Some paradoxes and unresolved aspects of hepatic de novo lipogenesis
Szczepaniak, L. S. et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am. J. Physiol.-Endocrinol. Metab. 288, E462–E468 (2005).
Google Scholar
Petersen, K. F. et al. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54, 603–608 (2005).
Google Scholar
Luukkonen, P. K. et al. Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease. J. Hepatol. 76, 526–535 (2022).
Google Scholar
Smith, G. I. et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J. Clin. Investig. 130, 1453–1460 (2020).
Google Scholar
Lambert, J. E., Ramos-Roman, M. A., Browning, J. D. & Parks, E. J. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology 146, 726–735 (2014).
Google Scholar
Donnelly, K. L. et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Investig. 115, 1343–1351 (2005).
Google Scholar
Haynes, C. A. et al. Factors to consider in using [U-13C]palmitate for analysis of sphingolipid biosynthesis by tandem mass spectrometry. J. Lipid Res. 52, 1583–1594 (2011).
Google Scholar
Sunny, N. E., Parks, E. J., Browning, J. D. & Burgess, S. C. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab. 14, 804–810 (2011).
Google Scholar
Petersen, K. F., Befroy, D. E., Dufour, S., Rothman, D. L. & Shulman, G. I. Assessment of hepatic mitochondrial oxidation and pyruvate cycling in NAFLD by 13C magnetic resonance spectroscopy. Cell Metab. 24, 167–171 (2016).
Google Scholar
Stanhope, K. L. et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J. Clin. Investig. 119, 1322–1334 (2009).
Google Scholar
Sevastianova, K. et al. Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans. Am. J. Clin. Nutr. 96, 727–734 (2012).
Google Scholar
Hochuli, M. et al. Sugar-sweetened beverages with moderate amounts of fructose, but not sucrose, induce fatty acid synthesis in healthy young men: a randomized crossover study. J. Clin. Endocrinol. Metab. 99, 2164–2172 (2014).
Google Scholar
Timlin, M. T. & Parks, E. J. Temporal pattern of de novo lipogenesis in the postprandial state in healthy men. Am. J. Clin. Nutr. 81, 35–42 (2005).
Google Scholar
Satapati, S. et al. Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. J. Clin. Investig. 125, 4447–4462 (2015).
Google Scholar
Satapati, S. et al. Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver. J. Lipid Res. 53, 1080–1092 (2012).
Google Scholar
Fu, X. R. et al. Persistent fasting lipogenesis links impaired ketogenesis with citrate synthesis in humans with nonalcoholic fatty liver. J. Clin. Investig. 133, (2023).
Samuel, V. T. & Shulman, G. I. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J. Clin. Investig. 126, 12–22 (2016).
Google Scholar
Fabbrini, E. et al. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 134, 424–431 (2008).
Google Scholar
Guan, D. Y. et al. Diet-induced circadian enhancer remodeling synchronizes opposing hepatic lipid metabolic processes. Cell 174, 831–842 (2018).
Google Scholar
Uyeda, K., Yamashita, H. & Kawaguchi, T. Carbohydrate responsive element-binding protein (ChREBP): a key regulator of glucose metabolism and fat storage. Biochem. Pharmacol. 63, 2075–2080 (2002).
Google Scholar
Kabashima, T., Kawaguchi, T., Wadzinski, B. E. & Uyeda, K. Xylulose 5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated protein phosphatase in rat liver. Proc. Natl Acad. Sci. USA 100, 5107–5112 (2003).
Google Scholar
Dentin, R. et al. Glucose 6-phosphate, rather than xylulose 5-phosphate, is required for the activation of ChREBP in response to glucose in the liver. J. Hepatol. 56, 199–209 (2012).
Google Scholar
Softic, S. et al. Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling. J. Clin. Investig. 127, 4059–4074 (2017).
Google Scholar
Azzout-Marniche, D. et al. Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes. Biochem. J. 350, 389–393, (2000).
Google Scholar
Foretz, M., Guichard, C., Ferré, P. & Foufelle, F. Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. Proc. Natl Acad. Sci. USA 96, 12737–12742 (1999).
Google Scholar
Eckel-Mahan, K. L. et al. Reprogramming of the circadian clock by nutritional challenge. Cell 155, 1464–1478 (2013).
Google Scholar
Kohsaka, A. et al. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab. 6, 414–421 (2007).
Google Scholar
Dentin, R. et al. Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP-1c on glycolytic and lipogenic gene expression. J. Biol. Chem. 279, 20314–20326 (2004).
Google Scholar
Feng, D. et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331, 1315–1319 (2011).
Google Scholar
Ishii, S., Iizuka, K., Miller, B. C. & Uyeda, K. Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription. Proc. Natl Acad. Sci. USA 101, 15597–15602 (2004).
Google Scholar
Shamir, M., Bar-On, Y., Phillips, R. & Milo, R. SnapShot: timescales in cell biology. Cell 164, 1302–U1235 (2016).
Google Scholar
Gibbons, G. F., Pullinger, C. R. & Bjornsson, O. G. Changes in the sensitivity of lipogenesis in rat hepatocytes to hormones and precursors over the diurnal cycle and during longer-term starvation of donor animals. J. Lipid Res. 25, 1358–1367 (1984).
Google Scholar
Chen, J., et al Hepatic glycogenesis antagonizes lipogenesis by blocking S1P via UDPG. Science 383, (2024).
Zhao, S. et al. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. Nature 579, 586–591 (2020).
Google Scholar
Beysen, C. et al. Dose-dependent quantitative effects of acute fructose administration on hepatic de novo lipogenesis in healthy humans. Am. J. Physiol.-Endocrinol. Metab. 315, E126–E132 (2018).
Google Scholar
Viegas, I. et al. Integration of liver glycogen and triglyceride nmr isotopomer analyses provides a comprehensive coverage of hepatic glucose and fructose metabolism. Metabolites 12, (2022).
Silva, J. C. P. et al. Determining contributions of exogenous glucose and fructose to de novo fatty acid and glycerol synthesis in liver and adipose tissue. Metab. Eng. 56, 69–76 (2019).
Google Scholar
DiNunzio, G. et al. Determining the contribution of a high-fructose corn syrup formulation to hepatic glycogen synthesis during ad-libitum feeding in mice. Sci. Rep. 10, 12852 (2020).
Google Scholar
Hengist, A., Koumanov, F. & Gonzalez, J. T. Fructose and metabolic health: governed by hepatic glycogen status? J. Physiol.-Lond. 597, 3573–3585 (2019).
Google Scholar
Yoshida, C., Shikata, N., Seki, S., Koyama, N. & Noguchi, Y. Early nocturnal meal skipping alters the peripheral clock and increases lipogenesis in mice. Nutr. Metab. 9, (2012).
Iwayama, K., Tanabe, Y., Tanji, F., Ohnishi, T. & Takahashi, H. Diurnal variations in muscle and liver glycogen differ depending on the timing of exercise. J. Physiol. Sci. 71, (2021).
Parks, E. J. & Hellerstein, M. K. Recent advances in liver triacylglycerol and fatty acid metabolism using stable isotope labeling techniques. J. Lipid Res. 47, 1651–1660 (2006).
Google Scholar
De Feyter, H. M. et al. Deuterium metabolic imaging (DMI) for MRI-based 3D mapping of metabolism in vivo. Sci. Adv. 4, eaat731410 (2018).
Google Scholar
Poli, S. et al. Interleaved trinuclear MRS for single-session investigation of carbohydrate and lipid metabolism in human liver at 7T. NMR Biomed. (2024).
Mucinski, J. M. et al. High-throughput LC-MS method to investigate postprandial lipemia: considerations for future precision nutrition research. Am. J. Physiol.-Endocrinol. Metab. 320, E702–E715 (2021).
Google Scholar
Parks, E. J., Skokan, L. E., Timlin, M. T. & Dingfelder, C. S. Dietary sugars stimulate fatty acid synthesis in adults. J. Nutr. 138, 1039–1046 (2008).
Google Scholar
Belew, G. D. et al. Estimating pentose phosphate pathway activity from the analysis of hepatic glycogen 13C-isotopomers derived from [U-13C]fructose and [U-13C]glucose. Magn. Reson. Med. 84, 2765–2771 (2020).
Google Scholar
Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–U166 (2012).
Google Scholar
Zhang, Z. et al. Serine catabolism generates liver NADPH and supports hepatic lipogenesis. Nat. Metab. 3, 1608–1620 (2021).
Gameiro, P. A., Laviolette, L. A., Kelleher, J. K., Iliopoulos, O. & Stephanopoulos, G. Cofactor balance by nicotinamide nucleotide transhydrogenase (NNT) coordinates reductive carboxylation and glucose catabolism in the tricarboxylic acid (TCA) cycle. J. Biol. Chem. 288, 12967–12977 (2013).
Google Scholar
Safadi, R. et al. The fatty acid-bile acid conjugate aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 12, 2085–U2365 (2014).
Google Scholar
Ratziu, V. et al. Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial. Nat. Med. 27, 1825–1835 (2021).
Google Scholar
Stiede, K. et al. Acetyl-Coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: a randomized, double-blind, crossover study. Hepatology 66, 324–334 (2017).
Google Scholar
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