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Cited by 364Chronic Kidney Disease and DiabetesRenal Diseases and GlomerulopathiesAcute Kidney Injury Research

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Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

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Opazo-Ríos, Lucas, Mas, Sebastián, Marín-Royo, Gema, Mezzano, Sergio, Gómez-Guerrero, Carmen, Moreno, Juan Antonio, Egido, Jesús·2020·International Journal of Molecular Sciences
DOI 10.3390/ijms21072632PMC PMC7177360
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Abstract

Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.

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Crossref · 10.3390/ijms21072632

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Figure 1 Lipotoxicity origin. The positive energy balance (high fat and/or carbohydrates diet) is one of the main promoters associated with obesity development. Hypertrophy and hyperplasia of white adipose tissue is a process commonly observed in the progression of obesity. The abdominal subcutaneous deposit has been associated with a greater increase in plasma non-esterified fatty acids (NEFA), a characteristic finding of insulin-resistant patients. Although the onset of lipotoxicity is unknown, altered lipid signaling by white adipose tissue and dysregulation in adipokines production is a key factor in restricting the lipid storage capacity observed in adipocytes. This limitation in the lipid deposit activates a vicious circle that leads to specific adaptations in energy metabolism in certain tissues such as the skeletal muscle, heart, liver, pancreas, and kidney, thus activating signaling pathways associated with gluco(neo)genesis in the presence of active lipogenesis. Created with BioRender.com.
Figure 1 Lipotoxicity origin. The positive energy balance (high fat and/or carbohydrates diet) is one of the main promoters associated with obesity development. Hypertrophy and hyperplasia of white adipose tissue is a process commonly observed in the progression of obesity. The abdominal subcutaneous deposit has been associated with a greater increase in plasma non-esterified fatty acids (NEFA), a characteristic finding of insulin-resistant patients. Although the onset of lipotoxicity is unknown, altered lipid signaling by white adipose tissue and dysregulation in adipokines production is a key factor in restricting the lipid storage capacity observed in adipocytes. This limitation in the lipid deposit activates a vicious circle that leads to specific adaptations in energy metabolism in certain tissues such as the skeletal muscle, heart, liver, pancreas, and kidney, thus activating signaling pathways associated with gluco(neo)genesis in the presence of active lipogenesis. Created with BioRender.com.CC BY · PubMed Central
Figure 2 Effect of lipotoxicity on kidney nephron (left) and main pathways of action and detoxification of non-esterified fatty acids (NEFA) in podocytes and tubular cells (right). In brackets are shown selected references on lipotoxicity-mediated mechanisms. Adapted from Wikimedia glomerule image (CC BY-SA 4.0 Author: M. Komorniczak).
Figure 2 Effect of lipotoxicity on kidney nephron (left) and main pathways of action and detoxification of non-esterified fatty acids (NEFA) in podocytes and tubular cells (right). In brackets are shown selected references on lipotoxicity-mediated mechanisms. Adapted from Wikimedia glomerule image (CC BY-SA 4.0 Author: M. Komorniczak).CC BY · PubMed Central
Figure 3 Targeting lipotoxicity in DN. The intrarenal lipids reduction has been positively correlated with renoprotective effects observed in the progression of experimental diabetic nephropathy. On the left side, there are represented different strategies focused on enhancing signaling pathways that are considered beneficial to reduce lipid accumulation (adiponectin/PPAR signaling and cholesterol efflux) and prevent other derived damages such as inflammation and oxidative stress. On the right side are shown different approaches focused on blocking signaling pathways that have a harmful effect in the context of diabetic nephropathy (glucose excretion, cholesterol synthesis, lipid synthesis, and accumulation and FA uptake). ABCA1, ATP-Binding Cassette Transporter A1; ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; CBR1, Carbonyl reductase 1; CCR2, C-C chemokine receptor type 2; C5AR, complement component 5a receptor 1; FA, fatty acid; FATP3/4, fatty acid transport protein 3/4; GLP-1, glucagon-like peptide 1; LXR, live X receptor; PGC1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PPARα/γ, peroxisome proliferator-activated receptors α/γ; SGLT2, sodium-glucose co-transporter 2 inhibitors; SREBP, sterol regulatory element-binding proteins; TGFβ, transforming growth factor-beta; VEGF-B, vascular endothelial growth factor-beta; VEGFR1, vascular endothelial growth factor receptor. Created with BioRender.com.
Figure 3 Targeting lipotoxicity in DN. The intrarenal lipids reduction has been positively correlated with renoprotective effects observed in the progression of experimental diabetic nephropathy. On the left side, there are represented different strategies focused on enhancing signaling pathways that are considered beneficial to reduce lipid accumulation (adiponectin/PPAR signaling and cholesterol efflux) and prevent other derived damages such as inflammation and oxidative stress. On the right side are shown different approaches focused on blocking signaling pathways that have a harmful effect in the context of diabetic nephropathy (glucose excretion, cholesterol synthesis, lipid synthesis, and accumulation and FA uptake). ABCA1, ATP-Binding Cassette Transporter A1; ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; CBR1, Carbonyl reductase 1; CCR2, C-C chemokine receptor type 2; C5AR, complement component 5a receptor 1; FA, fatty acid; FATP3/4, fatty acid transport protein 3/4; GLP-1, glucagon-like peptide 1; LXR, live X receptor; PGC1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PPARα/γ, peroxisome proliferator-activated receptors α/γ; SGLT2, sodium-glucose co-transporter 2 inhibitors; SREBP, sterol regulatory element-binding proteins; TGFβ, transforming growth factor-beta; VEGF-B, vascular endothelial growth factor-beta; VEGFR1, vascular endothelial growth factor receptor. Created with BioRender.com.CC BY · PubMed Central

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Metadata

Authors
Opazo-Ríos, L., Mas, S., Marín-Royo, G., Mezzano, S., Gómez-Guerrero, C., Moreno, J. A., & Egido, J.
Affiliations
  • Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
  • Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
  • Austral University of Chile (CL)
  • Instituto Maimónides de Investigación Biomédica de Córdoba (ES)
Corresponding author
  • Mas, Sebastián
  • Moreno, Juan Antonio
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2020-04-10
Volume
21
Issue
7
Pages
2632
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms21072632
PMC
PMC7177360
OpenAlex
W3015924535
Cited by
363
References
257
Citations by year
2026: 61 · 2025: 68 · 2024: 72 · 2023: 66 · 2022: 61 · 2021: 27 · 2020: 6
FWCI
6.47
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion)
  • Biblos-e Archivo (Universidad Autónoma de Madrid) (submittedVersion, public-domain)
  • RISalud Institutional Health Repository of Andalucía (submittedVersion, cc-by-sa)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Universidad de Córdoba Insitutional Repository (Universidad de Córdoba) (submittedVersion, cc-by)
  • Hispana (submittedVersion)
  • RISalud Institutional Health Repository of Andalucía (submittedVersion, cc-by)
Funders
  • Instituto de Salud Carlos III (PI17/01495, PI17/00130, SAF2015-63696-R)
  • Ministerio de Ciencia e Innovación (DTS17/00203, RTI2018-098788-B-100, DTS19/00093, RYC-2017-22369)
  • Fondo Nacional de Desarrollo Científico y Tecnológico (1160465)
Topics
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
  • Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
Keywords
lipotoxicity, diabetic nephropathy, ectopic fat deposition, type 2 diabetes, insulin resistance, hyperinsulinemia, free fatty acids, lipid metabolism, podocyte injury, tubular damage, mesangial cell proliferation, endothelial activation, foam cells, inflammation, oxidative stress, mitochondrial dysfunction, cell death, treatment options
MeSH terms
Clinical Decision-Making, Adipose Tissue, Animals, Diabetic Nephropathies, Disease Susceptibility, Fatty Acids, Nonesterified, Glycogen, Humans, Kidney, Mitochondria, Obesity, Prognosis, Signal Transduction, Biomarkers, Disease Management, Dyslipidemias, Lipid Metabolism

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