As a Matter of Fat

Brookheart, Rita T.; Michel, Carlos I.; Schaffer, Jean E.

doi:10.1016/j.cmet.2009.03.011

Cited by 279Lipid metabolism and biosynthesisCancer, Lipids, and MetabolismAutophagy in Disease and Therapy

As a Matter of Fat

Open access

Brookheart, Rita T., Michel, Carlos I., Schaffer, Jean E.·2009·Cell Metabolism

DOI 10.1016/j.cmet.2009.03.011PMC PMC2751821

Open this paper in CoChat — free account Open PDF

Abstract

Excess fatty acid accumulation in nonadipose tissues is a hallmark of metabolic disease. When elevated lipid levels exceed the cell's capacity to store or utilize fatty acids, a lipotoxic-response is elicited, characterized by destruction of organelle membranes, activation of stress pathways, and apoptosis. This Minireview focuses on the mechanisms by which lipid overload causes nonadipose cell death and contributes to the pathogenesis of obesity and diabetes.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1016/j.cmet.2009.03.011

Cites

32 of 32 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Excess ectopic lipids are believed to induce lipotoxicity that can impair neuromuscular function.
“These excess ectopic lipids are believed to induce lipotoxicity, where dysfunctional lipid metabolism promotes inflammation, oxidative injury and disruption of several cell functions, including maintenance of the neuromuscular junction (NMJ) [55–57, 64], all of which could impair neuromuscular function.”
From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [56]
Ectopic deposition of lipids in muscle is associated with inflammation, oxidative injury, insulin resistance and disruption of several cell functions, a condition referred to as lipotoxicity.
“This ectopic deposition of lipids in muscle is a hallmark of pathology in several conditions and is associated with inflammation, oxidative injury, insulin resistance and disruption of several cell functions, a condition referred to as lipotoxicity [55–57].”
From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [56]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes
Özcan, U., Cao, Q., Yilmaz, E., Lee, A.-H., Iwakoshi, N. N., Özdelen, E., Tuncman, G., Görgün, C., Glimcher, L. H., & Hotamisligil, G. S. (2004) · Science · doi:10.1126/science.1103160 · Cited by 3,844 · see citing works
Chemical Chaperones Reduce ER Stress and Restore Glucose Homeostasis in a Mouse Model of Type 2 Diabetes
Özcan, U., Yilmaz, E., Özcan, L., Furuhashi, M., Vaillancourt, E., Smith, R. O., Görgün, C. Z., & Hotamisligil, G. S. (2006) · Science · doi:10.1126/science.1128294 · Cited by 2,413 · see citing works
Triglyceride accumulation protects against fatty acid-induced lipotoxicity
Listenberger, L. L., Han, X., Lewis, S. E., Cases, S., Farese, R. V., Ory, D. S., & Schaffer, J. E. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0630588100 · Cited by 2,075 · see citing works
Self-citation
Mitochondrial Overload and Incomplete Fatty Acid Oxidation Contribute to Skeletal Muscle Insulin Resistance
Koves, T. R., Ussher, J. R., Noland, R. C., Slentz, D., Mosedale, M., Ilkayeva, O., Bain, J., Stevens, R., Dyck, J. R. B., Newgard, C. B., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.013 · Cited by 1,990 · see citing works
High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells
Inoguchi, T., Li, P., Umeda, F., Yu, H. Y., Kakimoto, M., Imamura, M., Aoki, T., Etoh, T., Hashimoto, T., Naruse, M., et al. (2000) · Diabetes · doi:10.2337/diabetes.49.11.1939 · Cited by 1,577 · see citing works
Lipotoxic heart disease in obese rats: Implications for human obesity
Zhou, Y.-T., Grayburn, P., Karim, A., Shimabukuro, M., Higa, M., Baetens, D., Orci, L., & Unger, R. H. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.4.1784 · Cited by 1,265 · see citing works
Fatty acid-induced β cell apoptosis: A link between obesity and diabetes
Shimabukuro, M., Zhou, Y.-T., Levi, M., & Unger, R. H. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.5.2498 · Cited by 1,142 · see citing works
Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships.
Lee, Y., Hirose, H., Ohneda, M., Johnson, J. H., McGarry, J., & Unger, R. H. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.23.10878 · Cited by 832 · see citing works
Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart
Sharma, S., Adrogue, J. V., Golfman, L., Uray, I., Lemm, J., Youker, K., Noon, G. P., Frazier, O. H., & Taegtmeyer, H. (2004) · The FASEB Journal · doi:10.1096/fj.04-2263com · Cited by 790 · see citing works
A novel mouse model of lipotoxic cardiomyopathy
Chiu, H.-C., Kovács, A., Ford, D. A., Hsu, F., Garcia, R. A., Herrero, P., Saffitz, J. E., & Schaffer, J. E. (2001) · Journal of Clinical Investigation · doi:10.1172/jci10947 · Cited by 762 · see citing works
Self-citation
Chop deletion reduces oxidative stress, improves β cell function, and promotes cell survival in multiple mouse models of diabetes
Song, B., Scheuner, D. L., Ron, D., Pennathur, S., & Kaufman, R. J. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34587 · Cited by 693 · see citing works
Palmitate-induced Apoptosis Can Occur through a Ceramide-independent Pathway
Listenberger, L. L., Ory, D. S., & Schaffer, J. E. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010286200 · Cited by 594 · see citing works
Self-citation
Saturated Fatty Acids Synergize with Elevated Glucose to Cause Pancreatic β-Cell Death
El-Assaad, W., Buteau, J., Peyot, M., Nolan, C. J., Roduit, R., Hardy, S., Joly, E. C., Dbaibo, G. S., Rosenberg, L. C., & Prentki, M. (2003) · Endocrinology · doi:10.1210/en.2003-0410 · Cited by 586 · see citing works
Free Fatty Acids and Cytokines Induce Pancreatic β-Cell Apoptosis by Different Mechanisms: Role of Nuclear Factor-κB and Endoplasmic Reticulum Stress
Kharroubi, I., Ladrière, L., Cardozo, A. K., Doğusan, Z., Cnop, M., & Eizirik, D. L. (2004) · Endocrinology · doi:10.1210/en.2004-0478 · Cited by 582 · see citing works
Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death
Borradaile, N. M., Han, X., Harp, J. D., Gale, S. E., Ory, D. S., & Schaffer, J. E. (2006) · Journal of Lipid Research · doi:10.1194/jlr.m600299-jlr200 · Cited by 564 · see citing works
Self-citation
Monounsaturated Fatty Acids Prevent the Deleterious Effects of Palmitate and High Glucose on Human Pancreatic β-Cell Turnover and Function
Maedler, K., Oberholzer, J., Bucher, P., Spinas, G. A., & Donath, M. Y. (2003) · Diabetes · doi:10.2337/diabetes.52.3.726 · Cited by 552 · see citing works
Saturated Fatty Acids Promote Endoplasmic Reticulum Stress and Liver Injury in Rats with Hepatic Steatosis
Wang, D., Wei, Y., & Pagliassotti, M. J. (2005) · Endocrinology · doi:10.1210/en.2005-0570 · Cited by 529 · see citing works
Myocardial triglycerides and systolic function in humans: In vivo evaluation by localized proton spectroscopy and cardiac imaging
Szczepaniak, L. S., Dobbins, R. L., Metzger, G. J., Sartoni‐D'Ambrosia, G., Arbique, D., Vongpatanasin, W., Unger, R. H., & Victor, R. G. (2003) · Magnetic Resonance in Medicine · doi:10.1002/mrm.10372 · Cited by 441 · see citing works
Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy
Yagyu, H., Chen, G., Yokoyama, M., Hirata, K., Augustus, A. S., Kako, Y., Seo, T., Hu, Y., Lutz, E. P., Merkel, M., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci16751 · Cited by 394 · see citing works
Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance
Liu, L., Zhang, Y., Chen, N., Shi, X., Tsang, B., & Yu, Y.-H. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30565 · Cited by 356 · see citing works
Saturated but not mono-unsaturated fatty acids induce apoptotic cell death in neonatal rat ventricular myocytes
de Vries, J. E., Vork, M. M., Roemen, T. H., de Jong, Y. F., Cleutjens, J. P., van der Vusse, G. J., & van Bilsen, M. (1997) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)37421-6 · Cited by 324 · see citing works
Decreased Cardiolipin Synthesis Corresponds with Cytochromec Release in Palmitate-induced Cardiomyocyte Apoptosis
Ostrander, D. B., Sparagna, G. C., Amoscato, A. A., McMillin, J. B., & Dowhan, W. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m107067200 · Cited by 289 · see citing works
Selective Inhibition of Eukaryotic Translation Initiation Factor 2α Dephosphorylation Potentiates Fatty Acid-induced Endoplasmic Reticulum Stress and Causes Pancreatic β-Cell Dysfunction and Apoptosis
Cnop, M., Ladrière, L., Hekerman, P., Ortis, F., Cardozo, A. K., Doğusan, Z., Flamez, D., Boyce, M., Yuan, J., & Eizirik, D. L. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m607627200 · Cited by 287 · see citing works
Unraveling the Temporal Pattern of Diet-Induced Insulin Resistance in Individual Organs and Cardiac Dysfunction in <scp>c57bl/6</scp> Mice
Park, S.-Y., Cho, Y.-R., Kim, H.-J., Higashimori, T., Danton, C., Lee, M.-K., Dey, A., Rothermel, B., Kim, Y.-B., Kalinowski, A., et al. (2005) · Diabetes · doi:10.2337/diabetes.54.12.3530 · Cited by 286 · cited 1× · see citing works
“…of findings from leptin-deficient models to human obesity and diabetes has been debated, lipid accumulation and cell death in nonadipose tissues of murine models of diet-induced obesity are consistent with a role for lipid accumulation in the pathogenesis of organ dysfunction (Park et al., 2005).”
Background
Catalase Protects Cardiomyocyte Function in Models of Type 1 and Type 2 Diabetes
Ye, G., Metreveli, N. S., Donthi, R. V., Shen, X., Xu, M., Carlson, E. C., & Epstein, P. N. (2004) · Diabetes · doi:10.2337/diabetes.53.5.1336 · Cited by 278 · see citing works
AMPK inhibits fatty acid-induced increases in NF-κB transactivation in cultured human umbilical vein endothelial cells
Cacicedo, J. M., Yagihashi, N., Keaney, J. F., Ruderman, N. B., & Ido, Y. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.09.177 · Cited by 233 · see citing works
Palmitate-Induced Apoptosis in Cultured Bovine Retinal Pericytes
Cacicedo, J. M., Benjachareowong, S., Chou, E. L., Ruderman, N. B., & Ido, Y. (2005) · Diabetes · doi:10.2337/diabetes.54.6.1838 · Cited by 158 · see citing works
A Critical Role for Eukaryotic Elongation Factor 1A-1 in Lipotoxic Cell Death
Borradaile, N. M., Buhman, K. K., Listenberger, L. L., Magee, C. J., Morimoto, E., Ory, D. S., & Schaffer, J. E. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-08-0742 · Cited by 143 · see citing works
Self-citation
Protein Kinase C δ Activation and Translocation to the Nucleus Are Required for Fatty Acid-Induced Apoptosis of Insulin-Secreting Cells
Eitel, K., Staiger, H., Rieger, J., Mischak, H., Brandhorst, H., Brendel, M. D., Bretzel, R. G., Häring, H., & Kellerer, M. (2003) · Diabetes · doi:10.2337/diabetes.52.4.991 · Cited by 142 · see citing works
Adverse physicochemical properties of tripalmitin in beta cells lead to morphological changes and lipotoxicity in vitro
Moffitt, J. H., Fielding, B. A., Evershed, R. P., Berstan, R., Currie, J. M., & Clark, A. (2005) · Diabetologia · doi:10.1007/s00125-005-1861-9 · Cited by 114 · see citing works
The Non-coding RNA gadd7 Is a Regulator of Lipid-induced Oxidative and Endoplasmic Reticulum Stress
Brookheart, R. T., Michel, C. I., Listenberger, L. L., Ory, D. S., & Schaffer, J. E. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m806209200 · Cited by 83 · see citing works
Self-citation
α-Lipoic acid prevents lipotoxic cardiomyopathy in acyl CoA-synthase transgenic mice
Lee, Y., Naseem, R. H., Park, B., Garry, D. J., Richardson, J. A., Schaffer, J. E., & Unger, R. H. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.03.062 · Cited by 77 · see citing works
Self-citation

Flagged first, then by citations

Sorted by citations

RETRACTED ARTICLE: NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages
Moon, J.-S., Nakahira, K., Chung, K.-P., DeNicola, G. M., Koo, M. J., Pabón, M. A., Rooney, K. T., Yoon, J.-H., Ryter, S. W., Stout-Delgado, H., et al. (2016) · Nature Medicine · doi:10.1038/nm.4153 · Cited by 291 · see citing works
Retracted
Probing the Global Cellular Responses to Lipotoxicity Caused by Saturated Fatty Acids
Piccolis, M., Bond, L. M., Kampmann, M., Pulimeno, P., Chitraju, C., Jayson, C. B. K., Vaites, L. P., Boland, S., Lai, Z. W., Gabriel, K. R., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.01.036 · Cited by 269 · see citing works
What is lipotoxicity?
Engin, A. B. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-48382-5_8 · Cited by 260 · see citing works
Lifestyle and nutritional imbalances associated with Western diseases: causes and consequences of chronic systemic low-grade inflammation in an evolutionary context
Ruiz-Núñez, B., Pruimboom, L., Dijck-Brouwer, D. A. J., & Muskiet, F. A. J. (2013) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2013.02.009 · Cited by 246 · see citing works
Sweet Sixteenth for ChREBP: Established Roles and Future Goals
Abdul-Wahed, A., Guilmeau, S., & Postic, C. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.07.004 · Cited by 231 · see citing works
Induced polymerization of mammalian acetyl-CoA carboxylase by MIG12 provides a tertiary level of regulation of fatty acid synthesis
Kim, C.-W., Moon, Y.-A., Park, S. W., Cheng, D., Kwon, H. J., & Horton, J. D. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1001292107 · Cited by 136 · see citing works
Augmentation of Glucotoxicity, Oxidative Stress, Apoptosis and Mitochondrial Dysfunction in HepG2 Cells by Palmitic Acid
Alnahdi, A., John, A., & Raza, H. (2019) · Nutrients · doi:10.3390/nu11091979 · Cited by 134 · see citing works
Is fat so bad? Modulation of endoplasmic reticulum stress by lipid droplet formation
Hapala, I., Marza, E., & Ferreira, T. (2011) · Biology of the Cell · doi:10.1042/bc20100144 · Cited by 125 · see citing works
The effects of curcumin supplementation on glycemic status, lipid profile and hs-CRP levels in overweight/obese women with polycystic ovary syndrome: A randomized, double-blind, placebo-controlled clinical trial
Sohaei, S., Amani, R., Tarrahi, M. J., & Ghasemi-Tehrani, H. (2019) · Complementary Therapies in Medicine · doi:10.1016/j.ctim.2019.102201 · Cited by 100 · see citing works
SIRT1 activation attenuates palmitate induced apoptosis in C2C12 muscle cells
Taheripak, G., Sabeti, N., Najar, N., Razavi, Z., Saharkhiz, S., & Alipourfard, I. (2024) · Molecular Biology Reports · doi:10.1007/s11033-024-09250-w · Cited by 33 · see citing works
Targeting Intramyocellular Lipids to Improve Aging Muscle Function
Russ, D. W., Manickam, R., & Tipparaju, S. M. (2025) · Lipids in Health and Disease · doi:10.1186/s12944-025-02622-6 · Cited by 15 · see citing works

Authors: Brookheart, R. T., Michel, C. I., & Schaffer, J. E.
Affiliations: Washington University in St. Louis (US)
Corresponding author: Schaffer, Jean E.
ORCID: Brookheart, Rita T.
Schaffer, Jean E.
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2009-07
Volume: 10
Issue: 1
Pages: 9-12
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2009.03.011
PMC: PMC2751821
OpenAlex: W2013570209
Cited by: 279
References: 32
Citations by year: 2026: 4 · 2025: 6 · 2024: 16 · 2023: 15 · 2022: 16 · 2021: 15 · 2020: 21 · 2019: 20 · 2018: 23 · 2017: 15 · 2016: 18 · 2015: 15 · 2014: 14 · 2013: 17 · 2012: 27
FWCI: 1.63
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1477 d)
Locations: Cell Metabolism (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases (DK064989, R01DK064989, R56DK064989, F31DK077583, DK077583, F31DK077577, DK 077577)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords: lipotoxicity, fatty acid accumulation, lipid overload, cell death, apoptosis, stress response pathways, obesity, diabetes mellitus
MeSH terms: Cell Membrane, Endoplasmic Reticulum, Fatty Acids, Mitochondria, Signal Transduction, Apoptosis, Oxidative Stress, Lipid Metabolism

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

As a Matter of Fat

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Related

Record

About these checks