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.
1 Introduction
Diabetic kidney disease (DKD) is a common microvascular complication of diabetes mellitus (). DKD is characterized by glomerulopathy with diffuse and nodular tethered dilatation and thickening of the glomerular basement membranes, accompanied by tubular atrophy, interstitial inflammation, fibrosis, glomerular endothelial injury, podocyte loss, and glomerular vascular hyalinopathy (). DKD pathogenesis is complex and is associated with glucose and lipid metabolism disorders and stress (, ). Treatments, such as glycemic control and urinary albumin reduction, do not fundamentally alter the course of DKD (). The latest evidence-based guidelines recommend angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) and novel hypoglycemic agents, such as dipeptidyl peptidase-4 inhibitors, sodium-glucose transporter 2 inhibitors, and sodium-glucose transporter 2 inhibitors. Sodium-glucose transporter 2 inhibitors and glucagon-like peptide 1 agonists (–) have not been found to slow down the progression of DKD to end-stage renal disease (). Therefore, exploring the pathogenesis of DKD and identifying targets for intervention are important clinical goals. Lipid metabolism disorders, one of the pathogenic mechanisms of DKD, mainly involve abnormalities in lipid metabolism, such as triglycerides (TGs), cholesterol (CHOL), and lipid droplets (LDs) (–). Recently, there have been numerous studies on the mechanisms of lipid metabolism disorder lipophagy in DKD. Ferroptosis, the programmed death in DKD, is a direct result of lipid peroxidation, which is closely related to lipid metabolism disorders, especially disorders in the regulation of fatty acids (FAs) (, ). Another mode of programmed death is associated with defects in the autophagy-lysosomal system and abnormal lipid accumulation in podocytes in DKD (, ). The reprogramming of lipid metabolism also results in dysfunctional lipid uptake and oxidation, especially of FAs, which are exacerbated in DKD (, ). In addition, an imbalance of gut microbiota and increased permeability of the intestinal barrier, which is one of the pathological manifestations of DKD, and its involvement in immune imbalance, especially involving the liver-kidney axis, affect lipid metabolism, such as bile acid (BA) metabolism, and the immune imbalance aggravates renal injury (–). Recent studies related to lipid metabolism disorders in human and animal models of DKD have revealed that the deposition of toxic FAs metabolites leads to ectopic lipid deposition in podocytes and tubular epithelial cells, interstitial fibrosis, and DKD (, –). The causes and pathogenesis of lipid metabolism disorders in DKD have not yet been fully elucidated. Therefore, studying the mechanism of lipid metabolism changes in DKD and how to slow down the development of DKD through the regulation of different targets has become a hot research topic.
2 Characterization of lipid metabolism changes in DKD
Abnormalities in the metabolism of TG, CHOL, sphingolipids, phospholipids (PLs), LDs, and BAs are key factors in DKD progression. Both the quality and quantity of lipids are associated with this process and produce reactive oxygen species (ROS), which exacerbate oxidative stress, inflammation, and cell death ().
2.1 Abnormal TG metabolism in DKD
Abnormal TG metabolism in DKD is mainly characterized by abnormal uptake and oxidation of FAs. Fatty acid transport proteins(FATPs),cluster of differentiation 36 (CD36), and fatty acid-binding protein (FABP) are correlated with FA uptake in DKD. FATPs control FAs uptake, and fatty acid transport protein 2 (FATP2) deficiency improves renal outcomes (, ). fatty acid transport protein 4(FATP4) levels in diabetic mice are correlated with lipid accumulation in DKD (). CD36 is a transmembrane glycoprotein that mediates oxidized low-density lipoprotein (LDL) uptake. An increase in CD36 levels is strongly associated with kidney injury in DKD (–). Increased CD36 expression in mouse kidneys promotes TG accumulation in the kidney (). fatty acid-binding protein1(FABP1), another protein associated with abnormal lipid uptake in DKD, is a reliable marker of the onset and progression of DKD (–).
Fatty acid oxidation (FAO) is the primary pathway that reduces the renal lipid content. The expression of FAO genes, including peroxisome proliferators-activated receptors α (PPARα), acyl coenzyme A dehydrogenase, and acyl-CoA oxidase 1/2(ACOX1/2), was significantly reduced (, ).
Non esterified fatty acids (NEFA) and essential fatty acid (EFA) changes are also important in DKD. In the early stages of DKD, NEFAs increase and EFAs decrease (). Other NEFAs (Monounsaturated 16:1/18:1 FAs, omega-6/7/9 in the serum, and 10-nitrooleic acid in the urine) are also consistently elevated in DKD (). In addition, long-chain free fatty acid levels were reduced in rats with DKD ().
2.2 Abnormal CHOL metabolism in DKD
CHOL synthesis, endocytosis, and exocytosis are all closely associated with DKD. Studies have demonstrated that increased expression of sterol regulatory element-binding proteins (SREBP) and isoforms associated with CHOL synthesis that mediate intracellular CHOL sensing leads to renal damage in DKD (–) and plays a role in the accumulation of LDs (). Increased expression of SREBP and its isoforms in glomeruli of patients with DKD leads to renal injury (48–50). Inhibition of CHOL efflux and increased CHOL influx in DKD cells increases free CHOL levels, which activate sterol O-acyltransferase 1 to form cholesteryl esters (ChEs) that are stored in LDs, causing excessive accumulation of CHOL in podocytes (, , 51). In contrast, induction of CHOL efflux ameliorates DKD progression and DKD-like glomerulosclerosis (, 52). ATP-binding cassette transporter A1 (ABCA1), which promotes CHOL efflux, and another CHOL efflux scavenger receptor, BI (SR-BI), were found to be significantly inhibited in DKD (53).
2.3 Sphingolipids anomalies in DKD
Expression of the sphingolipids metabolites ceramide (Cer), sphingosine-1-phosphate (S1P), Ceramide-1-phosphate (C1P) is specific to DKD. Long-chain Cer and ultra-long-chain Cer levels are elevated in DKD (54–56). Renal S1P levels are elevated in diabetic mice (57, 58), and sphingosine kinase, which produces S1P, exhibits increased expression and activity (59). Receptor signaling for S1P is specifically expressed during glomerular injury (60, 61). Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is increased in DKD mice in association with a C1P-deficient state in podocytes (62–64). In addition, increased ganglioside GM3(GM3) in the renal cortex during the early stages of diabetes alters pro-survival receptor-related Automatic Kernel Tunables (Akt) and Protein kinase B signaling to exacerbate DKD (65–68). This suggests a role for sphingolipids in the development of DKD.
2.4 Abnormal metabolism of PLs in DKD
PLs are key structural components of all cellular lipid bilayers that contain multiple fatty acyl groups and are potential biomarkers of DKD (69–72). Phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphocholine (PC) and sphingomyelin (SM) were significantly altered (73, 74). Levels of two lysolecithins (PC and lysophosphatidic acid (LPA)) and Sphingomyelin (SM) (d18:1/16:0) were found to be significantly elevated in the glomeruli of diabetic mice (75–77), and the levels of glucose-modified aminoketoses (Amadori-PEs) were even higher in the renal cortex. PI (40:6) levels tended to decrease in the serum of patients with type 2 DKD (78). In addition, it has been shown that diabetic mice also show reduced relative abundance of Cardiolipin (CL) and its subpopulations in the proximal tubules of the renal cortex (79).
2.5 Accumulation of LDs in DKD
LDs are cellular reservoirs of CHOL and acylglycerols (80). LDs alleviate DKD by preventing lipotoxicity and lipid apoptosis (81–83) or enhancing autophagic pathways (84). Increased accumulation of LDs in DKD was found (, 52, 85),and an increase in LDs in glomerular and/or tubular cells of the kidneys of hyperglycemic mice was accompanied by an increase in markers of oxidative stress (xanthine oxidoreductase (XOR) and nitrotyrosine with tail-interacting protein of 47 kDa (TIP47)) (86). The expression of perilipin 2 (PLIN2), a family of lipoproteins present in the coating of LDs, is significantly upregulated in DKD pedunculated cells (, 87).
2.6 Abnormal metabolism of BAs in DKD
BAs are oxidized hepatic enzymes derived from CHOL and are found mainly in the enterohepatic circulatory system; they may be directly involved in the regulation of blood glucose (88) or indirectly involved through the gut-kidney axis, improving lipid metabolism to protect the kidney (89). BAs and total CHOL were negatively correlated with the severity of DKD, and BAs may ameliorate DKD through the activation of receptors and downstream signaling pathways in the glomerular cells. The farnesoid X Receptor (FXR) pathway and takeda G protein-coupled receptor 5 (TGR5), which are directly activated by BAs, are highly expressed in the kidney after activation and can play a role in slowing down renal injury (90–94). However, the association between BAs and DKD remains unclear. (Figure 1)
Figure 1
3 Mechanisms of lipid metabolic changes in DKD
3.1 Metabolic reprogramming (MR)
MR refers to the ability of cells to adapt their metabolic processes in response to changing environmental conditions (95) and MR in DKD mainly manifests as renal lipid accumulation (96). Among these, abnormal metabolic pathways of TG, CHOL, sphingolipids, LDs, and BAs are key aspects of MR in DKD.
Renal TG accumulation in patients with DKD is associated with the dysregulated expression of genes involved in lipid metabolism (97). Renal biopsies from patients with DKD showed decreased expression of genes encoding PPAR-α and PPARδ and their downstream acyl-coenzyme A oxidase and carnitine palmitoyl transferase (CPT1) involved in the fatty acid β-oxidation pathway, and SREBP, a transcription factor regulating FA synthesis, induced fluorescent antibody serum neutralization (FASN) and acetyl Coenzyme A(CoA) carboxylation. The expression of genes involved in the fatty acid β-oxidation pathway, such as (),and SREBP, a transcription factor regulating the synthesis of FAs, induced FASN and acetyl CoA carboxylase to increase the cytosolic TG content (98, 99),and it was found that Streptozotocin(STZ)-induced diabetic rat renal cortex and DKD patients’ renal tubules increased their TG content and increased sterol regulatory element-binding proteins 1(SREBP-1) expression in the renal tubular epithelium of STZ-induced diabetic rats (100–103). In addition, elevated renal TC was also associated with decreased PPAR-α and PPAR-δ expression, which also led directly to decreased FAO (), showing a direct pathway between decreased FAO and net accumulation of lipids in the renal cortex of patients with DKD.
In CHOL metabolism, low-density lipoprotein receptor (LDLr) and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) were involved in CHOL uptake and synthesis, respectively. The expression of LDLr and HMG-CoA reductase was significantly elevated in DKD, whereas the expression of genes involved in CHOL efflux, including ABCA1, ATP-binding cassette transporter G1(ABCG1), and apoipoprotein E (apoE), was significantly reduced (, 104, 105). Moreover, sterol regulatory element-binding proteins 2(SREBP-2) activates LDLr and HMG-CoA reductase, enhancing CHOL uptake and synthesis (, 106). ABCA1 mediates CHOL transport to apolipoprotein A-I (Apo A-I) for further efflux, and strong downregulation of ABCA1 mRNA was observed in DKD, leading to the inhibition of CHOL efflux in pedicle cells (52, 107).
In terms of sphingolipids metabolism, the rs267734 gene variant of Ceramide synthases 2 (CerS2) in patients with DKD resulted in increased proteinuria (108), and polymorphisms in the Sphingosine-1-phosphate lyase 1(SGPL1) gene encoding S1P lyase 1 were associated with reduced enzymatic activity of S1P lyase 1 and the development of nephropathy. In mice, knockdown of the Sgpl1 gene encoding S1P lyase 1 resulted in loss of peduncles and severe proteinuria (109, 110). Studies on C1P have shown that increased SMPDL3b expression in DKD mice is associated with podocyte C1P deficiency (62). SMPDL3b expression is elevated in the glomeruli of patients with DKD (63), whereas SMPDL3b overexpression in podocytes leads to S1P accumulation (64).
Accumulation of LDs in DKD may be related to abnormal protein expression in the coating of LDs. It was found that variations in Perilipin 1(PLIN1) can lead to DKD-like renal injury (111). Clinical studies have shown that the polymorphism rs4578621 in the Perilipin(PLIN) gene is associated with type 2 diabetes mellitus, and the expression of Perilipin 2(PLIN2) is upregulated in the kidneys of diabetic db/db mice (103, 112),which may be the reason.
In BA metabolism, the ATP-binding cassette transporter C 3 (Abcc3) encodes multidrug resistance-associated protein 3 (MRP3), and Abcc4 encodes MRP4. Both of transport taurine and glycine conjugates of bile acids and unconjugated bile acid cholate into the bloodstream. Solute carrier organic anion transporter family member 1A1 (Slco1a1) encodes organic anion transport peptide 1A1 (OATP1A1), which transports unconjugated and conjugated bile acids into the cell (113),and type 2 diabetic db/db mice exhibit decreased Slco1a1 and increased Abcc3 and Abcc4 expression in the kidney, resulting in the loss of bound and unconjugated bile acids and bile salts from the cells (114, 115). (Figure 2)
Figure 2
3.2 Ferroptosis
Lipid metabolism disorders in DKD are primarily characterized by disturbances in FA, BA, and CHOL metabolism (116, 117). DKD serum is markedly decreased in l-methionine, which can be methylated in vivo to produce L-(+)-cysteine. The latter is one of the three amino acids used for the synthesis of glutathione (GSH) (118). Elevated Fatty Acid Binding Protein 4(FABP4) expression may lead to altered lipid deposition in DKD and is associated with ferroptosis (119). Elevated expression of FABP4 was found in HG-HK2 cells from patients with DKD who showed iron deposition in renal tubules and loss of mitochondrial cristae, whereas Carnitine Palmitoyl transferase 1A(CPT1A), glutathione peroxidase 4, ferritin heavy chain (FTH), and ferritin light chain (FTL) were found to be elevated in HG-HK2 cells from patients with DKD who showed iron deposition in renal tubules and loss of mitochondrial cristae. FTH and FTL decrease and promotes ferroptosis, leading to renal tubular injury. Simultaneous inhibition of FABP4 restores FAO, thereby reducing lipid accumulation and peroxidation while increasing CPT1A expression, which, in turn, inhibits ferroptosis and reduces renal injury and fibrosis (120). Acyl-CoA synthetase long-chain family4 (ACSL4) is overexpressed in DKD (121), and FA regulation modulates lipid metabolism to affect ferroptosis. The upregulation of ACSL4 increased Arachidonoyl-Phosphatidylethanolamine (AA-PE) and Adrenoyl-Phosphatidylethanolamine (AdA-PE) levels, promoted ferroptosis, and exacerbated tubular fibrosis in DKD (122). In addition, ACSL4 inhibition may ameliorate renal injury by decreasing the levels of lipid peroxidation products and inhibiting ferroptosis (123). CD36 expression is increased in patients with DKD (124). CD36 transports polyunsaturated fatty acids (PUFAs), which are essential for lipid peroxidation, intracellularly, and its increased expression has been shown to correlate with ROS production (). CD36 has been shown to promote proximal tubular fibrosis under hyperglycemic conditions, which may be mediated by its regulation of ferroptosis suppressor function in the proximal tubular cells. CD36 has been shown to promote proximal tubular fibrosis under hyperglycemic conditions. This may promote ferroptosis by regulating the ubiquitination of ferroptosis suppressor protein 1 in proximal tubular cells (125, 126). A correlation has been found between BA metabolism and glomerulosclerosis and tubulointerstitial fibrosis in DKD (127, 128), possibly through the inhibition of ligand-activated nuclear receptor Farnesoid X Receptor(FXR)/retinoid X receptor activation, which is strongly associated with ferroptosis (129). In addition, compared to soybean oil (SO) and linoleic acid (LN), which are rich in PUFAs, peanut oil (PO), lined oil (LO), and rapeseed oil (RO), which are rich in saturated fatty acids and monosaturated fatty acids, are highly likely to reduce the reabsorption of BAs in the colon, which has a different impact on BA metabolism. This may be related to changes in the gut microbiota structure of DKD (130). Impairment of CHOL efflux and the accumulation of CHOL lead to glomerulosclerosis and podocyte ferroptosis in early DKD, and is related to the reduction of ABCA1, the main protein of CHOL efflux (131, 132). The interaction between CHOL metabolism and ferroptosis (133, 134) may be a potential cause of DKD progression, suggesting that ferroptosis is correlated with FAs, BAs, CHOL metabolism disorders, and DKD development.
3.3 Lipophagy
Autophagy is an intracellular pathway that maintains cellular homeostasis by degrading cytoplasmic components via autolysosome formation of autolysosomes (135). Studies have shown that the development of DKD is associated with defective renal autophagy (119, 136–140). In DKD, the microtubule-associated protein 1A/1b-light chain 3 (LC3-II) is dependent on phagocytosis of endoplasmic reticulum membranes to form lipid autophagosomes, which with their cargoes, mainly composed of ChE and TG, fuse with lysosomes to form autophagic lysosomes, in which the cargo is degraded to produce FAs, a process known as lipophagy (141–147). The accumulation of ChE and FAs metabolites in DKD podocytes has been implicated in the pathogenesis of glomerular dysfunction and lipotoxicity in DKD (148). LDs, as reservoirs of excess lipids, inhibit lipotoxicity, and over-activation of lipophagy can promote renal fibrosis (81, 149). Adipose triglyceride lipase (ATGL) is a critically important signaling node for lipophagy, and sirtuin 1 (SIRT1) acts as a key mediator downstream of ATGL whose role is to promote lipophagy (150) and decreased expression of SIRT1 in the kidney promotes DKD (151–153). In addition, LDs are subject to a variety of cellular factors that can influence the development of lipophagy. Lipophagy is regulated by the nutritional state of the cell and proteins that detect changes in the nutritional stores (154). Mechanistic target of rapamycin complex 1(mTORC1) inhibits lipophagy, and activation of AMP-activated protein kinase (AMPK) promotes lipophagy (155, 156). Specific activation of mTORC1 in the podocytes in DKD leads to many changes in DKD, including increased albuminuria, podocyte loss, and thylakoid membrane expansion, while AMPK in DKD decreased autophagic activity in podocytes and increased cytotoxicity and apoptosis (157, 158).
Sphingolipids may be a regulator of lipophagy (159). The sphingolipids metabolite C1P also regulates renal autophagy (160, 161). Cer itself induces autophagy, and treatment with exogenous C1P can upregulate the expression of beclin1, leading to autophagy through c-Jun N-terminal kinase (JNK) activation (162), whereas AMPK can initiate autophagy either by phosphorylating beclin1 or by blocking mTORC1 (163, 164). This indicates an important role for the AMPK/mTOR pathway in autophagy. CHOL removal also plays a crucial role in autophagosome initiation (165, 166). It was found that STZ induced a decrease in autophagic activity in podocyte cells after diabetes, which ultimately led to the development of DKD (167), and the abnormalities of sphingolipids and CHOL exhibited by lipid metabolism disorder in patients with DKD may be responsible for the inhibition of autophagy in DKD podocyte cells. The above suggests that in DKD, lipophagy abnormalities and autophagy inhibition caused by sphingolipids and CHOL metabolism disorders are closely related to the development of DKD.
3.4 Immunomodulation of gut microbiota
Gut microorganisms produce metabolites, such as short-chain FAs (SCFAs), which are involved in the synthesis and metabolism of the human body and in the immunomodulatory processes of the body (168, 169). The gut microbiota influences both innate and adaptive immune systems. During innate immunity, the gut microbiota of Bacteroides, Bifidobacterium, Lactobacillus, and Aspergillus are involved in the maturation of the immune system (170). SCFAs, metabolites of gut microbiota, are involved in immunomodulation by regulating nuclear factor kappa-B (NF-кB) signaling in neutrophils, eosinophils, and macrophages in the gut and by strengthening the physical barrier of the gut (171–174). During adaptive immunity, Lactobacillus, Clostridium, Bifidobacterium, and Enterococcus in the gut can reduce inflammatory responses by producing lipid metabolites and reducing tumor necrosis factor α (TNF-α), and inflammatory mediators interleukin-1(IL-1), interleukin-6 (IL-6), and interleukin-18(IL-18) (175–178).
In DKD, the gut microbiota are associated with immune dysregulation, lipid metabolism disorders, and DKD development (172–174, 179, 180). The gut microbiota of Lactobacillus, Clostridium, Bifidobacterium, and Enterococcus (175) can control BAs as lipid metabolism modulators to modulate the adaptive immunosuppression of inflammatory responses by altering CHOL secretion (177, 178). The gut-liver-kidney axis is the pathway by which lipid metabolites are metabolized in the liver through intestinal absorption and excreted from the kidney (181). Organic anion transporter 3(OAT3) is mainly expressed in the kidney, and the absence of OAT3 alters the normal metabolite transport function in the gut-liver-kidney axis, resulting in the accumulation of endogenous lipid metabolites, such as bile acids and lipids, and G-protein-coupled receptor 35(GPR35), which is a key receptor for lipid metabolism. The coupled GPR35 is associated with inflammation (182–184). This suggests that the disturbance of the gut microbiota and imbalance of immune homeostasis in patients with DKD may affect lipid metabolism through the gut-liver-kidney axis and ultimately contribute to the development of DKD (Figure 3).
Figure 3
4 Targeting lipid metabolism for DKD treatment
4.1 Conventional drugs
4.1.1 Atorvastatin
Atorvastatin effectively reduced the levels of low-density lipoprotein CHOL (LDL-C), creatinine (CREA), and urinary albumin and creatinine (UACR) and downregulated the expression of the inflammatory factors TNF-α, monocyte chemoattractant protein-1 (MCP-1), and IL-6 expression in renal tissues, which ameliorates renal injury and delays the progression of DKD by reducing morphological lesions and renal fibrosis and increases transforming growth factor beta (TGF-β) and collagen I staining (185).
4.1.2 Fenofibrate
Fenofibrate decreased TG content and lipid accumulation in DKD and increased activation of the AMPK/FOXA2/medium-chain acyl-CoA dehydrogenase pathway, significantly reducing renal function and tubular cell apoptosis and slowing DKD progression (186).
4.1.3 Betulinic acid (BA)
BA inhibits phospho-inhibitor of kappa Balpha (IκBα) degradation and NF-κB activity and reduces Fibronectin (FN) expression. It inhibited the DNA-binding activity and transcriptional activity of NF-κB in high glucose-induced glomerular mesangial cells, enhanced the interaction between IκBα and β-arrestin 2 in mesangial cells, and prevented diabetic renal fibrosis by stabilizing the NF-κB inhibitory protein, IκBα, to inhibit NF-κB activation (187).
4.1.4 Liraglutide
Liraglutide is a novel hypoglycemic drug. Inhibition of SREBP-1 and Fatty Acid Synthase (FAS) increases ATGL and hormone-sensitive lipase protein expression levels, promoting AMPK phosphorylation to attenuate ectopic lipid deposition in renal tubules, improving PA-induced lipid accumulation in renal tubular epithelial cells, inhibiting lipid synthesis, and promoting lipolysis (188). Liraglutide increased the expression of phosphorylated (p)-eNOS and p-AMPK in the glomeruli, downregulated the expression of p-mTOR, increased the renal expression of LC3B-II, activated autophagy, ameliorated DKD kidney injury, and decreased urinary albumin and Liver-type Fatty Acid Binding Protein (L-FABP) levels ().
4.1.5 α-lipoic acid (ALA)
ALA plays a role as an antioxidant in the mitochondrial dehydrogenase reaction, which improves the antioxidant status and lipid distribution, and reduces inflammation by regulating lipid levels, enhancing the body’s antioxidant capacity, protecting vascular endothelial function, and activating the renal cystathionine gamma-lyase/hydrogen sulfide pathway to delay DKD (189).
4.1.6 Adiponectin Receptor Agonist AdipoRon
AdipoRon is an active synthetic lipocalin receptor agonist. AdipoRon ameliorates DKD by activating the intracellular Ca2+/Liver Kinase B1(LKB1)-AMPK/PPARα pathway to ameliorate glomerular endothelial cells(GECs) and podocyte injury (190). AdipoRon reduces palmitate-induced lipotoxicity in the kidney by improving lipid metabolism, especially in GECs and podocytes, and reduces oxidative stress and apoptosis, and preventing renal injury, thereby improving endothelial dysfunction and delaying DKD progression in type 2 diabetic nephropathy (191).
4.1.7 Apolipoprotein A-IV (apoD) and apolipoprotein D (apoA-IV)
APOD is an essential component of plasma lipoproteins and plays an important role in plasma lipoprotein metabolism. Increased apoD and apoA-IV help counteract the chemical modification of high-density lipoprotein (HDL) by advanced glycation end products (AGEs) and carbamylation, which contributes to the loss of function of HDL in maturing DKD, thereby delaying DKD (192).
4.1.8 Metrnl
Metrnl is a recently discovered hormone produced by skeletal muscles and adipose tissue in response to exercise and cold exposure. Metrnl-specific overexpression or recombinant Metrnl administration in the kidney regulates renal tubular lipid metabolism through mitochondrial homeostasis mediated by the Sirtuin 3(Sirt3)-AMPK/uncoupling protein 1(UCP1) signaling axis, alleviates renal injury, and delays DKD in diabetic mice (193).
4.1.9 Lipin-1
Lipin-1 inhibits adipose synthesis, upregulates FAO, attenuates proximal tubular epithelial cell injury in tubulointerstitial fibrosis, and delays DKD by promoting proliferator-activated receptor-gamma co-activator-1alpha(PGC-1α)/PPARα-mediated Carnitine Palmitoyltransferase 1 Alpha(Cpt1α)/hepatocyte nuclear factor 4alpha signaling and upregulating SREBPs (194).
4.1.10 Leptin
Leptin is a 167-amino acid lipoprotein that plays a role in the regulation of energy metabolism. It attenuates lipid deposition present in the kidney by activating AMPK phosphorylation, which upregulates insulin-induced gene 1 (Insig-1) expression in PA-induced renal tubular epithelial cell lines(NRK-52E) and delays DKD (195).
4.1.11 ABCA1
ABCA1 is one of the most important proteins involved in the maintenance of CHOL homeostasis. In the human renal glomerular endothelial cell line cultured under high-glucose and high-CHOL conditions, ABCA1 deficiency increases cellular CHOL deposition, leads to inflammation and apoptosis, disrupts the endothelial glycoconjugate barrier, and induces endoplasmic reticulum stress (ERS). In contrast, ABCA1 overexpression enhances CHOL efflux or inhibits ERS in vitro, significantly prevents high glucose- and high-CHOL-stimulated glomerular endothelial injury, and delays DKD (196).
4.1.12 Maresin 1 (MaR1)
MaR1 is a widespread anti-inflammatory lipid mediator, and serum MaR1 concentrations are negatively correlated with hemoglobin A1c, diabetes duration, UACR, neutrophils, and the neutrophil-lymphocyte ratio and positively correlated with HDL CHOL (HDL-C) and estimated glomerular filtration rate. MaR1 alleviated the pathological progression of hyperglycemia, UACR, and DKD through the leucine-rich repeat domain-containing G protein-coupled receptor 6(LGR6)-mediated cyclic adenosine monophosphate-superoxide dismutase-2 antioxidant pathway (197).
4.1.13 Exogenous Adropin (Ad) in nanocapsules
Ad reverses the effects of nanocapsules on ameliorating mitochondrial damage by knocking down the overexpression of Neuronatin (Nnat) or translocator protein(TSPO) to improve lipid metabolism and inhibit TSPO activity, thereby enhancing mitochondrial function. It protects hexokinase 2(HK2) from high glucose (HG) stimulation. It also effectively controls blood glucose and lipid levels, improves renal function, inhibits ROS overproduction, protects mitochondria from damage, improves lipid deposition in renal tissues, and downregulates the expression of lipogenic proteins SEBP-1 and Adipose Differentiation-Related Protein (ADRP) in DKD mice (198).
4.1.14 Novel phosphate and bile acid storage agent polymer SAR442357
SAR442357 is a newly developed non-absorbable polymeric sequestering agent with optimal phosphate and bile salt sequestration properties. Long-term treatment of diabetes mellitus type 2(T2DM) obese Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) leads to enhanced segregation of BAs and phosphates in the gut, improved glycemic control, reduced serum CHOL, and delayed DKD progression (199).
4.1.15 Complement factor B knockout (Cfb-knockout)
Effects of Complement Factor B(CFB) on lipid metabolism in developing DKD, Cfb-knockout diabetic mice had significantly less vas deferens interstitial injury and less Cer biosynthesis. Cfb knockout further blocked the transcription of Ceramides (CERs) by inhibiting the NF-κB signaling pathway, which inhibited the activation of the complement alternative pathway and attenuated renal injury in DKD, especially vas deferens mesenchymal injury. CERs regulated the biosynthesis of Cer (200). (Table 1)
Table 1
| Categorization | Veterinary drug | Experimental model | Signaling pathway | Mechanism of action | Related Literature |
|---|---|---|---|---|---|
| Antihyperlipidemic drug | Atorvastatin | STZ rats | TNF-α, MCP-1 and IL-6 downregulated | (185) | |
| Fenoprofibrate | db/db mice; PA/HG-induced HK2 cells | AMPK/FOXA2/MCAD pathway | (186) | ||
| BA | STZ-induced diabetic rats; HG-induced GMCs | Inhibition of NF-κB activation | Stabilization of the NF-κB inhibitory protein IκBα | (187) | |
| Antihyperglycemic drug | Liraglutide | SDT rats | (p)-eNOS and p-AMPK upregulated; p-mTOR downregulated; LC3B-II expression increased | (188) | |
| Male SD rats were treated with a combination of high-fat diet + unilateral nephrectomy + low-dose STZ in order to establish a rat model of DN | AMPK phosphorylation | SREBP-1 and FAS inhibition; ATGL and HSL upregulation | () | ||
| Improve blood vessels | ALA | Nicotinamide/STZ SD rats | Renal CSE/H2S pathway | (189) | |
| New drug | The Adiponectin Receptor Agonist AdipoRon | db/db mice | Ca2+/LKB1-AMPK/PPARα pathway | Upregulation of CaMKKβ, phosphorylated Ser431LKB1, phosphorylated Thr172AMPK and PPARα expression | (191) |
| apoD and apoA-IV | DKD patients | HDLand AGEs downregulated | (192) | ||
| Metrnl | HFDs/STZ-induced mice; db/db mice | Sirt3-AMPK/UCP1 signaling axis | (193) | ||
| Lipin-1 | Lipin-1-deficient db/db mouse model and STZ/HFD-induced T2DM mice | PGC-1α/PPARα-mediated Cpt1α/HNF4α signaling | SREBPs upregulated | (194) | |
| Leptin | STZ rats | AMPK phosphorylation | Insig-1 expression is upregulated in NRK-52E cells | (195) | |
| ABCA1 | T2DM mice | Enhanced CHOL efflux; ERS inhibition | (196) | ||
| MaR1 | Patients with glucose tolerance/T2DM/DKD; STZ vs. HFD mice | LGR6-mediated cAMP-SOD2 antioxidant pathway | (197) | ||
| Ad | knocking down the overexpression of Nnat or TSPO | inhibits ROS overproduction;, SEBP-1 and ADRP downregulated | (198) | ||
| SAR442357 | ZSF1 rats | enhanced segregation of BAs and phosphates,;improved glycemic control, reduced serum CHOL | (199) | ||
| Gene therapy | Cfb-knockout | DN patients | NF-κB signaling pathway | CERS transcriptional down-regulation | (200) |
Therapeutic advances related to conventional drug-targeted lipid metabolism in diabetic kidney disease.
4.2 Traditional Chinese medicine (TCM) monomers and compound formulas
4.2.1 Lipid metabolism reprogramming
4.2.1.1 Berberine (BBR)
BBR is a potent compound from TCM (201) that can reverse lipid metabolism disorders and ameliorate kidney injury in patients with DKD. BBR stabilizes mitochondrial morphology in podocytes by eliminating PA-induced activation with dynamin related protein 1 (202).BBR peroxisome Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha(PGC-1α) signaling pathway activation promotes mitochondrial energetic homeostasis and FAO in podocytes, and PGC-1α-mediated mitochondrial bioenergetics can play a key role in lipid disorder-induced podocyte injury and development of DKD in mice (203).
4.2.1.2 Breviscapine
Breviscapine is a purified flavonoid extract of Erigeron breviscapus (204), which attenuates dyslipidemia by decreasing 24-h urine protein, serum creatinine (Scr),and blood urea nitrogen levels; modulates lipid profiles by increasing levels of TC, TG, and HDL; and protects against kidney injury (205).
4.2.1.3 Microvascular endothelial differentiation gene-1 (MDG-1)
MDG-1 is a polysaccharide derived from TCM japonicas (206). MDG-1 reduced blood glucose, TG, Blood Urea Nitrogen (BUN), and albumin levels by activating the phosphatidylinositol-3 kinase/Akt signaling pathway and significantly suppressed the expression of TGF-β1 and connective tissue growth factor. MDG-1 attenuated glomerular mesangial dilatation and tubulointerstitial fibrosis in diabetic mice. MDG-1 ameliorated DKD by reducing hyperglycemia, hyperinsulinemia, and hyperlipidemia and by inhibiting intracellular signaling pathways (207).
4.2.2 Ferroptosis
4.2.2.1 Proteoglycan FYGL
FYGL is a water-soluble substance extracted from Ganoderma lucidum, highly branched proteoglycan that protects tissues from oxidative stress damage (208). FYGL significantly inhibited HG/PA-induced proliferation of HBZY-1 cells, ROS generation, and malondialdehyde (MDA) production; promoted Superoxide Dismutase(SOD) activity; and suppressed the expression of NADPH oxidase 1(NOX1), NADPH oxidase 4(NOX4), mitogen-activated protein kinase, NF-κB, and pro-fibronectin expression. It significantly alleviates lipid metabolism disorders and protects the kidneys from oxidative stress-induced dysfunction, delaying DKD (209).
4.2.2.2 Notoginsenoside R1 (NGR1)
NGR1 is a novel saponin from Panax notoginseng, a TCM for the adjuvant treatment of DKD (210),which demonstrated that NGR1 treatment increased serum lipids in db/db mice, reduced AGE-induced mitochondrial damage, limited the increase in ROS, reduced apoptosis in HK-2 cells, promoted the expression of nuclear factor erythroid 2-related factor 2(Nrf2) and heme oxygenase-1(HO-1) to abrogate apoptosis-inducing and TGF-β signaling by ROS, attenuated histological abnormalities in the kidney, reduced glomerular volume in DKD, inhibited oxidative stress-induced apoptosis and renal fibrosis, and delayed DKD (211).
4.2.2.3 Triptolide
The TCM Tripterygium wilfordii (TWH) has been used clinically to treat renal diseases (212). Triptolide, the main active ingredient of TWH, can reduce the 24-h urine total protein quantity (24-h UTP), resulting in decreased renal MDA and nitrotyrosine expression, downregulation of renal oxidative carbonyl protein (OCP) expression, and elevated renal SOD to delay DKD (213). In addition, triptolide is an active diterpene purified from the TCM TWH, which can ameliorate hyperlipidemia and albuminuria in db/db diabetic mice, alleviate glomerular hypertrophy and pedunculated cell injury, and attenuate inflammation and oxidative stress in the kidneys (214).
4.2.2.4 Mulberry extract
Mulberry extract is considered a potential therapeutic drug for diabetes (215). Mulberry extract can lead to a significant reduction in serum TG and very low-density lipoprotein CHOL and HDL-C concentrations, improve plasma GSH and Malondialdehyde (MDA), and delay the development of DKD (216).
4.2.3 Lipophagy
4.2.3.1 Panax japonicus C.A. Meyer (PJ)
PJ has been shown to exert a therapeutic effect on DKD (217). PJ can reduce hyperlipidemia, serum BUN, and 24-h UTP in diabetic mice by modulating unsaturated FAs, glycerophospholipid metabolism, and purine metabolism; protect against pathological changes in renal tissues; and prevent apoptosis of renal cells by modulating the beclin-2/caspase 3 apoptosis signaling pathway to delay DKD (218).
4.2.3.2 Resveratrol (RSV)
RSV, an extract of the Chinese herb Tiger Balm, is a naturally occurring polyphenolic compound that reduces blood glucose and lipid concentrations and is a Sirt1 agonist (219). Resveratrol improves circulating lipids and renal dysfunction, reduces lipid deposition in the kidney by modulating the junctional adhesion molecule-like protein/Sirt1 lipid synthesis pathway, and ameliorates DKD (220).
4.2.4 Immunomodulation of gut microbiota
4.2.4.1 Cordyceps cicadae polysaccharides (CCP)
CCP is a fungus that parasitizes ghost moth larvae, modulates lipids, and improves DKD (221). CCP increases Lactobacillus and Anaplasma community abundance while decreasing the abundance of LPS-producing bacteria and reducing the levels of serum TNF-α, IL-1β, and IL-6 in mice. Significant improvements in 24-h urine output levels and urinary protein, albumin to creatinine ratio, and Scr levels and a decrease in glomerular mesangial zone collagen fibers and lipid accumulation were observed in renal tissue samples (222).
4.2.4.2 Magnesium lithospermate B (MLB)
MLB, an aqueous extract of Salvia miltiorrhiza, an erect perennial herb of the genus Salvia and family Labiatae, is a potential therapeutic agent for kidney disease (223). The abundance of Shigella and Aspergillus species and fecal BAs levels in the rat intestine were significantly reduced by MLB intervention, suggesting that MLB may restore the integrity of the intestinal barrier and inhibit the release of BA-induced inflammatory cells through localized modulation of the gut microbiota and BA metabolism, slowing renal injury (224). (Table 2)
Table 2
| Categorization | Veterinary drug | Base | Experimental model | Signaling pathway | Mechanism of action | Related Literature |
|---|---|---|---|---|---|---|
| Lipid metabolism reprogramming | BBR | Coptis chinensis | db/db mice | PGC-1α signaling pathway | (202) | |
| HFD/STZ-induced DKD rats | Protein expression of GRKs in the G protein-AC-cAMP signaling pathway | GRK2, GRK3 downward; GRK6 upward | (203) | |||
| Breviscapine. | Erigeron breviscapus (Vant.) Hand.-Mazz | A meta-analysis of patients with RCT and DN is shown | decreasing 24-h urine protein, Scr and blood urea nitrogen levels; increasing levels of TC, TG, and HDL | (205) | ||
| MDG-1 | Ophiopogon japonicus | KKAy mice | PI3K/Akt signaling pathway | Decreased levels of blood glucose, TG, BUN, and albumin;suppressed expression of TGF-β1 and connective tissue growth factor | (207) | |
| Ferroptosis | FYGL | G. lucidum | db/db mice; HG/PA-induced rat glomerular body mesangial cells (HBZY-1) | HBZY-1 cell proliferation,;ROS, MDA inhibition; SOD upregulation;Inhibition of NOX1, NOX4, MAPK, NF-κB, and Fibronectin Expression | (209) | |
| NGR1 | Panax notoginseng | AGEs-induced db/db mice; HK-2 cells | Nrf2 and HO-1 expression promotes | (211) | ||
| Triptolide | Tripterygium wilfordiiHook.f., TWH | STZ rats | 24-h UTP,MDA, nitrotyrosine, OCP downregulated; SOD upregulated | (213, 214) | ||
| Mulberry extract | Mulberry | DKD patients | GSH and MDA downregulated | (216) | ||
| Lipid autophagy | PJ | Panax japonicus C.A. Meyer | HFD/STZ-induced diabetic mice | Bcl-2/caspase 3 apoptosis signaling pathway | (218) | |
| RSV | Tiger Balm | Patients with type 2 diabetes and albuminuria | JAML/Sirt1 lipid synthesis pathway | reduces lipid deposition | (220) | |
| Immunomodulation of intestinal flora | CCP | ghost moth larvae | mice | TNF-α, IL-1β, IL-6 downregulated; ACR and Scr upregulated | (222) | |
| MLB | Salvia miltiorrhiza | rats | BAs downregulated | (224) |
Therapeutic advances related to herbal targeting of lipid metabolism in diabetic kidney disease.
5 Summary
The altered manifestations of lipid metabolism disorder present in DKD have been gradually clarified, and the mechanisms affecting this process mainly include cellular ferroptosis, lipophagy, reprogramming of lipid metabolism, and immune modulation of the gut microbiota (involving the liver-kidney axis) in the body, which, in turn, accelerates the progression of DKD, a process that suggests one of the relationships between lipid metabolism disorder and DKD. Recent research has suggested that interventions targeting altered lipid metabolism disorder may help improve DKD prognosis. However, this requires further clarification of the specific targets of the interventions; otherwise, the interventions may not be effective. In addition, compared with known lipid-lowering drugs, natural drugs have the advantage of multiple targets and multiple pathways in the treatment of DKD, but their mechanism of action and scope of application have not yet been clarified. Most of the existing studies have focused on the monomers of TCM, whereas the complexity of the components of TCM prescriptions commonly used in the clinic makes it difficult to elucidate the mechanism of action. The role of lipid-lowering as a target of natural drug action warrants further study of the relevant mechanisms between DKD and these two diseases and provides a potential research direction for the effective treatment of DKD.
Computer modeling and simulation technologies are now pivotal in identifying therapeutic targets for diseases like cancer, liver fibrosis, and Takotsubo syndrome (TTS) (225–230). Future studies can leverage cost-effective methods like quantitative lipid analysis with ES-MSI and incorporate molecular dynamics (MD) simulations alongside computational bioinformatics to investigate lipid metabolism’s role in diabetic kidney disease (DKD) and natural drug effects on lipid disorders. Starting with MD simulations for atomic-level molecular interaction insights, crucial for DKD’s molecular understanding, followed by computational tools to analyze complex data for genetic and protein stability patterns, this approach aims to elucidate lipid metabolism’s link to DKD and refine therapeutic targets by analyzing lipid profile shifts and SNPs.
This streamlined, multidisciplinary approach promises a deeper understanding of DKD’s pathophysiology and treatment, underscoring the importance of merging computational and experimental methods in biomedical research to enhance knowledge and therapeutic developments.
Statements
Author contributions
Y-ZH: Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. B-XD: Writing – original draft, Methodology, Data curation. X-YZ: Writing – original draft, Methodology, Data curation. Y-Z-YW: Writing – original draft, Methodology. H-JZ: Writing – review & editing, Validation, Supervision, Resources, Project administration, Methodology, Funding acquisition, Conceptualization. W-JL: Writing – review & editing, Validation, Supervision, Resources, Methodology, Funding acquisition, Conceptualization.
Funding
This study was supported by The National Natural Youth Science Foundation of China (No. 82004196), National Natural Science Foundation of China (Grant No. 82374382), and Chinese Medicine Inheritance and Innovation Talent Project-Leading Talent Support Program of National Traditional Chinese Medicine (Grant No. 2018, No. 12), Tongzhou District to promote the medical and health industry development project(Grant No.JX2023YJ025).
Acknowledgments
We would like to thank Editage (www.editage.cn) for English language editing.
Conflict of interest
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.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Summary
Keywords
diabetic kidney disease, ferroptosis, gut microbiota, lipid metabolism, metabolic reprogramming, treatment
Citation
Han Y-Z, Du B-X, Zhu X-Y, Wang Y-Z-Y, Zheng H-J and Liu W-J (2024) Lipid metabolism disorder in diabetic kidney disease. Front. Endocrinol. 15:1336402. doi: 10.3389/fendo.2024.1336402
Received
10 November 2023
Accepted
09 April 2024
Published
29 April 2024
Volume
15 - 2024
Edited by
Vinod Tiwari, Indian Institute of Technology (BHU), India
Reviewed by
Sergey Shityakov, ITMO University, Russia
Tongtong Liu, China Academy of Chinese Medical Sciences, China
Dan-Qian Chen, Northwest University, China
Updates
Copyright
© 2024 Han, Du, Zhu, Wang, Zheng and Liu.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Hui-Juan Zheng, tcmzhenghuijuan@163.com; Wei-Jing Liu, liuweijing-1977@hotmail.com
†These authors have contributed equally to this work
Disclaimer
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