Fatty Acid β-Oxidation in Kidney Diseases: Perspectives on Pathophysiological Mechanisms and Therapeutic Opportunities

Abstract

The kidney is a highly metabolic organ and requires a large amount of ATP to maintain its filtration-reabsorption function, and mitochondrial fatty acid β-oxidation serves as the main source of energy to meet its functional needs. Reduced and inefficient fatty acid β-oxidation is thought to be a major mechanism contributing to kidney diseases, including acute kidney injury, chronic kidney disease and diabetic nephropathy. PPARα, AMPK, sirtuins, HIF-1, and TGF-β/SMAD3 activation have all been shown to play key roles in the regulation of fatty acid β-oxidation in kidney diseases, and restoration of fatty acid β-oxidation by modulation of these molecules can ameliorate the development of such diseases. Here, we disentangle the lipid metabolism regulation properties and potential mechanisms of mesenchymal stem cells and their extracellular vesicles, and emphasize the role of mesenchymal stem cells on lipid metabolism. This review aims to highlight the important role of fatty acid β-oxidation in the progression of kidney diseases, and to explore the fatty acid β-oxidation effects and therapeutic potential of mesenchymal stem cells for kidney diseases.

Keywords: acute kidney injury; chronic kidney disease; diabetic nephropathy; fatty acid β-oxidation; mesenchymal stem cell therapy.

FIGURE 1

Major FAO pathways involved in kidney diseases and drug targets. Fatty acids (FAs) enter the cytoplasm through CD36, FABPs, or FATPs. In the cytosol, FAs are activated to fatty acyl-CoA and transported into the mitochondrial matrix through CPT1A. The acyl-CoA undergoes a β-oxidation reaction to form acetyl-CoA, which is completely oxidized by the tricarboxylic acid cycle. FAO is promoted by upregulating CPT1A and PPAR signaling. Drugs are highlighted in light purple boxes. Enzymes are shown in blue and metabolites are shown in light green. Regulatory molecules are shown in green boxes. FAO, fatty acid β-oxidation; CPT1A, carnitine palmitoyl transferase 1A; FABP, FA-binding protein; FATPs, FA-transport protein; PPAR, peroxisome proliferators-activated receptor; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1α; AMPK, adenosine monophosphate-activated protein kinase; LKB1, Liver kinase B1; ACC, acetyl-CoA carboxylase; LCAD, long-chain acyl-CoA dehydrogenase; ECHA, enoyl-CoA hydratase; SIRT3, sirtuin 3; SIRT5, sirtuin 5.