The evolving understanding of the contribution of lipid metabolism to diabetic kidney disease

Abstract

Although diabetes is mainly diagnosed based on elevated glucose levels, dyslipidemia is also observed in these patients. Chronic kidney disease (CKD), a frequent occurrence in patients with diabetes, is associated with major abnormalities in circulating lipoproteins and renal lipid metabolism. At baseline, most renal epithelial cells rely on fatty acids as their energy source. CKD, including that which occurs in diabetes, is characterized by tubule epithelial lipid accumulation. Whether this is due to increased uptake or greater local fatty acid synthesis is unknown. We have recently shown that CKD also leads to decreased fatty acid oxidation, which might be an additional mechanism leading to lipid accumulation. Defective fatty acid utilization causes energy depletion resulting in increased apoptosis and dedifferentiation, which in turn contributes to fibrosis and CKD progression. Enhanced fatty acid oxidation in the kidney induced by fenofibrate, a peroxisomal proliferator-activated receptor (PPAR)-α agonist, showed benefit in mouse models of CKD. Fenofibrate treatment also reduced albuminuria in patients with diabetes in multiple clinical trials. Taken together, these findings suggest that further understanding of lipid metabolism in diabetic kidney disease may lead to novel therapeutic approaches.

Fig. 1

Expression of lipid metabolism-related factors in normal human kidney samples. Immunohistochemistry images of normal human kidney samples stained with antibodies against fatty acid synthase (FASN) and solute carrier family 27 (SLC27A2 or fatty acid transport protein 2; FATP2), very low-density lipoprotein receptor (VLDLR), carnitine palmitoyltransferase 1A (CPT1A), carnitine palmitoyltransferase 1B (CPT1B), and carnitine-O-acetyltransferase (CRAT). Images were downloaded from Human Protein Atlas (www.proteinatlas.org)

Fig. 2

Decreased fatty acid oxidation contributes to CKD progression. Schematic model describing lipid abnormalities in renal tubule cells during fibrosis. Renal tubule cells take up long-chain fatty acids taken up via CD36. Fatty acids are then either stored in lipid droplets or oxidized in the mitochondria. The rate-limiting step in fatty acid oxidation is the uptake of fatty acids by mitochondria; this is regulated by CPT1. The RXR/PGC1a complex plays a critical role in transcriptional regulation of fatty acid oxidation and mitochondrial biogenesis. Smad3 and TGFB1 and the LKB1 and AMPK pathway play an important role in regulating the PGC1a/RXR complex. Defective fatty acid oxidation in CKD results in energy depletion and increased apoptosis and dedifferentiation and kidney fibrosis development. CD36 CD36 molecule (thrombospondin receptor); TGFB1 transforming growth factor, beta 1; RXR retinoid X receptor, alpha; PGC1A peroxisome proliferator-activated receptor gamma, coactivator 1 alpha; LKB1 liver kinase B1; AMPK AMPK-activated protein kinase; CPT1 carnitine palmitoyltransferase