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Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver
Open accessAbstract
The manner in which insulin resistance impinges on hepatic mitochondrial function is complex. Although liver insulin resistance is associated with respiratory dysfunction, the effect on fat oxidation remains controversial, and biosynthetic pathways that traverse mitochondria are actually increased. The tricarboxylic acid (TCA) cycle is the site of terminal fat oxidation, chief source of electrons for respiration, and a metabolic progenitor of gluconeogenesis. Therefore, we tested whether insulin resistance promotes hepatic TCA cycle flux in mice progressing to insulin resistance and fatty liver on a high-fat diet (HFD) for 32 weeks using standard biomolecular and in vivo (2)H/(13)C tracer methods. Relative mitochondrial content increased, but respiratory efficiency declined by 32 weeks of HFD. Fasting ketogenesis became unresponsive to feeding or insulin clamp, indicating blunted but constitutively active mitochondrial β-oxidation. Impaired insulin signaling was marked by elevated in vivo gluconeogenesis and anaplerotic and oxidative TCA cycle flux. The induction of TCA cycle function corresponded to the development of mitochondrial respiratory dysfunction, hepatic oxidative stress, and inflammation. Thus, the hepatic TCA cycle appears to enable mitochondrial dysfunction during insulin resistance by increasing electron deposition into an inefficient respiratory chain prone to reactive oxygen species production and by providing mitochondria-derived substrate for elevated gluconeogenesis.
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“In line with these arguments, both hepatic insulin resistance and simple steatosis were already established in mice fed a high-fat diet for 8 weeks, well before changes in mitochondrial bioenergetics became evident166,167.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [167]
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“Thus, repression of hepatic ketogenesis may precede insulin resistance in NASH through mTORC1 signaling pathways (Satapati et al., 2012) (Kucejova et al.”
BackgroundEcheverría, F., Valenzuela, R., Bustamante, A., Álvarez, D., Ortíz, M., Espinosa, A., Illesca, P., Gonzalez‐Mañán, D., & Videla, L. A. (2019) · Food & Function · doi:10.1039/c9fo01373c · Cited by 86
Mitochondrial genome architecture in non‐alcoholic fatty liver disease
Sookoian, S. C., Flichman, D., Scian, R., Rohr, C., Dopazo, H., Gianotti, T. F., Martino, J. S., Castaño, G. O., & Pirola, C. J. (2016) · The Journal of Pathology · doi:10.1002/path.4803 · Cited by 86
“Recent evidence from experimental [7;8] and human studies [9-11] have consistently demonstrated that NAFLD is associated with impaired tricarboxylic acid (TCA) cycle functioning, which takes place primarily in the mitochondrial (mt)-matrix.”
Le, L., Jiang, B., Wan, W., Zhai, W., Xu, L., Hu, K., & Xiao, P. (2016) · Scientific Reports · doi:10.1038/srep36184 · Cited by 87
“TCA intermediates and the components of glucose metabolism are strongly associated; insulin resistance promotes hepatic TCA flux in mice tending toward insulin resistance due to a HFD 48 .”
Rincón‐Cervera, M. Á., Valenzuela, R., Hernández‐Rodas, M. C., Marambio, M., Espinosa, A., Mayer, S., Romero, N., Barrera, C. R., Valenzuela, A., & Videla, L. A. (2016) · Nutrition · doi:10.1016/j.nut.2016.04.006 · Cited by 87
Williams, K. J., & Wu, X. (2016) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2016.02.004 · Cited by 83
“In contrast to normal physiology, high-fat-fed mice [823] and, more importantly, humans with non-alcoholic fatty liver disease [824] exhibit increased TCA cycling in liver, despite increased hepatic DNL (Section”
BackgroundMitochondrial heterogeneity in diseases
Chen, L., Zhou, M., Li, H., Liu, D., Liao, P., Yao, Z., Zhang, C., Zou, W., & Gao, J. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01546-w · Cited by 88
“232 ,233 Mitochondrial proteome sequencing of mouse acute liver injury, NAFLD or liver fi broblasts showed the high plasticity of mitochondrial proteins (Table 2).”
BackgroundRahim, M., Ragavan, M., Deja, S., Merritt, M. E., Burgess, S. C., & Young, J. D. (2021) · Metabolic Engineering · doi:10.1016/j.ymben.2021.12.009 · Cited by 80
Self-citationHasenour, C. M., Wall, M. L., Ridley, D. E., Hughey, C. C., James, F. D., Wasserman, D. H., & Young, J. D. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00003.2015 · Cited by 80
Zhang, W., Bu, S. Y., Mashek, M. T., O‐Sullivan, I., Sibai, Z., Khan, S. A., Ilkayeva, O., Newgard, C. B., Mashek, D. G., & Unterman, T. G. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.03.021 · Cited by 82
“Treatment with a low dose of etomoxir (3 mg/kg), which is sufficient to suppress FAO in the liver (Satapati et al., 2012) and BHB levels in briefly fasted FoxO1 Tgn mice (Figure S5A), restored normal glucose tolerance in FoxO1 Tgn mice (Figure 5E).”
BackgroundTompkins, S. C., Sheldon, R. D., Rauckhorst, A. J., Noterman, M. F., Solst, S. R., Buchanan, J. L., Mapuskar, K. A., Pewa, A. D., Gray, L. R., Oonthonpan, L., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.098 · Cited by 79
“In previous investigations, increased pyruvate anaplerosis in NAFLD increased TCA cycle flux, oxidative stress, and inflammation (Satapati et al., 2012, 2015).”
Regulation of Hepatic Energy Metabolism and Gluconeogenesis by BAD
Giménez-Cassina, A., García-Haro, L., Choi, C. S., Osundiji, M. A., Lane, E. A., Hu, H., Yıldırım, M. A., Szlyk, B., Fisher, J. K., Polak, K. Z., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2013.12.001 · Cited by 81
“OCR values in Figures 3 and 4 represent the difference between the maximal rate in the presence of ADP and the rate after addition of oligomycin, thus indicating ATP production by mitochondrial oxidative phosphorylation.”
InfluentialGo, Y., Jeong, J. Y., Jeoung, N. H., Jeon, J., Park, B.-Y., Kang, H., Ha, C., Choi, Y., Lee, S. J., Ham, H. J., et al. (2016) · Diabetes · doi:10.2337/db16-0223 · Cited by 78
“In agreement with our data, it has been demonstrated that hepatic PC activity correlates with gluconeogenesis in vivo and ex vivo in lipidinduced obesity models (20,26).”
BackgroundResultProtective effect of metformin against palmitate-induced hepatic cell death
Geng, Y., Villanueva, A. H., Oun, A., Buist‐Homan, M., Blokzijl, H., Faber, K. N., Dolga, A. M., & Moshage, H. J. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.165621 · Cited by 76
“Both clinical studies and animal experiments have shown that there is a significant increase in mitochondrial oxidative metabolism in NAFLD patients and animal models [29,30].”
BackgroundDallio, M., Sangineto, M., Romeo, M., Villani, R., Romano, A. D., Loguercio, C., Serviddio, G., & Federico, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22010436 · Cited by 77
“In the lipid-rich condition indeed, the liver tries to counteract the excessive production of lipotoxic molecules, by accumulating triglycerides and controlling FAO [24,54,55], even if several factors such as IR, leptin and enterokines might also play a role in this scenario [56].”
BackgroundMassey, V. L., Parrish, A., Argemí, J., Moreno, M., Mello, A., Garcı́a-Rocha, M., Altamirano, J., Òdena, G., Dubuquoy, L., Louvet, A., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.12.008 · Cited by 73
Potential Role of Oxidative Stress in the Production of Volatile Organic Compounds in Obesity
Oyerinde, A. S., Selvaraju, V., Babu, J. R., & Geetha, T. (2023) · Antioxidants · doi:10.3390/antiox12010129 · Cited by 75
“This raises the proton gradient along the inner mitochondrial membrane, causing electron leakage at complex III and superoxide production [10].”
BackgroundUndamatla, R., Fagunloye, O. G., Chen, J., Edmunds, L. R., Murali, A., Mills, A. S., Xie, B., Pangburn, M. M., SIPULA, I. J., Gibson, G. A., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-34710-x · Cited by 73
Moreno, K. X., Satapati, S., DeBerardinis, R. J., Burgess, S. C., Malloy, C. R., & Merritt, M. E. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.613265 · Cited by 69
“The fractional contribution to gluconeogenesis from glycogenolysis, glycerol, and phosphoenolpyruvate was determined from the relative deuterium enrichments in the H2, H5, and H6s positions of MAG as described previously (21, 22).”
MethodSelf-citationKhan, S. A., Wollaston-Hayden, E. E., Markowski, T. W., Higgins, L., & Mashek, D. G. (2015) · Journal of Lipid Research · doi:10.1194/jlr.m056812 · Cited by 64
Latorre‐Muro, P., Baeza, J., Armstrong, E. A., Hurtado‐Guerrero, R., Corzana, F., Wu, L. E., Sinclair, D. A., López‐Buesa, P., Carrodeguas, J. A., & Denu, J. M. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.07.031 · Cited by 68
“High TCA flux activity (Satapati et al., 2012; Sunny et al., 2011) has been observed in SIRT1 deficient mice (Purushotham et al.”
BackgroundMueller, K. M., Hartmann, K., Kaltenecker, D., Vettorazzi, S., Bauer, M., Mauser, L., Amann, S., Jall, S., Fischer, K., Esterbauer, H., et al. (2016) · Diabetes · doi:10.2337/db16-0381 · Cited by 67
“This demonstrates a considerable impact of adipocyte GR deficiency on the plasma metabolome and, thus, systemic substrate partitioning, which likely affects whole-body glucose and lipid metabolism in GR mice (6,29).”
BackgroundKalavalapalli, S., Bril, F., Koelmel, J. P., Abdo, K. I., Guingab, J., Andrews, P. M., Li, W., Jose, D., Yost, R. A., Frye, R. F., et al. (2018) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00023.2018 · Cited by 66
Self-citationGutiérrez‐Cuevas, J., Lucano‐Landeros, S., López-Cifuentes, D., Santos, A., & Armendáriz‐Borunda, J. (2022) · Cancers · doi:10.3390/cancers15010023 · Cited by 64
Garcia‐Berumen, C. I., Ortiz‐Avila, O., Vargas-Vargas, M. A., del Rosario-Tamayo, B. A., Guajardo-López, C., Saavedra‐Molina, A., Rodríguez-Orozco, A. R., & Cortés‐Rojo, C. (2019) · Lipids in Health and Disease · doi:10.1186/s12944-019-1024-5 · Cited by 68
Mitochondrial role in the neonatal predisposition to developing nonalcoholic fatty liver disease
Baker, P. R., & Friedman, J. E. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120846 · Cited by 64
Tsilingiris, D., Tzeravini, E., Koliaki, C. C., Dalamaga, Μ., & Kokkinos, A. D. (2021) · Current Obesity Reports · doi:10.1007/s13679-021-00434-0 · Cited by 60
“In line with preclinical data supporting an upregulated TCA flux in mice with dietinduced hepatic steatosis and IR [129, 130], Sunny et al.”
BackgroundPerry, R. J., Peng, L., Cline, G. W., Butrico, G. M., Wang, Y., Zhang, X., Rothman, D. L., Petersen, K. F., & Shulman, G. I. (2017) · Nature Communications · doi:10.1038/s41467-017-01143-w · Cited by 61
Shannon, C. E., Ragavan, M., Palavicini, J. P., Fourcaudot, M. J., Bakewell, T. M., Valdez, I., Ayala, I., Jin, E. S., Madesh, M., Han, X., et al. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101154 · Cited by 64
“In rodent models of NAFLD, increased hepatic lipid delivery following an obesogenic diet enhances TCA cycle activity and anaplerotic/cataplerotic fluxes, which augments oxidative stress and inflammation [7,8].”
BackgroundInfluentialGancheva, S., Kahl, S., Pesta, D., Mastrototaro, L., Dewidar, B., Strassburger, K., Sabah, E., Esposito, I., Weiß, J., Sarabhai, T., et al. (2022) · Diabetes Care · doi:10.2337/dc21-1758 · Cited by 60
Hepatocyte Injury and Hepatic Stem Cell Niche in the Progression of Non-Alcoholic Steatohepatitis
Overi, D., Carpino, G., Franchitto, A., Onori, P., & Gaudio, E. (2020) · Cells · doi:10.3390/cells9030590 · Cited by 62
“In NAFLD patients, products of lipid metabolism lead to damage to mtDNA and mitochondrial respiratory chain (MRC) proteins [23,25,67,74]; moreover, the binding of activated JNK to MRC complexes leads to increased ROS formation [25,35].”
BackgroundNayak, N., & Mishra, M. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119758 · Cited by 60
Guerra, S., Mocciaro, G., & Gastaldelli, A. (2021) · European Journal of Clinical Investigation · doi:10.1111/eci.13695 · Cited by 61
Integrated omics analysis reveals the alteration of gut microbe–metabolites in obese adults
Li, R., Huang, X., Xiao, L., Su, M., Lai, K. P., & Chen, J. (2020) · Briefings in Bioinformatics · doi:10.1093/bib/bbaa165 · Cited by 60
Simões, I. C. M., Amorim, R., Teixeira, J., Karkucińska‐Więckowska, A., Carvalho, A., Pereira, S. P., Simões, R. F., Szymańska, S., Dąbrowski, M., Janikiewicz, J., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136848 · Cited by 62
“These data are consistent with Satapati’s study, in which a similar obesogenic diet decreased the RCR in mice after just 32 weeks of feeding [18].”
BackgroundResultHigh‐Fat Diet Induces Oxidative Stress and MPK2 and HSP83 Gene Expression in Drosophila melanogaster
de Paula, M. T., Poetini, M. R., Araújo, S. M., Bortolotto, V. C., Meichtry, L. B., Zemolin, A. P. P., Wallau, G. L., Jessé, C. R., Franco, J. L., Posser, T., et al. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/4018157 · Cited by 57
“Studies have demonstrated that this oxidative stress process generates different responses such as the activation of signaling pathways implicated in protecting cells against oxidative damage, such as heat shock proteins (HSP) and mitogenactivated protein kinase (MAPK) [3], peroxidation of lipids and modification of p…”
BackgroundHigh Protein Diet and Metabolic Plasticity in Non-Alcoholic Fatty Liver Disease: Myths and Truths
Chiara, F. D., Checcllo, C. U., & Ramón‐Azcón, J. (2019) · Nutrients · doi:10.3390/nu11122985 · Cited by 58
“Lipids overload induce increase in hepatic mitochondrial oxidative and anaplerotic TCA cycle activity [73,77].”
Background
Metadata
- Authors
- Satapati, S., Sunny, N. E., Kucejova, B., Fu, X., He, T. T., Méndez-Lucas, A., Shelton, J. M., Perales, J. C., Browning, J. D., & Burgess, S. C.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Universitat de Barcelona (ES)
- Corresponding author
- Burgess, Shawn C.
- ORCID
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 53
- Issue
- 6
- Pages
- 1080-1092
- ISSN
- 0022-2275 (ISSN-L)
- PMC
- PMC3351815
- OpenAlex
- W2036097574
- Cited by
- 407
- References
- 70
- Citations by year
- 2026: 19 · 2025: 33 · 2024: 23 · 2023: 41 · 2022: 35 · 2021: 30 · 2020: 44 · 2019: 36 · 2018: 25 · 2017: 24 · 2016: 31 · 2015: 23 · 2014: 22 · 2013: 17 · 2012: 2
- FWCI
- 8.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK058398, R01DK087977, R01DK078184)
- National Institute of Dental and Craniofacial Research (UL1DE019584)
- National Center for Research Resources (P41RR002584, RR‐02584)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- TCA cycle, hepatic insulin resistance, high-fat diet, mitochondrial dysfunction, mitochondrial respiration, fat oxidation, ketogenesis, gluconeogenesis, oxidative stress, inflammation, insulin signaling, reactive oxygen species, mitochondrial beta-oxidation
- MeSH terms
- Animals, Citric Acid Cycle, Fatty Liver, Gluconeogenesis, Hyperglycemia, Insulin Resistance, Ketone Bodies, Liver, Male, Mice, Inbred C57BL, Mitochondria, Obesity, Time Factors, Oxidative Stress, Cell Respiration, Mice, Diet, High-Fat
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