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Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease.
Dig Dis Sci 2016; 61(5):1282-93DD

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome. Overconsumption of high-fat diet (HFD) and increased intake of sugar-sweetened beverages are major risk factors for development of NAFLD. Today the most commonly consumed sugar is high fructose corn syrup. Hepatic lipids may be derived from dietary intake, esterification of plasma free fatty acids (FFA) or hepatic de novo lipogenesis (DNL). A central abnormality in NAFLD is enhanced DNL. Hepatic DNL is increased in individuals with NAFLD, while the contribution of dietary fat and plasma FFA to hepatic lipids is not significantly altered. The importance of DNL in NAFLD is further established in mouse studies with knockout of genes involved in this process. Dietary fructose increases levels of enzymes involved in DNL even more strongly than HFD. Several properties of fructose metabolism make it particularly lipogenic. Fructose is absorbed via portal vein and delivered to the liver in much higher concentrations as compared to other tissues. Fructose increases protein levels of all DNL enzymes during its conversion into triglycerides. Additionally, fructose supports lipogenesis in the setting of insulin resistance as fructose does not require insulin for its metabolism, and it directly stimulates SREBP1c, a major transcriptional regulator of DNL. Fructose also leads to ATP depletion and suppression of mitochondrial fatty acid oxidation, resulting in increased production of reactive oxygen species. Furthermore, fructose promotes ER stress and uric acid formation, additional insulin independent pathways leading to DNL. In summary, fructose metabolism supports DNL more strongly than HFD and hepatic DNL is a central abnormality in NAFLD. Disrupting fructose metabolism in the liver may provide a new therapeutic option for the treatment of NAFLD.

Authors+Show Affiliations

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, One Joslin Place, Boston, MA, 02215, USA. Department of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, One Joslin Place, Boston, MA, 02215, USA. c.ronald.kahn@joslin.harvard.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Review

Language

eng

PubMed ID

26856717

Citation

Softic, Samir, et al. "Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease." Digestive Diseases and Sciences, vol. 61, no. 5, 2016, pp. 1282-93.
Softic S, Cohen DE, Kahn CR. Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease. Dig Dis Sci. 2016;61(5):1282-93.
Softic, S., Cohen, D. E., & Kahn, C. R. (2016). Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease. Digestive Diseases and Sciences, 61(5), pp. 1282-93. doi:10.1007/s10620-016-4054-0.
Softic S, Cohen DE, Kahn CR. Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease. Dig Dis Sci. 2016;61(5):1282-93. PubMed PMID: 26856717.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease. AU - Softic,Samir, AU - Cohen,David E, AU - Kahn,C Ronald, Y1 - 2016/02/08/ PY - 2016/01/13/received PY - 2016/01/21/accepted PY - 2016/2/10/entrez PY - 2016/2/10/pubmed PY - 2016/8/26/medline KW - De novo lipogenesis KW - Fructose KW - HFD KW - Liver KW - Metabolism KW - NAFLD KW - NASH SP - 1282 EP - 93 JF - Digestive diseases and sciences JO - Dig. Dis. Sci. VL - 61 IS - 5 N2 - Nonalcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome. Overconsumption of high-fat diet (HFD) and increased intake of sugar-sweetened beverages are major risk factors for development of NAFLD. Today the most commonly consumed sugar is high fructose corn syrup. Hepatic lipids may be derived from dietary intake, esterification of plasma free fatty acids (FFA) or hepatic de novo lipogenesis (DNL). A central abnormality in NAFLD is enhanced DNL. Hepatic DNL is increased in individuals with NAFLD, while the contribution of dietary fat and plasma FFA to hepatic lipids is not significantly altered. The importance of DNL in NAFLD is further established in mouse studies with knockout of genes involved in this process. Dietary fructose increases levels of enzymes involved in DNL even more strongly than HFD. Several properties of fructose metabolism make it particularly lipogenic. Fructose is absorbed via portal vein and delivered to the liver in much higher concentrations as compared to other tissues. Fructose increases protein levels of all DNL enzymes during its conversion into triglycerides. Additionally, fructose supports lipogenesis in the setting of insulin resistance as fructose does not require insulin for its metabolism, and it directly stimulates SREBP1c, a major transcriptional regulator of DNL. Fructose also leads to ATP depletion and suppression of mitochondrial fatty acid oxidation, resulting in increased production of reactive oxygen species. Furthermore, fructose promotes ER stress and uric acid formation, additional insulin independent pathways leading to DNL. In summary, fructose metabolism supports DNL more strongly than HFD and hepatic DNL is a central abnormality in NAFLD. Disrupting fructose metabolism in the liver may provide a new therapeutic option for the treatment of NAFLD. SN - 1573-2568 UR - https://www.unboundmedicine.com/medline/citation/26856717/Role_of_Dietary_Fructose_and_Hepatic_De_Novo_Lipogenesis_in_Fatty_Liver_Disease_ L2 - https://doi.org/10.1007/s10620-016-4054-0 DB - PRIME DP - Unbound Medicine ER -