulating the entry of fructose Orange Ave., MSB H-621, Newark, NJ 07103 (e-mail: [email protected]. in our body. Deletion of GLUT5 reduces by Ͼ80% in vivo edu). intestinal fructose absorption as well as serum fructose con- http://www.ajpregu.org 0363-6119/15 Copyright © 2015 the American Physiological Society R499 R500 FRUCTOSE REGULATES FRUCTOLYTIC AND GLUCONEOGENIC GENES centration (2). Diet-induced specific increases in GLUT5 ex- for KHK-KO and GLUT5-KO, 129/B6 for Rab11a⌬IEC) mice were used as a control in all experiments involving genetically modified pression enhance the rate of fructose absorption and involve de ⌬ novo mRNA and protein synthesis (25, 44). Once GLUT5 mice (GLUT5-KO, KHK-KO, or Rab11a IEC). Generation and phe- notypic description of GLUT5-KO (55), KHK-KO (15), and synthesis has been upregulated by dietary fructose, trafficking ⌬IEC of GLUT5 to the apical membrane is important so transport Rab11a (57) mice was reported in detail previously. Previously validated primer sequences (15, 55, 57) confirmed genetic modifica- activity matches the increased luminal fructose concentration. tions in these mice. GLUT5-KO and KHK-KO mice showed normal Ras-related protein in brain 11a (Rab11a) is an important phenotypes. Rab11a⌬IEC mice exhibited previously reported runting GTPase associated with recycling endosomes critical for both and growth retardation. Rab11a⌬IEC were used, before weaning, at 18 endocytic and exocytic protein pathways (57). It is mainly days of age, since there was high mortality in postweaning associated with the apical recycling endosome in polarized Rab11a⌬IEC mice (57). epithelia (21), and regulates the movement of known brush- border biomarkers dipeptidyl peptidase and alkaline phospha- Experimental Design tase to the apical membrane (46). The roles of Rab11a in Role of metabolism and intracellular
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