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Increased De Novo Lipogenesis Is a Distinct Characteristic of Individuals With Nonalcoholic Fatty Liver Disease
Open accessAbstract
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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“Fasting DNL correlated with plasma TAG concentrations48 and was higher in individuals with MASLD.49”
From Lipid metabolism in MASLD and MASH: From mechanism to the clinic (2024) · cites this paper as [49]
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“Postprandial DNL contributes to 15-26% of liver TAGs in individuals with MASLD49,56 vs. 1-6% in the fasting state in healthy individuals.48”
From Lipid metabolism in MASLD and MASH: From mechanism to the clinic (2024) · cites this paper as [49]
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Breakthroughs in therapies for NASH and remaining challenges
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“For instance, obesity and NAFLD are associated with increased rates of hepatocyte de novo lipogenesis (10), which may be relatively low in normal human liver but is a significant contributor in obesityrelated NAFLD.”
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InfluentialAmino acid is a major carbon source for hepatic lipogenesis
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“These data suggest that, in contrast to previous studies that were done under fasting conditions (98–100), DNL is the major contributing factor to steatosis, and indicate the critical and interrelated role for adipose tissue insulin resistance in priming the DNL pathway (Figure 1).”
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“In a recent study comparing individuals with high and lowliver fat, who were matched for body composition and insulin sensitivity, the key difference between those with and without fatty liver was the extent of DNL [15].”
BackgroundInfluentialSelf-citationTargeting ATP-Citrate Lyase in Hyperlipidemia and Metabolic Disorders
Pinkosky, S. L., Groot, P. H. E., Lalwani, N. D., & Steinberg, G. R. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.09.001 · Cited by 118
Fukuda, Y., Hashimoto, Y., Hamaguchi, M., Fukuda, T., Nakamura, N., Ohbora, A., Kato, T., Kojima, T., & Fukui, M. (2015) · Liver International · doi:10.1111/liv.12977 · Cited by 114
“In addition, insulin resistance decreased ability of insulin to suppress adipose tissue lipolysis (28) and increased de novo lipogenesis (29).”
BackgroundTaskinen, M., Söderlund, S., Bogl, L. H., Hakkarainen, A., Matikainen, N., Pietiläinen, K. H., Räsänen, S., Lundbom, N. M. I., Björnson, E., Eliasson, B., et al. (2017) · Journal of Internal Medicine · doi:10.1111/joim.12632 · Cited by 122
Torre, S. D. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.572490 · Cited by 125
“In the hepatocytes, estrogens, mainly acting through ERα, limit gluconeogenesis (241, 288) preventing increased HGP and insulin resistance (288), limit the uptake of FFAs, inhibit DNL (153) and promotes FA oxidation (289) and export (287), thus preventing lipid deposition in the liver and the generation of lipotoxicit…”
BackgroundInfluentialLiver Clock Protein BMAL1 Promotes de Novo Lipogenesis through Insulin-mTORC2-AKT Signaling
Zhang, D., Tong, X., Arthurs, B., Guha, A., Rui, L., Kamath, A., Inoki, K., & Yin, L. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.567628 · Cited by 115
“It has been proposed that constantly elevated de novo lipogenesis contributes to the pathogenesis of nonalcoholic fatty liver diseases (5, 7).”
BackgroundStiede, K., Miao, W., Blanchette, H., Beysen, C., Harriman, G. C. B., Harwood, H. J., Kelley, H., Kapeller, R., Schmalbach, T., & Westlin, W. (2017) · Hepatology · doi:10.1002/hep.29246 · Cited by 115
“There exists both indirect and direct evidence that elevated lipogenesis provides a significant source of the fatty acids accumulating in the livers of patients with NAFLD.”
BackgroundInfluentialThe role of PNPLA3 in health and disease
Pingitore, P., & Romeo, S. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2018.06.018 · Cited by 115
Nonalcoholic fatty liver disease and type 2 diabetes: where do Diabetologists stand?
Tomah, S., Alkhouri, N., & Hamdy, O. (2020) · Clinical Diabetes and Endocrinology · doi:10.1186/s40842-020-00097-1 · Cited by 122
MicroRNA-27a regulates hepatic lipid metabolism and alleviates NAFLD via repressing FAS and SCD1
Zhang, M., Sun, W., Zhou, M., & Tang, Y. (2017) · Scientific Reports · doi:10.1038/s41598-017-15141-x · Cited by 113
Roles of Ceramides in Non-Alcoholic Fatty Liver Disease
Hajduch, É., Lachkar, F., Ferré, P., & Foufelle, F. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10040792 · Cited by 116
“[76] shows that if one considers the various sources of TG produced by the liver, free fatty acids coming from adipose tissue, meals, or lipogenesis, lipogenesis is the only one which is markedly increased in NAFLD patients.”
BackgroundMetabolic Changes of Hepatocytes in NAFLD
Lu, Q., Tian, X., Wu, H., Huang, J., Li, M., Mei, Z., Zhou, L., Xie, H., & Zheng, S. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.710420 · Cited by 118
Bitter, A., Rümmele, P., Klein, K., Kandel, B. A., Rieger, J. K., Nussler, A. K., Zanger, U. M., Trauner, M. A., Schwab, M. G., & Burk, O. (2014) · Archives of Toxicology · doi:10.1007/s00204-014-1348-x · Cited by 112
“…excess release of fatty acids by lipolysis in adipose tissue due to insulin resistance is generally accepted as contributing to the etiology of hepatic steatosis (Sanyal 2005), a significant role of increased hepatic de novo lipogenesis (DNL) was only very recently proven (Lambert et al. 2014).”
BackgroundLi, Y., Qiao, J., Wang, B., Bai, M., Shen, J.-D., & Cheng, Y. (2018) · Nutrients · doi:10.3390/nu10081024 · Cited by 114
“A previous study revealed that the TG synthesized via de novo lipogenesis was significantly enhanced in NAFLD subjects compared with normal [19].”
BackgroundXi, Y., Wu, M., Li, H., Dong, S., Luo, E., Gu, M., Shen, X. Z., Jiang, Y., Liu, Y., & Liu, H. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000374037 · Cited by 110
Chambers, E. S., Byrne, C., Rugyendo, A., Morrison, D. J., Preston, T., Tedford, C. M., Bell, J. D., Thomas, E. L., Akbar, A. N., Riddell, N. E., et al. (2018) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13500 · Cited by 112
“patients are reported to have rates of DNL up to 3-fold higher compared with BMI-matched controls.(17) The current data suggest that in”
ResultSasaki, Y., Asahiyama, M., Tanaka, T., Yamamoto, S., Murakami, K., Kamiya, W., Matsumura, Y., Osawa, T., Anai, M., Fruchart, J., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-64902-8 · Cited by 110
Macronutrients and the Adipose-Liver Axis in Obesity and Fatty Liver
Duwaerts, C. C., & Maher, J. J. (2019) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2019.02.001 · Cited by 113
Kitae, A., Hashimoto, Y., Hamaguchi, M., Obora, A., Kojima, T., & Fukui, M. (2019) · Canadian Journal of Gastroenterology and Hepatology · doi:10.1155/2019/5121574 · Cited by 108
“In fact, de novo lipogenesis is increased by threefold in patients with NAFLD compared to individuals without NAFLD [24, 26].”
Hormone-sensitive lipase: sixty years later
Recazens, E., Mouisel, É., & Langin, D. (2020) · Progress in Lipid Research · doi:10.1016/j.plipres.2020.101084 · Cited by 118
Fatty acid metabolism is altered in non-alcoholic steatohepatitis independent of obesity
Walle, P., Takkunen, M. J., Männistö, V., Vaittinen, M., Lankinen, M. A., Kärjä, V. J., Käkelä, P., Ågren, J., Tiainen, M., Schwab, U., et al. (2016) · Metabolism · doi:10.1016/j.metabol.2016.01.011 · Cited by 108
“Abbreviations: NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; FA, fatty acid; VLCD, very low calorie diet; CE, cholesteryl esters; TG, triglycerides; PL, phospholipids; METSIM, Metabolic Syndrome in Men; ALT, alanine aminotransferase; KOBS, Kuopio Obesity Surgery Study; SCD1, stearoyl-C…”
BackgroundInfluentialO’Farrell, M., Duke, G. M., Crowley, R., BUCKLEY, D. I., Martins, E. B., Bhattacharya, D., Friedman, S. L., & Kemble, G. W. (2022) · Scientific Reports · doi:10.1038/s41598-022-19459-z · Cited by 104
Mellemkjær, A., Kjær, M. B., Haldrup, D., Grønbæk, H., & Thomsen, K. L. (2023) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2023.11.012 · Cited by 110
Non-Alcoholic Fatty Liver Disease: From Pathogenesis to Clinical Impact
Caturano, A., Acierno, C., Nevola, R., Pafundi, P. C., Galiero, R., Rinaldi, L., Salvatore, T., Adinolfi, L. E., & Sasso, F. C. (2021) · Processes · doi:10.3390/pr9010135 · Cited by 109
“As already described, NAFLD patients display a de novo h patic lipogene is higher than healthy controls, which is neither suppressed in fasting nor with higher FFA plasma levels [41].”
BackgroundInsights into Nonalcoholic Fatty-Liver Disease Heterogeneity
Arrese, M. A., Arab, J. P., Francisco Barrera, M., Kaufmann, B. K., Valenti, L. V. C., & Feldstein, A. E. (2021) · Seminars in Liver Disease · doi:10.1055/s-0041-1730927 · Cited by 109
The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD
Hong, T., Chen, Y., Li, X., & Lü, Y. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/6889533 · Cited by 110
“The hepatic and whole-body metabolisms are improved in diabetic patients with estrogen treatment [48].”
BackgroundGrowth Hormone Inhibits Hepatic De Novo Lipogenesis in Adult Mice
Córdoba‐Chacón, J., Majumdar, N., List, E. O., Díaz‐Ruiz, A., Frank, S. J., Manzano, À., Bartrons, R., Puchowicz, M. A., Kopchick, J. J., & Kineman, R. D. (2015) · Diabetes · doi:10.2337/db15-0370 · Cited by 102
“of new fatty acids from glucose (6)) also plays a significant role in NAFLD progression (5; 7-9), 48 which may in part be driven by hyperinsulinemia (1).”
BackgroundRong, S., Xia, M., Vale, G., Wang, S., Kim, C.-W., Li, S., McDonald, J. G., Radhakrishnan, A., & Horton, J. D. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.01.011 · Cited by 102
Jin, R., Banton, S., Tran, V., Konomi, J. V., Li, S., Jones, D. P., & Vos, M. B. (2016) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2016.01.026 · Cited by 105
“NAFLD is a multifaceted disease and known metabolic disturbances in NAFLD include upregulated de novo lipogenesis and elevated free fatty acids (18, 19).”
BackgroundColeman, R. (2019) · Journal of Lipid Research · doi:10.1194/jlr.s091843 · Cited by 98
“Evidence for compartmentalization of glycerol-3-phosphate acyltransferases Of the three liver GPAT isoenzymes, only GPAT1 is an integral member of the pathway that converts excess dietary carbohydrate into TAG, a principal source of diet-related hepatic steatosis (13).”
BackgroundLuukkonen, P. K., Tukiainen, T., Juuti, A., Sammalkorpi, H. E., Haridas, P. A. N., Niemelä, O. J., Arola, J. T., Orho‐Melander, M., Hakkarainen, A., Kovanen, P. T., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.132158 · Cited by 103
“This could be secondary to hyperinsulinemia and increased de novo lipogenesis (DNL) in NAFLD associated with insulin resistance (9) or a consequence of HSD17B13, because overexpression of this protein caused steatosis in mice and increased lipid droplet size and number in cultured human hepatocytes (6).”
BackgroundLuukkonen, P. K., Porthan, K., Ahlholm, N., Rosqvist, F., Dufour, S., Zhang, X., Lehtimäki, T. E., Seppänen, W., Orho‐Melander, M., Hodson, L., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.10.008 · Cited by 97
Tricò, D., Caprio, S., Umano, G. R., Pierpont, B. M., Nouws, J., Galderisi, A., Kim, G., Mata, M. M., & Santoro, N. (2018) · Hepatology · doi:10.1002/hep.30035 · Cited by 95
“Finally, although hepatic de novo lipogenesis (DNL) is a major contributor of intra-hepatic fat accumulation (37), whether differences in DNL exist among ethnic groups remains unexplored.”
BackgroundHepatic De Novo Lipogenesis in Obese Youth Is Modulated by a Common Variant in the GCKR Gene
Santoro, N., Caprio, S., Pierpont, B. M., Name, M. A. V., Savoye, M., & Parks, E. J. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-1587 · Cited by 100
“Moreover, given the strong relationship between hepatic fat content and DNL (1, 12), to test the sole effect of the gene variant and rule out the effect of fatty liver on DNL, the two groups were matched also for hepatic fat content.”
BackgroundMethodSelf-citationAcetyl-CoA Carboxylase Inhibition Improves Multiple Dimensions of NASH Pathogenesis in Model Systems
Ross, T. T., Crowley, C., Kelly, K. L., Rinaldi, A., Beebe, D. A., Lech, M. P., Martinez, R. V., Carvajal-Gonzalez, S., Boucher, M., Hirenallur-Shanthappa, D., et al. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.06.001 · Cited by 94
“Increased rates of hepatic de novo lipogenesis (DNL) have been reported to be a distinctive characteristic of NAFLD.(4) Human subjects with increased liver fat showed an approximately 3-fold increase in the rate of hepatic DNL relative to subjects with normal liver fat.”
BackgroundChoi, W. J., Dong, H. J., Jeong, H. U., Ryu, D. W., Song, S. M., Kim, Y. R., Jung, H. H., Kim, Y., & Kim, Y. (2020) · Scientific Reports · doi:10.1038/s41598-020-57615-5 · Cited by 102
Effects of exercise training on intrahepatic lipid content in humans
Brouwers, B., Hesselink, M. K. C., Schrauwen, P., & Schrauwen-Hinderling, V. B. (2016) · Diabetologia · doi:10.1007/s00125-016-4037-x · Cited by 94
“In patients with NAFL, DNL contributed up to one-fourth of the hepatic TAG pool measured after an overnight fast [9], and DNLwas significantly higher in insulin-resistant individuals with NAFL than in people with low IHL content [28].”
BackgroundFructose metabolism, cardiometabolic risk, and the epidemic of coronary artery disease
Mirtschink, P., Jang, C., Arany, Z. P., & Krek, W. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehx518 · Cited by 95
“contribution of DNL in the liver becomes more prominent in the presence of NAFLD, rising from 10% up to 26%.(82,83) Although both increased fat and sugar intake can induce NAFLD, enzymes of DNL are particularly upregulated in fructose-rich diets.”
BackgroundJin, S., Jiang, S., & Hu, A. (2018) · Sleep And Breathing · doi:10.1007/s11325-018-1625-7 · Cited by 96
“Exposure to a continuous hypoxia might induce hepatic lipid accumulation by upregulating a key hepatic transcription factor of lipid biosynthesis, sterol regulatory element-binding protein 1c, acetyl-CoA carboxylase, and fatty acid synthase via HIF [39, 40].”
BackgroundGrowth Hormone and Insulin-Like Growth Factor 1 Regulation of Nonalcoholic Fatty Liver Disease
Dichtel, L. E., Córdoba‐Chacón, J., & Kineman, R. D. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac088 · Cited by 93
Lipotoxicity-driven metabolic dysfunction-associated steatotic liver disease (MASLD)
Iturbe-Rey, S., Maccali, C., Arrese, M. A., Aspichueta, P., de Oliveira, C. P. M. S., Castro, R. E., Lapitz, A., Izquierdo‐Sánchez, L., Bujanda, L., Perugorria, M. J., et al. (2024) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2024.119053 · Cited by 102
Metadata
- 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)
- 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
- 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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