Lipid metabolism disorder in diabetic kidney disease

Abstract

Diabetic kidney disease (DKD), a significant complication associated with diabetes mellitus, presents limited treatment options. The progression of DKD is marked by substantial lipid disturbances, including alterations in triglycerides, cholesterol, sphingolipids, phospholipids, lipid droplets, and bile acids (BAs). Altered lipid metabolism serves as a crucial pathogenic mechanism in DKD, potentially intertwined with cellular ferroptosis, lipophagy, lipid metabolism reprogramming, and immune modulation of gut microbiota (thus impacting the liver-kidney axis). The elucidation of these mechanisms opens new potential therapeutic pathways for DKD management. This research explores the link between lipid metabolism disruptions and DKD onset.

Keywords: diabetic kidney disease; ferroptosis; gut microbiota; lipid metabolism; metabolic reprogramming; treatment.

Figure 1

Characteristics of lipid metabolism changes in DKD. The metabolic abnormalities of TG, CHOL, sphingolipids, PLs, LDs, and BAs were mainly reflected in the metabolic abnormalities of TG, which were reflected in the uptake and oxidation process of FAs. The abnormalities of CHOL were related to its own synthesis, endocytosis, and exocytosis. The expression of the metabolites of sphingolipids, Cer, S1P, and C1P was specific to DKD. The metabolic abnormalities of PLs (PC, LPA, SM, CL, PE, and PI) were significantly altered in kidney-associated cell membranes. Changes in LDs were mainly associated with the accumulation of Lipid in DKD cells. BAs may delay renal injury through direct activation of the FXR pathway and TGR5 membrane receptors. The upregulation of CD36 expression facilitated triglyceride accumulation in the kidney, while the increase in SMPDL3b was linked to ceramide-1-phosphate deficiency in podocytes. The coordinated actions of SOAT1/ACAT1, ABCG1/SR-B1, and ABCG1/SR-B were involved in lipid droplet accumulation. However, dysregulation of Akt and protein kinase B signaling by Cer/GM3 exacerbated lipid metabolism abnormalities in renal podocytes, tubule cells, and mesangial cells. These processes are closely associated with the intestine, liver, and blood vessels.

Figure 2

MR in DKD. The main manifestations were abnormal reprogramming of TG, CHOL, sphingolipids, LDs, and BAs metabolic pathways in renal mesangial cells, renal tubular cells, and podocytes. TG abnormalities were associated with increased expression of FA synthesis transcription factors and decreased expression of proteins of the fatty acid β-oxidation pathway (PPAR-α, PPAR-δ, and SREBP). The abnormalities in CHOL metabolism were related to the abnormal expression of genes encoding CHOL uptake and synthesis proteins (ABCA1, ABCG1, and apoE).Abnormalities in sphingolipids metabolism were associated with deletion of the SGPL1 gene and increased expression of the SMPDL3b protein. Changes in LDs were associated with increased expression of PLIN2. Changes in BAs metabolism were associated with increased expression of the genes encoding BAs transporter proteins (Abcc3, Abcc4, and Slco1a1).

Figure 3

Mechanism of lipid metabolism changes in DKD. The main manifestations are abnormalities of ferroptosis, lipophagy, and immunoregulation of gut microbiota in renal mesangial cells, renal tubular cells, and podocytes. Ferroptosis abnormalities are reflected in the transport of PUFAs and changes in the enzymatic response to the LPO process. Abnormalities in lipophagy are associated with abnormalities in cytosolic C1P and CHOL metabolism, leading to the regulation of autophagy by the JNK/AMPK/mTOR channel activation to regulate autophagy in LDs. Abnormalities in gut microbiota immunoregulation are reflected in disorders of gut-derived SCFAs, BAs, and immune factors (TNF-α,IL-1, IL-6, and IL-18) via the NF-кB, OAT3 pathway directly contributing to renal inflammation and lipid accumulation in DKD.