A Synthetic Peptide Designed to Neutralize Lipopolysaccharides Attenuates Metaflammation and Diet-Induced Metabolic Derangements in Mice

Abstract

Metabolic endotoxemia has been suggested to play a role in the pathophysiology of metaflammation, insulin-resistance and ultimately type-2 diabetes mellitus (T2DM). The role of endogenous antimicrobial peptides (AMPs), such as the cathelicidin LL-37, in T2DM is unknown. We report here for the first time that patients with T2DM compared to healthy volunteers have elevated plasma levels of LL-37. In a reverse-translational approach, we have investigated the effects of the AMP, peptide 19-2.5, in a murine model of high-fat diet (HFD)-induced insulin-resistance, steatohepatitis and T2DM. HFD-fed mice for 12 weeks caused obesity, an impairment in glycemic regulations, hypercholesterolemia, microalbuminuria and steatohepatitis, all of which were attenuated by Peptide 19-2.5. The liver steatosis caused by feeding mice a HFD resulted in the activation of nuclear factor kappa light chain enhancer of activated B cells (NF-ĸB) (phosphorylation of inhibitor of kappa beta kinase (IKK)α/β, IκBα, translocation of p65 to the nucleus), expression of NF-ĸB-dependent protein inducible nitric oxide synthase (iNOS) and activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, all of which were reduced by Peptide 19-2.5. Feeding mice, a HFD also resulted in an enhanced expression of the lipid scavenger receptor cluster of differentiation 36 (CD36) secondary to activation of extracellular signal-regulated kinases (ERK)1/2, both of which were abolished by Peptide 19-2.5. Taken together, these results demonstrate that the AMP, Peptide 19-2.5 reduces insulin-resistance, steatohepatitis and proteinuria. These effects are, at least in part, due to prevention of the expression of CD36 and may provide further evidence for a role of metabolic endotoxemia in the pathogenesis of metaflammation and ultimately T2DM. The observed increase in the levels of the endogenous AMP LL-37 in patients with T2DM may serve to limit the severity of the disease.

Lactobacillus plantarum ZJUIDS14 alleviates non-alcoholic fatty liver disease in mice in association with modulation in the gut microbiota

“…We also examined the mRNA expression level of cramp , which is a unique antimicrobial peptide in the gut produced by colonic epithelial cells and playing an important role in regulating gut microbes ( 52 , 53 ). Mohammad et al found that cramp was significantly higher in patients with T2DM than in healthy subjects and it could regulate lipid accumulation in adipocytes and hepatocytes ( 54 ). In our present study, cramp was elevated in the HFD group, suggesting the attempt to re-establish the disturbed barrier.…”

CD36 genetic polymorphism and salivary cues are associated with oleic acid sensitivity and dietary fat intake

“…This model emphasises the significance of co‐receptor activity in initiating TLR4‐TLR6 signalling and activating inflammatory pathways, which increases IL‐6, TNF‐α and other inflammatory markers (Stewart, Stuart, et al, 2010). Further, CD36 has been implicated in the association between obesity and metaflammation (the metabolic inflammation accompanying metabolic diseases) (Mohammad et al, 2021). Its increased expression and activity in individuals with obesity may contribute to the development of metaflammation and associated metabolic complications (Caputo et al, 2017).…”

Foxa2 attenuates steatosis and inhibits the NF-κB/IKK signaling pathway in nonalcoholic fatty liver disease

“…The free NF-κB becomes activated and enters the nucleus to regulate the transcription of immune-related receptors, cytokines, adhesion molecules, and other target genes, causing tissue damage ( Fattori et al, 2017 ). It is well documented that NF-κB is essential in regulating inflammatory signaling pathways in the liver and inhibition of NF- κB reduces the extent of liver injury ( Mohammad et al, 2021 ). In our study, we found that the levels of p-NF-κB/NF-κB and p-IKK/IKK were increased in OA-stimulated HepG2 cells, which were attenuated by Foxa2 overexpression.…”