The key role of altered tubule cell lipid metabolism in kidney disease development

Abstract

Kidney epithelial cells have very high energy requirements, which are largely met by fatty acid oxidation. Complex changes in lipid metabolism are observed in patients with kidney disease. Defects in fatty acid oxidation and increased lipid uptake, especially in the context of hyperlipidemia and proteinuria, contribute to this excess lipid build-up and exacerbate kidney disease development. Recent studies have also highlighted the role of increased de novo lipogenesis in kidney fibrosis. The defect in fatty acid oxidation causes energy starvation. Increased lipid uptake, synthesis, and lower fatty acid oxidation can cause toxic lipid build-up, reactive oxygen species generation, and mitochondrial damage. A better understanding of these metabolic processes may open new treatment avenues for kidney diseases by targeting lipid metabolism.

Keywords: acute kidney injury; chronic kidney disease; de novo lipogenesis; fatty acid oxidation; lipid; metabolism.

Figure 1.. Schematic representation of fatty acid oxidation and de novo lipogenesis.

a. The fatty acids are transported by CD36 and FATP2 into the cells, where they either stored as lipid droplets or undergo mitochondrial oxidation. Prior to mitochondrial oxidation, fatty acids are converted into fatty acyl CoA. Two key molecules for transporting FA to the mitochondria; Carnitine palmiotyltransferases-1 and 2 (CPT1, CPT2), are highlighted. Also depicted are the central transcriptional regulators of fatty acid oxidation and mitochondrial biogenesis, namely PGC1a, PPARα, FXR, LXR, and ESRRα. b. The insulin/AKT/PI3K pathway is the primary mechanism allowing cells to store excess nutrients. The phosphatidylinositol 3 phosphate kinase (P13K)/AKT / mechanistic target of rapamycin (mTOR) pathways control de Novo Lipogenesis (DNL). Mix and ChREBP dimerize and translocate into the nucleus, where they bind to the CHORE promoter, initiating transcription of target genes (ACC, FAS, SCD1, and ELOVL6) crucial for the final stages of fatty acid synthesis. HIF/AKT/mTOR pathways induce SREBP-1c, a transcription factor central to the biosynthesis of lipid, TG, FA, and cholesterol metabolism. SREBP-1c binds to the SRE promoter, promoting the transcription of the same target genes (ACC, FAS, SCD1, and ELOVL6). Both transcription factors increase the transcription of ACLY and ACSS, which convert citrate and acetate, respectively, into Acetyl CoA. In renal Proximal Tubule (PT) cells, acetate is converted into acetyl CoA via ACSS2 to promote de novo lipogenesis, is also illustrated, along with the utilization of cytosolic malonyl CoA. The final conversion of Acetyl-CoA to Malonyl-CoA to palmitate, carried out by ACC, FAS, SCD1, and ELOVL6 in the cytosol.

Figure 2.. Expression of key metabolic regulators in healthy and diseased human and mouse kidneys at single cell level.

Single cell gene expression of FAO genes such as PPARA, ESRRA, and CPT1B and other metabolic genes hexokinase 1 (HK1) and 2 (HK2 in healthy controls and DKD patient kidneys. Single cell gene expression of metabolic regulators in various mouse kidney disease models including chronic kidney disease (CKD) and acute kidney injury (AKI) models. UUO (unilateral ureteral obstruction, a surgical CKD model), FAN (folic acid nephropathy, a crystal precipitation-induced CKD model), ischemia-reperfusion (IRI), Notch1 transgenic mice (Notch), Peroxisome proliferator-activated receptor γ-coactivator 1 alpha transgenic mice (PGC-1α), Apolipoprotein L1 transgenic mice (APOL1), Estrogen related receptor alpha (Esrrα) knockout mice, and bacterial lipopolysaccharide induced AKI (LPS). The size of the dot indicates the percent positive cells, and the intensity of the color indicates the transcript amount. The size of the circle indicates the percent of cells expressing the target gene, while the color intensity indicates the level of gene expression.

Figure 3.. Expression of key genes in fatty acid oxidation (FAO) and de novo lipogenesis (DNL) in bulk mouse and human kidney samples.

Top Row (FAO): Expression of major FAO genes in FAN and UUO kidney injury models and mice with genetic deletion of Tfam in kidney tubule cells compared to control kidneys. Genes: Acox1, Acox 2, Cd36, Cpt1a, Cpt2, Fabp1, Hadha, Hadhb, Ppara, Scl25a20, Slc27a2). Bottom Row (DNL): Expression of some of the core DNL genes in FAN, UUO kidney injury models, and mice with genetic deletion of Tfam in kidney tubule cells compared to control kidneys. Genes: Acaca, Acacb, Acly, Acss2, Elovl6, Epas1, Fasn, MIxipl, Scap, Scd1, Scd2, Srebf1. UUO (unilateral ureteral obstruction, a surgical CKD model), FAN (folic acid nephropathy, a crystal precipitation-induced CKD model), TFAM (kidney tubule specific knockout of mitochondrial transcription factor A). Each row is one gene, each column is one animal, red indicates higher gene expression while blue indicates lower gene expression.