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Fatty acids are novel nutrient factors to regulate mTORC1 lysosomal localization and apoptosis in podocytes
Open accessAbstract
Podocyte apoptosis is a potent mechanism of proteinuria in diabetic nephropathy. More detailed mechanistic insight into podocyte apoptosis is needed to better understand the pathogenesis of diabetic nephropathy. An elevated level of serum free fatty acid (FFA), as well as hyperglycemia, is a clinical characteristic in diabetes, although its causal role in podocyte apoptosis remains unclear. This study examined the effect of three types of FFAs, saturated, monounsaturated and polyunsaturated FFAs, on podocyte apoptosis. Palmitate, a saturated FFA, induced endoplasmic reticulum (ER) stress-dependent apoptosis in podocytes. Oleate, a monounsaturated FFA, and eicosapentaenoic acid (EPA), an ω-3 polyunsaturated FFA did not induce apoptosis; rather, they antagonized palmitate-induced apoptosis. Palmitate activated mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a nutrient-sensing kinase regulating a wide range of cell biology. Furthermore, inhibition of mTORC1 activity by rapamycin or siRNA for Raptor, a component of mTORC1, ameliorated palmitate-induced ER stress and apoptosis in podocytes. Activity of mTORC1 is regulated by upstream kinases and Rag/Ragulator-dependent recruitment of mTOR onto lysosomal membranes. Palmitate activated mTORC1 by enhancing recruitment of mTOR onto lysosomal membranes, which was inhibited by co-incubation with oleate or EPA. Inhibition of mTOR translocation onto lysosomes by transfection with dominant-negative forms of Rag ameliorated palmitate-induced apoptosis. This study suggests that saturated and unsaturated FFAs have opposite effects on podocyte apoptosis by regulating mTORC1 activity via its translocation onto lysosomal membranes, and the results provide a better understanding of the pathogenesis in diabetic nephropathy and a novel role of mTORC1 in cell apoptosis.
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“and activates both the NLRP3 inflammasome and mTORC116,17”
From Sebaceous-immunobiology is orchestrated by sebum lipids (2017) · cites this paper as [16]
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“Palmitic acid, the primary saturated fatty acid of milk fat globules, also activates mTORC1 at the lysosome [40].”
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“Several research groups also reported that FFAs activated mTORC1 and induced inflammation and cell injury in various cell types [13,15,26,27].”
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“However, it was determined that oleic acid and EPA inhibit the apoptosis induced by palmitate [24].”
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“FAs have a significant impact on mTORC1 regulation (Yasuda et al., 2014).”
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“In addition to the aforementioned effects of mTOR inhibition, Yasuda et al. [33] showed that mTOR inhibition ameliorated podocyte apoptosis.”
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“Notably, PA activates mTORC1 by enhancing its recruitment onto lysosomal membranes (153-155).”
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“19,20 21 – 23 For example, mTORC1 signaling should be suppressed in tubular cells exposed to hypoxia, 24 but this does not occur in diabetic atherosclerosis conditions, such as hyperglycemia and high fatty acids.”
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Inositol-requiring enzyme 1α links palmitate-induced mTOR activation and lipotoxicity in hepatocytes
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“One proposed mechanism of how FFAs-related lipotoxi-city can cause kidney injury is via the activation of the mTOR pathway (20, 167).”
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“In addition, palmitate exposure was reported to enhance mTORC1-dependent p70S6K1 activation in hepatocytes [62] and podocytes [63] as well.”
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“Moreover, saturated FFAs activate mTOR pathway and induce cell apoptosis [186].”
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“Moreover, rapamycin significantly diminishes FFA-induced podocyte apoptosis ( Yasuda et al., 2014 ), supporting its potential ability to suppress possible outcomes of FFA upregulation in the Drosophila brain, thus improving glial phenotype in mutants with BBB breakdown.”
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Self-citation
Metadata
- Authors
- Yasuda, M., Tanaka, Y., Kume, S., Morita, Y., Chin-Kanasaki, M., Araki, H., Isshiki, K., Araki, S.-I., Koya, D., Haneda, M., Kashiwagi, A., Maegawa, H., & Uzu, T.
- Affiliations
- Shiga University of Medical Science (JP)
- Kanazawa Medical University (JP)
- Asahikawa Medical University (JP)
- Corresponding author
- Kume, Shinji
- ORCID
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 1842
- Issue
- 7
- Pages
- 1097-1108
- ISSN
- 0925-4439 (ISSN-L)
- OpenAlex
- W2033453768
- Cited by
- 123
- References
- 57
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 7 · 2023: 4 · 2022: 9 · 2021: 20 · 2020: 16 · 2019: 14 · 2018: 9 · 2017: 10 · 2016: 10 · 2015: 9 · 2014: 5
- FWCI
- 8.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Uehara Memorial Foundation
- Japan Society for the Promotion of Science (25713033, 24890089)
- Topics
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- podocyte apoptosis, mTORC1, free fatty acids, palmitate, oleate, eicosapentaenoic acid, endoplasmic reticulum stress, lysosomal translocation, raptors, diabetic nephropathy, proteinuria, saturated fatty acids, omega-3 fatty acids
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Cell Line, Diabetic Nephropathies, Fatty Acids, Food, Humans, Lysosomes, Palmitates, Eicosapentaenoic Acid, Apoptosis, Oleic Acid, Multiprotein Complexes, Podocytes, Mice, HEK293 Cells, TOR Serine-Threonine Kinases, Endoplasmic Reticulum Stress
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