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Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease
Open accessAbstract
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.
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“Fructose enhances its own metabolism by upregulating ketohexokinase (KHK), which is elevated in MASLD; diets high in both fat and fructose worsen MASLD, but fructose alone more strongly induces DNL enzymes like ACC1, FASN, and stearoyl-CoA desaturase 1 (SCD1) compared to HFDs [13].”
From Hepatic Insulin Resistance and Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Insights into Mechanisms and Clinical Implications (2025) · cites this paper as [13]
In the citing paper
“Fructose enhances its own metabolism by upregulating ketohexokinase (KHK), which is elevated in MASLD; diets high in both fat and fructose worsen MASLD, but fructose alone more strongly induces DNL enzymes like ACC1, FASN, and stearoyl-CoA desaturase 1 (SCD1) compared to HFDs [13].”
From Hepatic Insulin Resistance and Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Insights into Mechanisms and Clinical Implications (2025) · cites this paper as [13]
In the citing paper
“Fructose enhances its own metabolism by upregulating ketohexokinase (KHK), which is elevated in MASLD; diets high in both fat and fructose worsen MASLD, but fructose alone more strongly induces DNL enzymes like ACC1, FASN, and stearoyl-CoA desaturase 1 (SCD1) compared to HFDs [13].”
From Hepatic Insulin Resistance and Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Insights into Mechanisms and Clinical Implications (2025) · cites this paper as [13]
In the citing paper
“Patients with MASLD often show reduced hepatic ATP [13].”
From Hepatic Insulin Resistance and Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Insights into Mechanisms and Clinical Implications (2025) · cites this paper as [13]
In the citing paper
“Importantly, DAG buildup, not TG, is linked to hepatic IR via PKC activation.”
From Hepatic Insulin Resistance and Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Insights into Mechanisms and Clinical Implications (2025) · cites this paper as [13]
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Metadata
- Authors
- Softic, S., Cohen, D. E., & Kahn, C. R.
- Affiliations
- Boston Children's Hospital (US)
- Brigham and Women's Hospital (US)
- Joslin Diabetes Center (US)
- Corresponding author
- Kahn, C. Ronald
- Venue
- Digestive Diseases and Sciences
- Published
- 2016-02-08
- Volume
- 61
- Issue
- 5
- Pages
- 1282-1293
- ISSN
- 0163-2116 (ISSN-L)
- 1573-2568
- PMC
- PMC4838515
- OpenAlex
- W2286797029
- Cited by
- 709
- References
- 133
- Citations by year
- 2026: 52 · 2025: 76 · 2024: 88 · 2023: 78 · 2022: 92 · 2021: 79 · 2020: 88 · 2019: 57 · 2018: 44 · 2017: 42 · 2016: 13
- FWCI
- 7.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Digestive Diseases and Sciences (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK031036, R01 DK033201, K12 HD000850, R37 DK048873, R01 DK056626, R01 DK103046)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- non-alcoholic fatty liver disease, dietary fructose, hepatic de novo lipogenesis, high fructose corn syrup, high-fat diet, sugar-sweetened beverages, insulin resistance, SREBP-1c, endoplasmic reticulum stress, uric acid, mitochondrial fatty acid oxidation, reactive oxygen species, hepatic lipid metabolism, metabolic syndrome
- MeSH terms
- Diet, Fructose, Humans, Liver, Lipogenesis, Non-alcoholic Fatty Liver Disease, High Fructose Corn Syrup
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