Fructosa, un factor clave modificable en la patogenia del síndrome metabólico, la esteatosis hepática y la obesidad
Palabras clave:
FRUCTOSA, SÍNDROME METABÓLICO, HÍGADO GRASO, RESISTENCIA A LA INSULINA, OBESIDAD, LIPOGÉNESIS DE NOVO
Resumen
En esta revisión se resume el rol específico que el exceso de consumo de fructosa más allá de sus calorías puede tener en el desarrollo del síndrome metabólico, la esteatosis hepática no alcohólica y su asociación con la obesidad. Se desglosan los efectos de la fructosa (en comparación con la glucosa) en la esteatosis hepática, lo que genera la insulino-resistencia y la hipertrigliceridemia. Por su metabolismo hepático mayoritario y la falta de regulación, los flujos altos de fructosa consumen ATP generando ácido úrico, producen metabolitos tóxicos, como ceramidas y metilglioxal, y activan la síntesis de lípidos. Además, se analizan los efectos en el tejido adiposo, la activación del cortisol y las hormonas involucradas en el control de la saciedad, todas las cuales se ven afectadas por el consumo de fructosa. La insulino-resistencia hepática inicial se complica con insulino-resistencia sistémica, que genera leptino-resistencia y un ciclo de hiperfagia. Estos resultados subrayan la necesidad de intervenciones clínicas y educativas dentro de la población para regular o reducir el consumo de fructosa, especialmente en niños y adolescentes, sus principales consumidores.
Citas
(1) Pisabarro R, Kaufmann P. Prevalence of obesity in Uruguay. Obes Rev 2004; 5(4):175-6.
(2) Reaven G. The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals. Endocrinol Metab Clin North Am 2004; 33(2):283-303.
(3) Reaven GM. Insulin resistance, cardiovascular disease, and the metabolic syndrome: how well do the emperor’s clothes fit? Diabetes Care 2004; 27(4):1011-2.
(4) Bremer AA, Mietus-Snyder M, Lustig RH. Toward a unifying hypothesis of metabolic syndrome. Pediatrics 2012; 129(3):557-70.
(5) Weiss R, Bremer AA, Lustig RH. What is metabolic syndrome, and why are children getting it? Ann N Y Acad Sci 2013; 1281:123-40.
(6) Bray GA. Fructose and risk of cardiometabolic disease. Curr Atheroscler Rep 2012; 14(6):570-8.
(7) Lim JS, Mietus-Snyder M, Valente A, Schwarz JM, Lustig RH. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol 2010; 7(5):251-64.
(8) Taskinen MR, Packard CJ, Borén J. Dietary fructose and the Metabolic Syndrome. Nutrients 2019; 11(9):1987.
(9) Duarte SMB, Stefano JT, Vanni DS, Carrilho FJ, Oliveira CPMS. Impact of current diet at the risk of non-alcoholic fatty liver disease (NAFLD). Arq Gastroenterol 2019; 56(4):431-9.
(10) Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem 2002; 277(50):48115-21.
(11) Jensen T, Abdelmalek MF, Sullivan S, Nadeau KJ, Green M, Roncal C, et al. Fructose and sugar: a major mediator of non-alcoholic fatty liver disease. J Hepatol 2018; 68(5):1063-75.
(12) Mirtschink P, Jang C, Arany Z, Krek W. Fructose metabolism, cardiometabolic risk, and the epidemic of coronary artery disease. Eur Heart J 2018; 39(26):2497-505.
(13) Yudkin J. The causes and cure of obesity. Lancet 1959; 2(7112):1135-8.
(14) Yudkin J. Dietary fat and dietary sugar in relation to ischaemic heart-disease and diabetes. Lancet 1964; 2(7349):4-5.
(15) Keys A. Prediction and possible prevention of coronary disease. Am J Public Health Nations Health 1953; 43(11):1399-407.
(16) Keys A. Atherosclerosis: a problem in newer public health. J Mt Sinai Hosp N Y 1953; 20(2):118-39.
(17) Keys A, Menotti A, Karvonen MJ, Aravanis C, Blackburn H, Buzina R, et al. The diet and 15-year death rate in the seven countries study. Am J Epidemiol 1986; 124(6):903-15.
(18) Bray GA. Soft drink consumption and obesity: it is all about fructose. Curr Opin Lipidol 2010; 21(1):51-7.
(19) Severi C, Moratorio X. Double burden of undernutrition and obesity in Uruguay. Am J Clin Nutr 2014; 100(6):1659S-62S.
(20) Gugliucci A. Formation of fructose-mediated advanced glycation end products and their roles in metabolic and inflammatory diseases. Adv Nutr 2017; 8(1):54-62.
(21) Mann J, McLean R, Skeaff M, Morenga LT. Low carbohydrate diets: going against the grain. Lancet 2014; 384(9953):1479-80.
(22) Te Morenga LA, Howatson AJ, Jones RM, Mann J. Dietary sugars and cardiometabolic risk: systematic review and meta-analyses of randomized controlled trials of the effects on blood pressure and lipids. Am J Clin Nutr 2014; 100(1):65-79.
(23) DiNicolantonio JJ, O’Keefe JH, Lucan SC. Added fructose: a principal driver of type 2 diabetes mellitus and its consequences. Mayo Clin Proc 2015; 90(3):372-81.
(24) Tappy L. Fructose metabolism and noncommunicable diseases: recent findings and new research perspectives. Curr Opin Clin Nutr Metab Care 2018; 21(3):214-22.
(25) Tappy L, Le KA. Metabolic effects of fructose and the worldwide increase in obesity. Physiol Rev 2010; 90(1):23-46.
(26) Lustig RH. Fructose: metabolic, hedonic, and societal parallels with ethanol. J Am Diet Assoc 2010; 110(9):1307-21.
(27) Lustig RH. Fructose and nonalcoholic fatty liver disease. J Calif Dent Assoc 2016; 44(10):613-7.
(28) Chaudhuri J, Bains Y, Guha S, Kahn A, Hall D, Bose N, et al. The role of advanced glycation end products in aging and metabolic diseases: bridging association and causality. Cell Metab 2018; 28(3):337-52.
(29) Rodriguez-Mortera R, Luevano-Contreras C, Solorio-Meza S, Caccavello R, Bains Y, Garay-Sevilla ME, et al. Higher D-lactate levels are associated with higher prevalence of small dense low-density lipoprotein in obese adolescents. Clin Chem Lab Med 2018; 56(7):1100-8.
(30) Rabbani N, Thornalley PJ. Glyoxalase 1 modulation in obesity and diabetes. Antioxid Redox Signal 2019; 30(3):354-74.
(31) Erkin-Cakmak A, Bains Y, Caccavello R, Noworolski SM, Schwarz JM, Mulligan K, et al. Isocaloric fructose restriction reduces serum d-lactate concentration in children with obesity and metabolic syndrome. j clin endocrinol metab 2019; 104(7):3003-11.
(32) Lanaspa MA, Andres-Hernando A, Orlicky DJ, Cicerchi C, Jang C, Li N, et al. Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice. J Clin Invest 2018; 128(6):2226-38.
(33) Bjornstad P, Lanaspa MA, Ishimoto T, Kosugi T, Kume S, Jalal D, et al. Fructose and uric acid in diabetic nephropathy. Diabetologia 2015; 58(9):1993-2002.
(34) Lanaspa MA, Sanchez-Lozada LG, Cicerchi C, Li N, Roncal-Jimenez CA, Ishimoto T, et al. Uric acid stimulates fructokinase and accelerates fructose metabolism in the development of fatty liver. PLoS One 2012; 7(10):e47948.
(35) Softic S, Stanhope KL, Boucher J, Divanovic S, Lanaspa MA, Johnson RJ, et al. Fructose and hepatic insulin resistance. Crit Rev Clin Lab Sci 2020:1-15.
(36) Johnson RJ, Lanaspa MA, Roncal-Jimenez C, Sanchez-Lozada LG. Effects of excessive fructose intake on health. Ann Intern Med. 2012; 156(12):905; author reply 905-6.
(37) Nakagawa T, Johnson RJ, Andres-Hernando A, Roncal-Jimenez C, Sanchez-Lozada LG, Tolan DR, et al. Fructose production and metabolism in the kidney. J Am Soc Nephrol 2020; 31(5):898-906.
(38) Francey C, Cros J, Rosset R, Creze C, Rey V, Stefanoni N, et al. The extra-splanchnic fructose escape after ingestion of a fructose-glucose drink: an exploratory study in healthy humans using a dual fructose isotope method. Clin Nutr ESPEN 2019; 29:125-32.
(39) Andres-Hernando A, Johnson RJ, Lanaspa MA. Endogenous fructose production: what do we know and how relevant is it? Curr Opin Clin Nutr Metab Care 2019; 22(4):289-94.
(40) DiNicolantonio JJ, Subramonian AM, O’Keefe JH. Added fructose as a principal driver of non-alcoholic fatty liver disease: a public health crisis. Open Heart 2017; 4(2):e000631.
(41) DiNicolantonio JJ, Mehta V, Onkaramurthy N, O’Keefe JH. Fructose-induced inflammation and increased cortisol: a new mechanism for how sugar induces visceral adiposity. Prog Cardiovasc Dis 2018; 61(1):3-9.
(42) Vasselli JR. Fructose-induced leptin resistance: discovery of an unsuspected form of the phenomenon and its significance. Focus on “Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding,” by Shapiro et al. Am J Physiol Regul Integr Comp Physiol 2008; 295(5):R1365-9.
(43) Sadowska J, Rygielska M. The effect of high fructose corn syrup on the plasma insulin and leptin concentration, body weight gain and fat accumulation in rat. Adv Clin Exp Med 2019; 28(7):879-84.
(44) Shapiro A, Mu W, Roncal C, Cheng KY, Johnson RJ, Scarpace PJ. Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding. Am J Physiol Regul Integr Comp Physiol 2008; 295(5):R1370-5.
(45) Le Bodo Y, Paquette MC, Vallieres M, Alméras N. Is sugar the new tobacco? Insights from laboratory studies, consumer surveys and public health. Curr Obes Rep 2015; 4(1):111-21.
(46) Braunstein CR, Noronha JC, Khan TA, Mejia SB, Wolever TM, Josse RG, et al. Effect of fructose and its epimers on postprandial carbohydrate metabolism: a systematic review and meta-analysis. Clin Nutr 2020; S0261-5614(20)30104-7.
(47) Sievenpiper JL, de Souza RJ, Jenkins DJ. Sugar: fruit fructose is still healthy. Nature 2012; 482(7386):470.
(48) Gugliucci A, Lustig RH, Caccavello R, Erkin-Cakmak A, Noworolski SM, Tai VW, et al. Short-term isocaloric fructose restriction lowers apoC-III levels and yields less atherogenic lipoprotein profiles in children with obesity and metabolic syndrome. Atherosclerosis 2016; 253:171-7.
(49) Lustig RH, Mulligan K, Noworolski SM, Tai VW, Wen MJ, Erkin-Cakmak A, et al. Isocaloric fructose restriction and metabolic improvement in children with obesity and metabolic syndrome. Obesity (Silver Spring) 2016; 24(2): 453-60.
(50) Schwarz JM, Noworolski SM, Erkin-Cakmak A, Korn NJ, Wen MJ, Tai VW, et al. Effects of dietary fructose restriction on liver fat, de novo lipogenesis, and insulin kinetics in children with obesity. Gastroenterology 2017; 153(3): 743-52.
(2) Reaven G. The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals. Endocrinol Metab Clin North Am 2004; 33(2):283-303.
(3) Reaven GM. Insulin resistance, cardiovascular disease, and the metabolic syndrome: how well do the emperor’s clothes fit? Diabetes Care 2004; 27(4):1011-2.
(4) Bremer AA, Mietus-Snyder M, Lustig RH. Toward a unifying hypothesis of metabolic syndrome. Pediatrics 2012; 129(3):557-70.
(5) Weiss R, Bremer AA, Lustig RH. What is metabolic syndrome, and why are children getting it? Ann N Y Acad Sci 2013; 1281:123-40.
(6) Bray GA. Fructose and risk of cardiometabolic disease. Curr Atheroscler Rep 2012; 14(6):570-8.
(7) Lim JS, Mietus-Snyder M, Valente A, Schwarz JM, Lustig RH. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol 2010; 7(5):251-64.
(8) Taskinen MR, Packard CJ, Borén J. Dietary fructose and the Metabolic Syndrome. Nutrients 2019; 11(9):1987.
(9) Duarte SMB, Stefano JT, Vanni DS, Carrilho FJ, Oliveira CPMS. Impact of current diet at the risk of non-alcoholic fatty liver disease (NAFLD). Arq Gastroenterol 2019; 56(4):431-9.
(10) Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem 2002; 277(50):48115-21.
(11) Jensen T, Abdelmalek MF, Sullivan S, Nadeau KJ, Green M, Roncal C, et al. Fructose and sugar: a major mediator of non-alcoholic fatty liver disease. J Hepatol 2018; 68(5):1063-75.
(12) Mirtschink P, Jang C, Arany Z, Krek W. Fructose metabolism, cardiometabolic risk, and the epidemic of coronary artery disease. Eur Heart J 2018; 39(26):2497-505.
(13) Yudkin J. The causes and cure of obesity. Lancet 1959; 2(7112):1135-8.
(14) Yudkin J. Dietary fat and dietary sugar in relation to ischaemic heart-disease and diabetes. Lancet 1964; 2(7349):4-5.
(15) Keys A. Prediction and possible prevention of coronary disease. Am J Public Health Nations Health 1953; 43(11):1399-407.
(16) Keys A. Atherosclerosis: a problem in newer public health. J Mt Sinai Hosp N Y 1953; 20(2):118-39.
(17) Keys A, Menotti A, Karvonen MJ, Aravanis C, Blackburn H, Buzina R, et al. The diet and 15-year death rate in the seven countries study. Am J Epidemiol 1986; 124(6):903-15.
(18) Bray GA. Soft drink consumption and obesity: it is all about fructose. Curr Opin Lipidol 2010; 21(1):51-7.
(19) Severi C, Moratorio X. Double burden of undernutrition and obesity in Uruguay. Am J Clin Nutr 2014; 100(6):1659S-62S.
(20) Gugliucci A. Formation of fructose-mediated advanced glycation end products and their roles in metabolic and inflammatory diseases. Adv Nutr 2017; 8(1):54-62.
(21) Mann J, McLean R, Skeaff M, Morenga LT. Low carbohydrate diets: going against the grain. Lancet 2014; 384(9953):1479-80.
(22) Te Morenga LA, Howatson AJ, Jones RM, Mann J. Dietary sugars and cardiometabolic risk: systematic review and meta-analyses of randomized controlled trials of the effects on blood pressure and lipids. Am J Clin Nutr 2014; 100(1):65-79.
(23) DiNicolantonio JJ, O’Keefe JH, Lucan SC. Added fructose: a principal driver of type 2 diabetes mellitus and its consequences. Mayo Clin Proc 2015; 90(3):372-81.
(24) Tappy L. Fructose metabolism and noncommunicable diseases: recent findings and new research perspectives. Curr Opin Clin Nutr Metab Care 2018; 21(3):214-22.
(25) Tappy L, Le KA. Metabolic effects of fructose and the worldwide increase in obesity. Physiol Rev 2010; 90(1):23-46.
(26) Lustig RH. Fructose: metabolic, hedonic, and societal parallels with ethanol. J Am Diet Assoc 2010; 110(9):1307-21.
(27) Lustig RH. Fructose and nonalcoholic fatty liver disease. J Calif Dent Assoc 2016; 44(10):613-7.
(28) Chaudhuri J, Bains Y, Guha S, Kahn A, Hall D, Bose N, et al. The role of advanced glycation end products in aging and metabolic diseases: bridging association and causality. Cell Metab 2018; 28(3):337-52.
(29) Rodriguez-Mortera R, Luevano-Contreras C, Solorio-Meza S, Caccavello R, Bains Y, Garay-Sevilla ME, et al. Higher D-lactate levels are associated with higher prevalence of small dense low-density lipoprotein in obese adolescents. Clin Chem Lab Med 2018; 56(7):1100-8.
(30) Rabbani N, Thornalley PJ. Glyoxalase 1 modulation in obesity and diabetes. Antioxid Redox Signal 2019; 30(3):354-74.
(31) Erkin-Cakmak A, Bains Y, Caccavello R, Noworolski SM, Schwarz JM, Mulligan K, et al. Isocaloric fructose restriction reduces serum d-lactate concentration in children with obesity and metabolic syndrome. j clin endocrinol metab 2019; 104(7):3003-11.
(32) Lanaspa MA, Andres-Hernando A, Orlicky DJ, Cicerchi C, Jang C, Li N, et al. Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice. J Clin Invest 2018; 128(6):2226-38.
(33) Bjornstad P, Lanaspa MA, Ishimoto T, Kosugi T, Kume S, Jalal D, et al. Fructose and uric acid in diabetic nephropathy. Diabetologia 2015; 58(9):1993-2002.
(34) Lanaspa MA, Sanchez-Lozada LG, Cicerchi C, Li N, Roncal-Jimenez CA, Ishimoto T, et al. Uric acid stimulates fructokinase and accelerates fructose metabolism in the development of fatty liver. PLoS One 2012; 7(10):e47948.
(35) Softic S, Stanhope KL, Boucher J, Divanovic S, Lanaspa MA, Johnson RJ, et al. Fructose and hepatic insulin resistance. Crit Rev Clin Lab Sci 2020:1-15.
(36) Johnson RJ, Lanaspa MA, Roncal-Jimenez C, Sanchez-Lozada LG. Effects of excessive fructose intake on health. Ann Intern Med. 2012; 156(12):905; author reply 905-6.
(37) Nakagawa T, Johnson RJ, Andres-Hernando A, Roncal-Jimenez C, Sanchez-Lozada LG, Tolan DR, et al. Fructose production and metabolism in the kidney. J Am Soc Nephrol 2020; 31(5):898-906.
(38) Francey C, Cros J, Rosset R, Creze C, Rey V, Stefanoni N, et al. The extra-splanchnic fructose escape after ingestion of a fructose-glucose drink: an exploratory study in healthy humans using a dual fructose isotope method. Clin Nutr ESPEN 2019; 29:125-32.
(39) Andres-Hernando A, Johnson RJ, Lanaspa MA. Endogenous fructose production: what do we know and how relevant is it? Curr Opin Clin Nutr Metab Care 2019; 22(4):289-94.
(40) DiNicolantonio JJ, Subramonian AM, O’Keefe JH. Added fructose as a principal driver of non-alcoholic fatty liver disease: a public health crisis. Open Heart 2017; 4(2):e000631.
(41) DiNicolantonio JJ, Mehta V, Onkaramurthy N, O’Keefe JH. Fructose-induced inflammation and increased cortisol: a new mechanism for how sugar induces visceral adiposity. Prog Cardiovasc Dis 2018; 61(1):3-9.
(42) Vasselli JR. Fructose-induced leptin resistance: discovery of an unsuspected form of the phenomenon and its significance. Focus on “Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding,” by Shapiro et al. Am J Physiol Regul Integr Comp Physiol 2008; 295(5):R1365-9.
(43) Sadowska J, Rygielska M. The effect of high fructose corn syrup on the plasma insulin and leptin concentration, body weight gain and fat accumulation in rat. Adv Clin Exp Med 2019; 28(7):879-84.
(44) Shapiro A, Mu W, Roncal C, Cheng KY, Johnson RJ, Scarpace PJ. Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding. Am J Physiol Regul Integr Comp Physiol 2008; 295(5):R1370-5.
(45) Le Bodo Y, Paquette MC, Vallieres M, Alméras N. Is sugar the new tobacco? Insights from laboratory studies, consumer surveys and public health. Curr Obes Rep 2015; 4(1):111-21.
(46) Braunstein CR, Noronha JC, Khan TA, Mejia SB, Wolever TM, Josse RG, et al. Effect of fructose and its epimers on postprandial carbohydrate metabolism: a systematic review and meta-analysis. Clin Nutr 2020; S0261-5614(20)30104-7.
(47) Sievenpiper JL, de Souza RJ, Jenkins DJ. Sugar: fruit fructose is still healthy. Nature 2012; 482(7386):470.
(48) Gugliucci A, Lustig RH, Caccavello R, Erkin-Cakmak A, Noworolski SM, Tai VW, et al. Short-term isocaloric fructose restriction lowers apoC-III levels and yields less atherogenic lipoprotein profiles in children with obesity and metabolic syndrome. Atherosclerosis 2016; 253:171-7.
(49) Lustig RH, Mulligan K, Noworolski SM, Tai VW, Wen MJ, Erkin-Cakmak A, et al. Isocaloric fructose restriction and metabolic improvement in children with obesity and metabolic syndrome. Obesity (Silver Spring) 2016; 24(2): 453-60.
(50) Schwarz JM, Noworolski SM, Erkin-Cakmak A, Korn NJ, Wen MJ, Tai VW, et al. Effects of dietary fructose restriction on liver fat, de novo lipogenesis, and insulin kinetics in children with obesity. Gastroenterology 2017; 153(3): 743-52.
Publicado
2020-12-01
Cómo citar
1.
Gugliucci A, Rodríguez-Mortera R. Fructosa, un factor clave modificable en la patogenia del síndrome metabólico, la esteatosis hepática y la obesidad. Rev. Méd. Urug. [Internet]. 1 de diciembre de 2020 [citado 26 de abril de 2024];36(4):418-30. Disponible en: http://www2.rmu.org.uy/ojsrmu311/index.php/rmu/article/view/648
Sección
Artículos Especiales
