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FABP1-Mediated Lipid Metabolic Reprogramming Buffers Lipotoxicity in Nephrolithiasis via Maintaining PPARγ Activity.

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Τίτλος: FABP1-Mediated Lipid Metabolic Reprogramming Buffers Lipotoxicity in Nephrolithiasis via Maintaining PPARγ Activity.
Συγγραφείς: He Q; Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.; Institute of Urology, Anhui Medical University, Hefei, China.; Anhui Provincial Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei, China., Song Z; Department of Urology, Anhui No. 2 Provincial People's Hospital, Hefei, China., Jiang Z; Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.; Institute of Urology, Anhui Medical University, Hefei, China.; Anhui Provincial Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei, China., Pan J; Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.; Institute of Urology, Anhui Medical University, Hefei, China.; Anhui Provincial Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei, China., Hou B; Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.; Institute of Urology, Anhui Medical University, Hefei, China.; Anhui Provincial Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei, China., Huang Q; Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.; Institute of Urology, Anhui Medical University, Hefei, China.; Anhui Provincial Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei, China., Xu Y; Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China., Hao Z; Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.; Institute of Urology, Anhui Medical University, Hefei, China.; Anhui Provincial Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei, China.
Πηγή: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2026 Sep 30; Vol. 40 (18), pp. e72320.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Federation of American Societies for Experimental Biology Country of Publication: United States NLM ID: 8804484 Publication Model: Print Cited Medium: Internet ISSN: 1530-6860 (Electronic) Linking ISSN: 08926638 NLM ISO Abbreviation: FASEB J Subsets: MEDLINE
Imprint Name(s): Publication: 2020- : [Bethesda, Md.] : Hoboken, NJ : Federation of American Societies for Experimental Biology ; Wiley
Original Publication: [Bethesda, Md.] : The Federation, [c1987-
Ιατρικοί όροι (MeSH): PPAR gamma*/metabolism , PPAR gamma*/genetics , Fatty Acid-Binding Proteins*/metabolism , Fatty Acid-Binding Proteins*/genetics , Nephrolithiasis*/metabolism , Nephrolithiasis*/pathology , Lipid Metabolism*, Animals ; Humans ; Mice ; Metabolic Reprogramming ; Cell Line
Περίληψη: Nephrolithiasis-induced lipotoxicity is a critical driver of tubular cell death and renal function decline, yet targeted pharmacological interventions remain a major unmet clinical need. While Fatty Acid-Binding Protein 1 (FABP1) is widely recognized as a passive injury biomarker, its active functional role in buffering lipotoxicity during nephrolithiasis remains uncharacterized. By integrating clinical specimens from nephrolithiasis patients, AAV9-mediated kidney-specific Fabp1 knockdown murine models, and HK-2 cell lines, we delineated the FABP1 regulatory landscape using transcriptomic and untargeted metabolomic profiling. Furthermore, the core mechanistic interactions were definitively validated via Co-Immunoprecipitation (Co-IP) and PPRE-driven dual-luciferase reporter assays. FABP1 is significantly upregulated in nephrolithiasis. Mechanistically, crystal-induced lysosomal stress triggers Ca2+ efflux, which activates the calcineurin pathway to drive TFEB nuclear translocation and subsequent FABP1 transcription. Crucially, FABP1 functions as an indispensable nuclear chaperone, physically engaging PPARγ to sustain its core transcriptional activity. FABP1 deficiency dismantles this defense, impairing protective lipid droplet biogenesis to sequester free fatty acids. This failure precipitates excessive 4-HNE accumulation, marked lipid peroxidation, TCA cycle collapse, a pronounced NF-κB-driven inflammatory storm, and ultimate renal functional deterioration. Importantly, targeted pharmacological activation of PPARγ utilizing rosiglitazone circumvents FABP1 depletion, rewiring global lipid and energetic fluxes to rescue tubular cell injury. Our findings redefine FABP1 from a passive clinical biomarker to an active homeostatic buffer. This study delineates the Ca2+/calcineurin-TFEB-FABP1-PPARγ axis as a vital defense mechanism against lipotoxicity, providing a compelling translational rationale for PPARγ-targeted metabolic interventions to treat nephrolithiasis.
(© 2026 Federation of American Societies for Experimental Biology.)
References: M. Bargagli, M. Scoglio, S. A. Howles, and D. G. Fuster, “Kidney Stone Disease: Risk Factors, Pathophysiology and Management,” Nature Reviews. Nephrology 21, no. 11 (2025): 794–808.
X. Tang and J. C. Lieske, “Acute and Chronic Kidney Injury in Nephrolithiasis,” Current Opinion in Nephrology and Hypertension 23, no. 4 (2014): 385–390.
X. Liu, J. Zhou, C. Liu, F. Shao, and Z. Li, “Analysis of Risk Factors for Kidney Stones in Patients With Hyperuricemia: A Cross‐Sectional Study Based on NHANES,” Translational Andrology and Urology 14, no. 10 (2025): 3194–3202.
D. Assimos, A. Krambeck, N. L. Miller, et al., “Surgical Management of Stones: American Urological Association/Endourological Society Guideline, PART I,” Journal of Urology 196, no. 4 (2016): 1153–1160.
F. Galli, M. Bonomini, D. Bartolini, et al., “Vitamin E (Alpha‐Tocopherol) Metabolism and Nutrition in Chronic Kidney Disease,” Antioxidants 11, no. 5 (2022): 989.
J. A. Olzmann and P. Carvalho, “Dynamics and Functions of Lipid Droplets,” Nature Reviews. Molecular Cell Biology 20, no. 3 (2019): 137–155.
A. P. Bailey, G. Koster, C. Guillermier, et al., “Antioxidant Role for Lipid Droplets in a Stem Cell Niche of Drosophila,” Cell 163, no. 2 (2015): 340–353.
T. C. Walther and R. V. J. Farese, “Lipid Droplets and Cellular Lipid Metabolism,” Annual Review of Biochemistry 81 (2012): 687–714.
S. Gaffar and A. S. Aathirah, “Fatty‐Acid‐Binding Proteins: From Lipid Transporters to Disease Biomarkers,” Biomolecules 13, no. 12 (2023): 1753.
K. Taguchi, L. Chen, M. Usawachintachit, et al., “Fatty Acid‐Binding Protein 4 Downregulation Drives Calcification in the Development of Kidney Stone Disease,” Kidney International 97, no. 5 (2020): 1042–1056.
E. Noiri, K. Doi, K. Negishi, et al., “Urinary Fatty Acid‐Binding Protein 1: An Early Predictive Biomarker of Kidney Injury,” American Journal of Physiology. Renal Physiology 296, no. 4 (2009): F669–F679.
B. Wilnes, B. Castello‐Branco, B. C. Branco, A. Sanglard, P. A. S. Vaz de Castro, and A. C. Simões‐e‐Silva, “Urinary L‐FABP as an Early Biomarker for Pediatric Acute Kidney Injury Following Cardiac Surgery With Cardiopulmonary Bypass: A Systematic Review and Meta‐Analysis,” International Journal of Molecular Sciences 25, no. 9 (2024): 4912.
A. D'Anneo, C. C. Bavisotto, A. M. Gammazza, et al., “Lipid Chaperones and Associated Diseases: A Group of Chaperonopathies Defining a New Nosological Entity With Implications for Medical Research and Practice,” Cell Stress & Chaperones 25, no. 6 (2020): 805–820.
S. R. Mulay, O. P. Kulkarni, K. V. Rupanagudi, et al., “Calcium Oxalate Crystals Induce Renal Inflammation by NLRP3‐Mediated IL‐1β Secretion,” Journal of Clinical Investigation 123, no. 1 (2013): 236–246.
X. Sun, Q. Gan, and J. Ouyang, “Calcium Oxalate Toxicity in Renal Epithelial Cells: The Mediation of Crystal Size on Cell Death Mode,” Cell Death Discovery 1 (2015): 15055.
C. Liu, W. Wei, Y. Huang, P. Fu, L. Zhang, and Y. Zhao, “Metabolic Reprogramming in Septic Acute Kidney Injury: Pathogenesis and Therapeutic Implications,” Metabolism, Clinical and Experimental 158 (2024): 155974.
F. G. Garcia, M. R. Moreno, S. Chetty, et al., “Integrated AAV Optimization Enables Efficient Gene Delivery to Kidney in Murine and Human Tissue,” Research Square 24 (2025): 7925411.
T. Mukai, M. Egawa, T. Takeuchi, H. Yamashita, and T. Kusudo, “Silencing of FABP1 Ameliorates Hepatic Steatosis, Inflammation, and Oxidative Stress in Mice With Nonalcoholic Fatty Liver Disease,” FEBS Open Bio 7, no. 7 (2017): 1009–1016.
H. Lu, X. Sun, M. Jia, et al., “Rosiglitazone Suppresses Renal Crystal Deposition by Ameliorating Tubular Injury Resulted From Oxidative Stress and Inflammatory Response via Promoting the Nrf2/HO‐1 Pathway and Shifting Macrophage Polarization,” Oxidative Medicine and Cellular Longevity 2021 (2021): 5527137.
S. Chaiyarit and V. Thongboonkerd, “Changes in Mitochondrial Proteome of Renal Tubular Cells Induced by Calcium Oxalate Monohydrate Crystal Adhesion and Internalization Are Related to Mitochondrial Dysfunction,” Journal of Proteome Research 11, no. 6 (2012): 3269–3280.
H. Zhu, Y. Chen, Y. Zhong, X. Xie, X. Zeng, and W. Deng, “Knockdown of Long Non‐Coding RNA SBF2‐AS1 Inhibits Calcium Oxalate‐Induced HK‐2 Cell Injury by Regulating the miR‐302e/NLRP3 Pathway,” Urolithiasis 52, no. 1 (2024): 113.
Y. Xiong, W. Huang, X. Ling, et al., “Mitochondrial Calcium Uniporter Promotes Kidney Aging in Mice Through Inducing Mitochondrial Calcium‐Mediated Renal Tubular Cell Senescence,” Acta Pharmacologica Sinica 45, no. 10 (2024): 2149–2162.
A. Pérez‐Martí, S. Ramakrishnan, J. Li, et al., “Reducing Lipid Bilayer Stress by Monounsaturated Fatty Acids Protects Renal Proximal Tubules in Diabetes,” eLife 11 (2022): e74391.
P. Gao, X. Cheng, M. Liu, et al., “GADD45α Is a Direct Target of TFEB and Contributes to Tacrolimus‐Induced Chronic Nephrotoxicity,” JCI Insight 10, no. 6 (2025): e183560.
M. I. Love, W. Huber, and S. Anders, “Moderated Estimation of Fold Change and Dispersion for RNA‐Seq Data With DESeq2,” Genome Biology 15, no. 12 (2014): 550.
J. Jumper, R. Evans, A. Pritzel, et al., “Highly Accurate Protein Structure Prediction With AlphaFold,” Nature 596, no. 7873 (2021): 583–589.
I. Rauluseviciute, R. Riudavets‐Puig, R. Blanc‐Mathieu, et al., “JASPAR 2024: 20th Anniversary of the Open‐Access Database of Transcription Factor Binding Profiles,” Nucleic Acids Research 52, no. D1 (2024): D174–D182.
S. Nakamura, S. Akayama, and T. Yoshimori, “Autophagy‐Independent Function of Lipidated LC3 Essential for TFEB Activation During the Lysosomal Damage Responses,” Autophagy 17, no. 2 (2021): 581–583.
S. R. Mulay, C. Shi, X. Ma, and H. J. Anders, “Novel Insights Into Crystal‐Induced Kidney Injury,” Kidney Diseases 4, no. 2 (2018): 49–57.
Y. Xu, Y. Xie, X. Shao, Z. Ni, and S. Mou, “L‐FABP: A Novel Biomarker of Kidney Disease,” Clinica Chimica Acta 445 (2015): 85–90.
K. Taguchi, A. Okada, S. Hamamoto, et al., “Proinflammatory and Metabolic Changes Facilitate Renal Crystal Deposition in an Obese Mouse Model of Metabolic Syndrome,” Journal of Urology 194, no. 6 (2015): 1787–1796.
X. Sun, S. Xu, Y. Ni, R. Chen, and C. Dai, “Depalmitoylation of TEAD1 Facilitates Lipid Droplet Accumulation and Resistance to Oxidative Stress by Transactivating PP2Acα,” Free Radical Biology & Medicine 240 (2025): 532–545.
L. Qi, J. Yi, Y. Ji, et al., “Network of Cell Death in Myocardial Ischemia‐Reperfusion Injury: Mechanisms and Targeted Therapeutic Strategies,” Biochemical Pharmacology 250, no. Pt 2 (2026): 117999.
N. Rusli, C. F. Ng, S. Makpol, Y. P. Wong, I. L. Mohd Isa, and R. Remli, “Antioxidant Effect in Diabetic Peripheral Neuropathy in Rat Model: A Systematic Review,” Antioxidants 13, no. 9 (2024): 1041.
F. Knauf, J. R. Asplin, I. Granja, et al., “NALP3‐Mediated Inflammation Is a Principal Cause of Progressive Renal Failure in Oxalate Nephropathy,” Kidney International 84, no. 5 (2013): 895–901.
M. A. Katsnelson, K. M. Lozada‐Soto, H. M. Russo, B. A. Miller, and G. R. Dubyak, “NLRP3 Inflammasome Signaling Is Activated by Low‐Level Lysosome Disruption but Inhibited by Extensive Lysosome Disruption: Roles for K+ Efflux and Ca2+ Influx,” American Journal of Physiology. Cell Physiology 311, no. 1 (2016): C83–C100.
N. Raben and R. Puertollano, “TFEB and TFE3: Linking Lysosomes to Cellular Adaptation to Stress,” Annual Review of Cell and Developmental Biology 32 (2016): 255–278.
K. Du, H. Chen, Z. Pan, et al., “Small‐Molecule Activation of TFEB Alleviates Niemann‐Pick Disease Type C via Promoting Lysosomal Exocytosis and Biogenesis,” eLife 13 (2025): RP103137.
T. Itoh, L. Fairall, K. Amin, et al., “Structural Basis for the Activation of PPARgamma by Oxidized Fatty Acids,” Nature Structural & Molecular Biology 15, no. 9 (2008): 924–931.
W. Liu, Z. Xiong, T. Fu, et al., “Regulation of Renal Ischemia‐Reperfusion Injury and Tubular Epithelial Cell Ferroptosis by pparγ m6a Methylation: Mechanisms and Therapeutic Implications,” Biology Direct 19, no. 1 (2024): 99.
H. M. Kang, S. H. Ahn, P. Choi, et al., “Defective Fatty Acid Oxidation in Renal Tubular Epithelial Cells Has a Key Role in Kidney Fibrosis Development,” Nature Medicine 21, no. 1 (2015): 37–46.
K. M. Ralto, E. P. Rhee, and S. M. Parikh, “NAD(+) Homeostasis in Renal Health and Disease,” Nature Reviews. Nephrology 16, no. 2 (2020): 99–111.
J. Liu, S. Ghosh, J. Kovalik, et al., “Profiling of Plasma Metabolites Suggests Altered Mitochondrial Fuel Usage and Remodeling of Sphingolipid Metabolism in Individuals With Type?2 Diabetes and Kidney Disease,” Kidney International Reports 2, no. 3 (2016): 470–480.
B. L. Gorman and J. K. Lukowski, “Spatial Metabolomics and Lipidomics in Kidney Disease,” Seminars in Nephrology 44, no. 6 (2024): 151582.
C. Tang, J. Cai, X. Yin, et al., “Mitochondrial Quality Control in Kidney Injury and Repair,” Nature Reviews. Nephrology 17, no. 5 (2021): 299–318.
X. Jin, Z. Jian, Y. Ma, et al., “Single‐Cell RNA Sequencing Analysis Reveals the Role of Macrophage‐Mediated CD44‐AKT‐CCL2 Pathways in Renal Tubule Injury During Calcium Oxalate Crystal Formation,” Research 8 (2025): 690.
S. R. Khan and P. A. Glenton, “Experimental Induction of Calcium Oxalate Nephrolithiasis in Mice,” Journal of Urology 184, no. 3 (2010): 1189–1196.
R. W. Nesto, D. Bell, R. O. Bonow, et al., “Thiazolidinedione Use, Fluid Retention, and Congestive Heart Failure: A Consensus Statement From the American Heart Association and American Diabetes Association,” Diabetes Care 27, no. 1 (2004): 256–263.
Grant Information: 82070724 MOST | National Natural Science Foundation of China (NSFC); 82370768 MOST | National Natural Science Foundation of China (NSFC)
Contributed Indexing: Keywords: fatty acid‐binding protein 1; lipotoxicity; metabolic reprogramming; nephrolithiasis; peroxisome proliferator‐activated receptor gamma
Substance Nomenclature: 0 (PPAR gamma)
0 (Fatty Acid-Binding Proteins)
0 (FABP1 protein, human)
Entry Date(s): Date Created: 20260918 Date Completed: 20260918 Latest Revision: 20260918
Update Code: 20260918
DOI: 10.1096/fj.202602800RR
PMID: 42757653
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1530-6860
DOI:10.1096/fj.202602800RR