Cited by 1,069Liver Disease Diagnosis and TreatmentLipid metabolism and biosynthesisLipid metabolism and disorders

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Increased De Novo Lipogenesis Is a Distinct Characteristic of Individuals With Nonalcoholic Fatty Liver Disease

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Lambert, Jennifer E., Ramos–Roman, Maria A., Browning, Jeffrey D., Parks, Elizabeth J.·2014·Gastroenterology

DOI 10.1053/j.gastro.2013.11.049PMC PMC6276362

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Abstract

Background & aims There have been few studies of the role of de novo lipogenesis in the development of nonalcoholic fatty liver disease (NAFLD). We used isotope analyses to compare de novo lipogenesis and fatty acid flux between subjects with NAFLD and those without, matched for metabolic factors (controls).Methods We studied subjects with metabolic syndrome and/or levels of alanine aminotransferase and aspartate aminotransferase >30 mU/L, using magnetic resonance spectroscopy to identify those with high levels (HighLF, n = 13) or low levels (LowLF, n = 11) of liver fat. Clinical and demographic information was collected from all participants, and insulin sensitivity was measured using the insulin-modified intravenous glucose tolerance test. Stable isotopes were administered and gas chromatography with mass spectrometry was used to analyze free (nonesterified) fatty acid (FFA) and triacylglycerol flux and lipogenesis.Results Subjects with HighLF (18.4% ± 3.6%) had higher plasma levels of FFAs during the nighttime and higher concentrations of insulin than subjects with LowLF (3.1% ± 2.7%; P = .04 and P < .001, respectively). No differences were observed between groups in adipose flux of FFAs (414 ± 195 μmol/min for HighLF vs 358 ± 105 μmol/min for LowLF; P = .41) or production of very-low-density lipoprotein triacylglycerol from FFAs (4.06 ± 2.57 μmol/min vs 4.34 ± 1.82 μmol/min; P = .77). In contrast, subjects with HighLF had more than 3-fold higher rates of de novo fatty acid synthesis than subjects with LowLF (2.57 ± 1.53 μmol/min vs 0.78 ± 0.42 μmol/min; P = .001). As a percentage of triacylglycerol palmitate, de novo lipogenesis was 2-fold higher in subjects with HighLF (23.2% ± 7.9% vs 10.1% ± 6.7%; P < .001); this level was independently associated with the level of intrahepatic triacylglycerol (r = 0.53; P = .007).Conclusions By administering isotopes to subjects with NAFLD and control subjects, we confirmed that those with NAFLD have increased synthesis of fatty acids. Subjects with NAFLD also had higher nocturnal plasma levels of FFAs and did not suppress the contribution from de novo lipogenesis on fasting. These findings indicate that lipogenesis might be a therapeutic target for NAFLD.

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The Effects of Modest Alcohol Consumption on Non-alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis
Wongtrakul, W., Niltwat, S., & Charatcharoenwitthaya, P. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.744713 · Cited by 30
Discovery of Ervogastat (PF-06865571): A Potent and Selective Inhibitor of Diacylglycerol Acyltransferase 2 for the Treatment of Non-alcoholic Steatohepatitis
Futatsugi, K., Cabral, S., Kung, D. W., Huard, K., Lee, E. C. Y., Boehm, M., Bauman, J. N., Clark, R. W., Coffey, S. B., Crowley, C., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01200 · Cited by 33
Current Therapeutical Approaches Targeting Lipid Metabolism in NAFLD
Vitulo, M., Gnodi, E., Rosini, G., Meneveri, R., Giovannoni, R., & Barisani, D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241612748 · Cited by 36
“This is a pivotal process in NAFL/NASH pathogenesis, since its contribution to lipid accumulation has been reported increased up to six times in NAFLD [105].”
Background
Fasting hepatic de novo lipogenesis is not reliably assessed using circulating fatty acid markers
Rosqvist, F., McNeil, C. A., Pramfalk, C., Parry, S. A., Low, W. S., Cornfield, T., Fielding, B. A., & Hodson, L. (2018) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqy304 · Cited by 29
“However, recirculation of labels might result in exaggerated values of DNL; our protocol for the assessment of DNL is in line with previous studies (8, 31, 45).”
Result
Liver-derived metabolites as signaling molecules in fatty liver disease
Keles, U., Ow, J. R., Kuentzel, K. B., Zhao, L. N., & Kaldis, P. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04658-8 · Cited by 32
“Excess circulating glucose upon skeletal muscle insulin resistance might be taken up by the liver and serves as a source for de novo lipogenesis, of which the primary output is saturated long-chain FA, culminating in further lipid deposition in the liver and secretion in VLDL particles [60].”
Background
Reduction of de novo lipogenesis mediates beneficial effects of isoenergetic diets on fatty liver: Mechanistic Insights from the MEDEA randomized clinical trial
Costabile, G., Della Pepa, G., Salamone, D., Luongo, D., Naviglio, D., Brancato, V., Cavaliere, C., Salvatore, M., Cipriano, P., Vitale, M., et al. (2022) · Nutrients · doi:10.3390/nu14102178 · Cited by 27
“DNL accounts for up to 30% of triglyceride production in people with NAFLD and insulin resistance, but accounts for only 5% in healthy people [21].”
Background
Sennoside A protects mitochondrial structure and function to improve high-fat diet-induced hepatic steatosis by targeting VDAC1
Le, J., Jia, W., & Sun, Y. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.04.108 · Cited by 28
Two Metabolomics Phenotypes of Human Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease According to Fibrosis Severity
Buchard, B., Teilhet, C., Samarakoon, N. A., Massoulier, S., Joubert-Zakeyh, J., Blouin, C., Reynès, C., Sabatier, R., Biesse-Martin, A., Vasson, M., et al. (2021) · Metabolites · doi:10.3390/metabo11010054 · Cited by 29
“These data may indicate abnormal activities of enzymes involved in de novo lipogenesis (DNL), such as Fatty Acid Synthase (FASN) and stearoyl-coA desaturase (SCD).”
Influential
Oxidized Lipids: Common Immunogenic Drivers of Non-Alcoholic Fatty Liver Disease and Atherosclerosis
Hoebinger, C., Rajcic, D., & Hendrikx, T. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.824481 · Cited by 32
“steatotic liver, is a consequence of increased calorie intake, enhanced free fatty acids (FFA) influx from lipolysis of peripheral adipose tissue, elevated triglyceride synthesis by hepatic de novo lipogenesis, and reduced lipid export from the liver via very-low-density lipoprotein (VLDL) particles (21, 22).”
Background
Complex impacts of gallstone disease on metabolic syndrome and nonalcoholic fatty liver disease
Lyu, J., Lin, Q., Fang, Z., Xu, Z., & Liu, Z. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1032557 · Cited by 31
“Lipolysis could be induced by peripheral insulin resistance (90).”
Background
Utility of Human Relevant Preclinical Animal Models in Navigating NAFLD to MAFLD Paradigm
Chua, D., Low, Z. S., Cheam, G. X., Ng, A. S., & Tan, N. S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232314762 · Cited by 30
“Many factors can instigate excessive lipid deposition; prolonged nutrient overloading [82], a sedentary lifestyle, and elevated de novo lipogenesis [83] promote increased deposition to both subcutaneous adipose tissue and VAT [84].”
Background
Human Sterol Regulatory Element-Binding Protein 1a Contributes Significantly to Hepatic Lipogenic Gene Expression
Bitter, A., Nussler, A. K., Thasler, W. E., Klein, K., Zanger, U. M., Schwab, M. G., & Burk, O. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000369739 · Cited by 31
Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation
Queathem, E. D., Moazzami, Z., Stagg, D. B., Nelson, A. B., Fulghum, K., Hayir, A., Seay, A., Gillingham, J. R., d’Avignon, D. A., Han, X., et al. (2025) · Science Advances · doi:10.1126/sciadv.ads0535 · Cited by 30
Poria cocos-Derived Exosome-like Nanovesicles Alleviate Metabolic Dysfunction-Associated Fatty Liver Disease by Promoting Mitophagy and Inhibiting NLRP3 Inflammasome Activation
Wang, T., Zhao, J., Li, Q.-Y., Yang, H., Li, M., Duan, R., Zhang, M., Yan, Q., Yu, J., & Yang, X. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26052253 · Cited by 27
“The occurrence of MAFLD is related to an excessive accumulation of lipids in the liver (exceeding its own clearance capacity), which is characterized by increased TC, TG, AST, ALT, and LDL-C content and decreased HDL-C content in the serum and liver [35].”
Lipogenic SREBP-1a/c transcription factors activate expression of the iron regulator hepcidin, revealing cross-talk between lipid and iron metabolisms
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Co‐option of PPARα in the regulation of lipogenesis and fatty acid oxidation in CLA‐induced hepatic steatosis
Cai, D., Li, Y., Zhang, K., Zhou, B., Guo, F., Holm, L. P., & Liu, H. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.30157 · Cited by 27
“Studies in humans and rodents show that hepatic TG accumulation is mainly linked to the upregulation of endogenous lipogenic pathway in the livers (Dubois et al., 2017; Lambert et al., 2014; Larter et al., 2008; Patsouris et al., 2006; Preidis et al., 2017).”
Background
Ufmylation on UFBP1 alleviates non-alcoholic fatty liver disease by modulating hepatic endoplasmic reticulum stress
Mao, Z., Ma, X., Jing, Y., Shen, M., Ma, X., Zhu, J., Liu, H., Zhang, G., & Chen, F. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06095-2 · Cited by 26
“However, due to the complexity of NAFLD, approved therapeutic strategies targeting the characteristics of NAFLD are limited [4, 5].”
Background
The Influence of Physical Exercise, Ketogenic Diet, and Time-Restricted Eating on De Novo Lipogenesis: A Narrative Review
Paoli, A. (2025) · Nutrients · doi:10.3390/nu17040663 · Cited by 30
“Moreover, DNL is significantly increased in patients with obesity, suggesting the reduction of DNL as one of the therapeutic approaches [6].”
Obesity and Metabolic Dysfunction‐Associated Steatotic Liver Disease ( MASLD ): A Literature Review on Pathophysiology and Treatment
Romanos, M., Cordova, J. M. G., Villamarin, J. L., Zurita, J. D. P., & Acosta, A. (2026) · Diabetes Obesity and Metabolism · doi:10.1111/dom.70659 · Cited by 33
Adipose Tissue Composition in Obesity and After Bariatric Surgery
Adami, G. F., Carbone, F., Montecucco, F., Camerini, G. B., & Cordera, R. (2019) · Obesity Surgery · doi:10.1007/s11695-019-04030-z · Cited by 26
Protocols for Mitochondria as the Target of Pharmacological Therapy in the Context of Nonalcoholic Fatty Liver Disease (NAFLD)
Grattagliano, I., Ciaula, A. D., Baj, J., Molina‐Molina, E., Shanmugam, H., Garruti, G., Wang, D. Q. ‐., & Portincasa, P. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1433-4_12 · Cited by 28
Noncoding RNAs and RNA-binding proteins: emerging governors of liver physiology and metabolic diseases
Sommerauer, C., & Kutter, C. (2022) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00232.2022 · Cited by 27
Fructose and liver function – is this behind nonalcoholic liver disease?
Jin, R., & Vos, M. B. (2015) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000203 · Cited by 28
Hepatic entrapment of esterified cholesterol drives continual expansion of whole body sterol pool in lysosomal acid lipase-deficient mice
Aqul, A. A., Lopez, A. M., Posey, K. S., Taylor, A. M., Repa, J. J., Burns, D. K., & Turley, S. D. (2014) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00243.2014 · Cited by 27
Zoledronic acid, an FPPS inhibitor, ameliorates liver steatosis through inhibiting hepatic de novo lipogenesis
Tang, Q., Jiang, S., Jia, W., Shen, D., Qiu, Y., Zhao, Y., Xue, B., & Li, C. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.08.010 · Cited by 26
“It was reported that subjects with NAFLD had more than 3-fold higher rates of de novo fatty acid synthesis than control subjects (Lambert et al., 2014).”
Background
Baicalin: an active natural product with potential medicinal values
Wen, Y., Wang, Y., Zhao, C., Zhao, B., & Wang, J. (2025) · Journal of Asian Natural Products Research · doi:10.1080/10286020.2025.2482054 · Cited by 26
How Useful Are Monogenic Rodent Models for the Study of Human Non-Alcoholic Fatty Liver Disease?
Mann, J. P., Semple, R. K., & Armstrong, M. J. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00145 · Cited by 26
Broad Views of Non-alcoholic Fatty Liver Disease
Mardinoğlu, A., Uhlén, M., & Borén, J. (2018) · Cell Systems · doi:10.1016/j.cels.2018.01.004 · Cited by 25
Gamma‐Tocotrienol Attenuates the Hepatic Inflammation and Fibrosis by Suppressing Endoplasmic Reticulum Stress in Mice
Kim, Y., Natarajan, S. K., & Chung, S. (2018) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201800519 · Cited by 25
Sex hormone-binding globulin suppresses NAFLD-triggered hepatocarcinogenesis after menopause
Lee, S. R., Lee, Y. H., Yang, H. J., Lee, H. W., Lee, G., An, B., Jeung, E., Park, B.-K., & Hong, E. (2019) · Carcinogenesis · doi:10.1093/carcin/bgz107 · Cited by 25
Jiuzhuan Huangjing Pills relieve mitochondrial dysfunction and attenuate high-fat diet-induced metabolic dysfunction-associated fatty liver disease
Mu, J.-K., Zi, L., Li, Y., Yu, L., Cui, Z., Shi, T., Zhang, F., Gu, W., Hao, J.-J., Yu, J., et al. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112092 · Cited by 25
Selective Acetyl-CoA Carboxylase 1 Inhibitor Improves Hepatic Steatosis and Hepatic Fibrosis in a Preclinical Nonalcoholic Steatohepatitis Model
Tamura, Y. O., Sugama, J., Iwasaki, S., Sasaki, M., Yasuno, H., Aoyama, K., Watanabe, M., Erion, D. M., & Yashiro, H. (2021) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.121.000786 · Cited by 27
Rho-Kinase as a Therapeutic Target for Nonalcoholic Fatty Liver Diseases
Sousa‐Lima, I., Kim, H. J., Jones, J. G., & Kim, Y. (2021) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2021.0197 · Cited by 24
“In summary, hepatic DNL contributes about 5% to 10% of hepatic triglyceride appearance in healthy post-absorptive humans, whereas this rate is significantly elevated to 15% to 25% for patients with NAFLD [11,81,84,86-88].”
Background
Mulberry Leaf (Morus alba L.) Extracts and Its Chlorogenic Acid Isomer Component Improve Glucolipotoxicity-Induced Hepatic Lipid Accumulation via Downregulating miR-34a and Decreased Inflammation
Yang, T., Yu, M.-H., Wu, Y.-L., Hong, C.-C., Chen, C., Chan, K., & Wang, C. (2022) · Nutrients · doi:10.3390/nu14224808 · Cited by 25
“In addition, hepatic inflammation can increase the influx of free fatty acids to the liver, inducing intrahepatic triglycerides and subsequently lipogenesis and hepatocellular injury via lipid peroxidation and mitochondrial dysfunction [3].”
Background
Ellagitannins-Derived Intestinal Microbial Metabolite Urolithin A Ameliorates Fructose-Driven Hepatosteatosis by Suppressing Hepatic Lipid Metabolic Reprogramming and Inducing Lipophagy
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Herpetrione, a New Type of PPARα Ligand as a Therapeutic Strategy Against Nonalcoholic Steatohepatitis
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“The majority of the free fatty acids that are esterified to form hepatic TGs mainly originate from adipose tissue lipolysis, but can also result from dietary fat intake and de novo lipogenesis [27].”
Background
Role of Insulin Resistance and Diabetes in the Pathogenesis and Treatment of Nonalcoholic Fatty Liver Disease
Portillo-Sánchez, P., Yavuz, S., Bril, F., & Cusi, K. J. (2014) · Current Hepatology Reports · doi:10.1007/s11901-014-0229-3 · Cited by 25
Stanniocalcin 2 Ameliorates Hepatosteatosis Through Activation of STAT3 Signaling
Zhao, J., Jiao, Y., Song, Y., Liu, J., Li, X., Zhang, H., Yang, J., & Lu, Y. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00873 · Cited by 26
Mechanisms coupling lipid droplets to MASLD pathophysiology
Reid, M. V., Fredrickson, G., & Mashek, D. G. (2024) · Hepatology · doi:10.1097/hep.0000000000001141 · Cited by 26
Nonalcohol fatty liver disease: balancing supply and utilization of triglycerides
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Lingonberry Improves Hepatic Lipid Metabolism by Targeting Notch1 Signaling
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“Increased hepatic de novo lipogenesis is a characteristic of NAFLD [5].”
Background
Apolipoprotein F is reduced in humans with steatosis and controls plasma triglyceride‐rich lipoprotein metabolism
Deprince, A., Hennuyer, N., Kooijman, S., Pronk, A. C. M., Baugé, E., Liénard, V., Verrijken, A., Dirinck, E. L., Vonghia, L., Woitrain, E., et al. (2022) · Hepatology · doi:10.1002/hep.32631 · Cited by 24
“Hepatic TG accumulation in insulin resistant individuals results from a combination of increased adipose tissue free fatty acid (FFA) release[5] and increased hepatic lipogenesis.[6,7] Importantly, these fluxes can be partially counterbalanced by enhanced hepatic TG output.”
Background
Measurement of lipid flux to advance translational research: evolution of classic methods to the future of precision health
Salvador, A. F., Shyu, C., & Parks, E. J. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00838-5 · Cited by 24
“Liver-TG can be synthesized from four pathways: (1) those originating in the diet and cleared to the liver, (2) plasma that originate in adipose tissue, (3) fatty acids prestored in hepatocytes, and (4) liver fatty acids that have been newly synthesized from carbohydrates and other precursors through the pathway of de…”
BackgroundMethodInfluentialSelf-citation
Erchen decoction alleviates the progression of NAFLD by inhibiting lipid accumulation and iron overload through Caveolin-1 signaling
Deng, G., Li, J., Huang, M., Li, Y., Shi, H., Wu, C., Zhao, J., Qin, M., Liu, C., Wang, Y., et al. (2023) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2023.117320 · Cited by 24

Authors: Lambert, J. E., Ramos–Roman, M. A., Browning, J. D., & Parks, E. J.
Affiliations: The University of Texas Southwestern Medical Center (US)
Corresponding author: Parks, Elizabeth J.
ORCID: Parks, Elizabeth J.
Venue: Gastroenterology
Publisher: Elsevier BV
Published: 2014-03
Volume: 146
Issue: 3
Pages: 726-735
ISSN: 0016-5085 (ISSN-L)
DOI: 10.1053/j.gastro.2013.11.049
PMC: PMC6276362
OpenAlex: W2139351004
Cited by: 1,069
References: 58
Citations by year: 2026: 67 · 2025: 111 · 2024: 110 · 2023: 108 · 2022: 124 · 2021: 111 · 2020: 106 · 2019: 92 · 2018: 75 · 2017: 47 · 2016: 49 · 2015: 45 · 2014: 23
FWCI: 28.42
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Gastroenterology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (RL1DK081187, UL1DE019584, UL1-RR024982)
National Center for Advancing Translational Sciences (RL1DK081187, UL1DE019584, UL1-RR024982)
Topics: Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords: de novo lipogenesis, non-alcoholic fatty liver disease, fatty acid synthesis, triglyceride synthesis, liver fat, metabolic syndrome, insulin sensitivity, stable isotope tracer studies, hepatic lipid metabolism, insulin
MeSH terms: Fatty Acids, Nonesterified, Fatty Liver, Female, Humans, Hyperlipidemias, Liver, Magnetic Resonance Imaging, Male, Comorbidity, Case-Control Studies, Metabolic Syndrome, Lipogenesis, Non-alcoholic Fatty Liver Disease

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Increased De Novo Lipogenesis Is a Distinct Characteristic of Individuals With Nonalcoholic Fatty Liver Disease

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