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Review
. 2024 Feb 23:15:1355674.
doi: 10.3389/fphar.2024.1355674. eCollection 2024.

Lipotoxicity and immunometabolism in ischemic acute kidney injury: current perspectives and future directions

Afolarin A Otunla  1 , Kumaran Shanmugarajah  2 , Alun H Davies  3 , Joseph Shalhoub  3
Affiliations
Review

Lipotoxicity and immunometabolism in ischemic acute kidney injury: current perspectives and future directions

Afolarin A Otunla et al. Front Pharmacol. .

Abstract

Dysregulated lipid metabolism is implicated in the pathophysiology of a range of kidney diseases. The specific mechanisms through which lipotoxicity contributes to acute kidney injury (AKI) remain poorly understood. Herein we review the cardinal features of lipotoxic injury in ischemic kidney injury; lipid accumulation and mitochondrial lipotoxicity. We then explore a new mechanism of lipotoxicity, what we define as "immunometabolic" lipotoxicity, and discuss the potential therapeutic implications of targeting this lipotoxicity using lipid lowering medications.

Keywords: acute kidney injury; immunometabolism; ischemia; lipotoxicity; mitcohondria.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The lipotoxic effects of ischemia on the proximal tubular epithelial cell in ischemic AKI. (A) We hypothesise that kidney ischemia causes a “metabolic switch” in the PTEC, stimulating glycolysis and inhibiting fatty acid oxidation. This leads to lipid accumulation. (B) We propose that extracellular lipid accumulation stimulates Toll-like receptors (TLRs) expressed by the PTEC. This leads to the production of pro-inflammatory cytokines. TLR stimulation also leads to HIF-1α stabilisation, activating the NLRP3 inflammasome which drives glycolysis and inhibits fatty acid oxidation, compounding the metabolic switch.
FIGURE 2
FIGURE 2
The uncoupling effect of FFA in the PTEC mitochondria. 1. FFA attracts proton on the cytosolic side of the mitochondrial membrane and becomes protonated. 2. FFA diffuses across the mitochondrial membrane in its protonated, non-polar form. 3. Proton dissociates from the FFA in the mitochondrial matrix. 4. Anion carrier transports FFA back across the mitochondrial membrane, out of the mitochondrial matrix where it can attract another proton.
FIGURE 3
FIGURE 3
Overview of TLR and NLR signalling within the PTEC in response to intracellular and extracellular lipid accumulation.
FIGURE 4
FIGURE 4
Linear (ischemia dependent) vs. cyclical (PRR dependent) models of lipotoxicity. PRR dependent lipotoxicity generates a positive feedback cycle, where lipid accumulation is no longer coupled to the original ischemic insult.
See this image and copyright information in PMC

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