Lipid deposition and metaflammation in diabetic kidney disease

Abstract

A critical link between metabolic disorders and a form of low-grade systemic and chronic inflammation has been recently established and named 'Metaflammation'. Metaflammation has been recognized as a key mediator of both microvascular and macrovascular complications of diabetes and as a significant contributor to the development of diabetic kidney disease (DKD). The goal of this review is to summarize the contribution of diabetes-induced inflammation and the related signaling pathways to diabetic complications, with a particular focus on how innate immunity and lipid metabolism influence each other.

Figure 1.. The role of lipid deposition and Metaflammation in the pathogenesis of diabetes and its complications.

Hypercaloric diet and genetics affect the function of pancreas, liver, muscles, and adipose tissue, leading to the formation of insulin resistance, hyperglycemia and hyperlipidemia via activation of the innate immune system, the production of pro-inflammatory cytokines and the deposition of lipids. Consequently, this results in diabetic micro- and macro-complications. This image was created using BioRender software (biorender.com). Abbreviations: TLRs – Toll-like receptors; CLRs – C-type lectin receptors; NLRs – nucleotide-binding domain and leucine-rich repeat-containing receptors; RLRs – retinoic acid-inducible gene I-like receptors; cGAS – cyclic GMP-AMP synthase; STING – stimulator of interferon genes; JNK – c-Jun N-terminal kinase; NF-κB – nuclear factor kappa-light-chain-enchancer of activated B cells; IL – interleukin; TNFα – tumor necrosis factor alpha; ICAM1 – intercellular adhesion molecule 1; VCAM1 – vascular cell adhesion molecule 1; CX3CL1 – C-X3-C motif chemokine ligand 1; CCL5 – C-C motif ligand 5; MCP-1 – monocyte chemoattractant protein-1; TAG – triacylglycerol; FFA – free fatty acids; CD36 – scavenger receptor class B member 3; ABCA1 – ATP-binding cassette subfamily A member 1; ABCG1 – ATP-binding cassette subfamily G member 1; DAG – diacylglycerol; Cer – ceramide; Sph – sphingosine; SphK2 – sphingosine kinase 2; S1P – sphingosine-1-phospahte; C1P – ceramide-1-phosphate; SMPDL3b – sphingomyelin phosphodiesterase acid-like 3b.

Figure 2.. Prostaglandins, leukotrienes and eicosanoids in the pathogenesis of diabetes and its complications.

Hyperglycemia and release of cytokines lead to the malfunction in the polyunsaturated fatty acids metabolism. In turn it causes overexpression of prostaglandins (mainly PGE2) and leukotrienes (mainly LTB4 and LTE4) and inhibition of eicosanoids (mainly RvE1, LXA4, LXB4 and RvD1), resulting in inability to inhibit inflammation and promotion of diabetic complications. The image is created using BioRender software (biorender.com). Abbreviations: ω3-PUFA – omega 3 polyunsaturated fatty acids; ω6-PUFA – omega 6 polyunsaturated fatty acids; EPA – eicosapentaenoic acid; DHA – docosahexaenoic acid; COX2 – cyclooxygenase 2; HPETE – hydroperoxyeicosatetraenoic acid; HPDHA – hydroperoxydocahexaenoic acid; LOX – lipoxygenase; HDHA – hydroxy-docosahexaenoic acid; RvD1 – resolvin D 1; RvE1, RvE2, RvE3 – resolvin E 1, 2 and 3, respectively; LXA4 – lipoxin A4; LXB4 – lipoxin B4; AA – arachidonic acid; PGG2 – prostaglandin G2; PGH2 – prostaglandin H2; PGE2 – prostaglandin E2; mPGES-1 – microsomal prostaglandin E synthase-1; 5-LO – 5-lipoxygenase; LTA4 – leukotriene A4; LTB4 – leukotriene B4; LTC4 – leukotriene C4; LTD4 – leukotriene D4; LTE4 – leukotriene E4; MyD88 – innate immune signal transduction adaptor.