Isoliquiritigenin Attenuates Adipose Tissue Inflammation in vitro and Adipose Tissue Fibrosis through Inhibition of Innate Immune Responses in Mice

Abstract

Isoliquiritigenin (ILG) is a flavonoid derived from Glycyrrhiza uralensis and potently suppresses NLRP3 inflammasome activation resulting in the improvement of diet-induced adipose tissue inflammation. However, whether ILG affects other pathways besides the inflammasome in adipose tissue inflammation is unknown. We here show that ILG suppresses adipose tissue inflammation by affecting the paracrine loop containing saturated fatty acids and TNF-α by using a co-culture composed of adipocytes and macrophages. ILG suppressed inflammatory changes induced by the co-culture through inhibition of NF-κB activation. This effect was independent of either inhibition of inflammasome activation or activation of peroxisome proliferator-activated receptor-γ. Moreover, ILG suppressed TNF-α-induced activation of adipocytes, coincident with inhibition of IκBα phosphorylation. Additionally, TNF-α-mediated inhibition of Akt phosphorylation under insulin signaling was alleviated by ILG in adipocytes. ILG suppressed palmitic acid-induced activation of macrophages, with decreasing the level of phosphorylated Jnk expression. Intriguingly, ILG improved high fat diet-induced fibrosis in adipose tissue in vivo. Finally, ILG inhibited TLR4- or Mincle-stimulated expression of fibrosis-related genes in stromal vascular fraction from obese adipose tissue and macrophages in vitro. Thus, ILG can suppress adipose tissue inflammation by both inflammasome-dependent and -independent manners and attenuate adipose tissue fibrosis by targeting innate immune sensors.

The Role of Tissue Macrophage-Mediated Inflammation on NAFLD Pathogenesis and Its Clinical Implications

“…Mincle has previously been described as a proinflammatory marker of M1 polarization stimulated by TLR-4/nuclear factor- (NF-) κ B signalling, which is the main pathway involved in ATM activation [32, 33]. Another gene that may play a regulatory role during adipose tissue resident macrophage differentiation is Tribbles homolog 1 (Trib1).…”

Isoliquiritigenin: A Unique Component That Attenuates Adipose Tissue Inflammation and Fibrosis by Targeting the Innate Immune Sensors

“…Histological analysis revealed that HFD treatment induced extensive interstitial fibrosis in eWAT, which was markedly suppressed by ILG supplementation (0.5% w/w in HFD) [51]. HFD treatment increased collagen 1, TGF-β, TIMP-1, and PDGF-B mRNA expression in eWAT.…”

“…On the other hand, ILG also acts on adipocytes, and consequently suppresses inflammatory changes elicited by macrophage-derived mediators such as TNF-α [51], suggesting that ILG targets multiple cells that constitute adipose tissue. Moreover, activation of various innate immune sensors is affected by ILG stimulation, consequently suppressing adipose tissue inflammation and fibrosis.…”

“…The SVF from HFD-fed mice was stimulated with a Mincle ligand trehalose-6,6′-dimycolate (TDM), a mycobacterial cell wall glycolipid [22,51]. TDM stimulation significantly increased TIMP-1 and PDGF-B mRNA expression in the SVF and these increases were significantly attenuated by ILG stimulation [51] (Figure 1). …”

Isoliquiritigenin Attenuates Atherogenesis in Apolipoprotein E-Deficient Mice

“…ISL potently inhibits the activation of the NLRP3 inflammasome and improves diet-induced adipose tissue inflammation [12]. ISL decreases phosphorylated c-Jun N-terminal kinase (JNK) expression in macrophages induced by palmitic acid, and suppresses the induced inflammatory changes by inhibiting nuclear factor kappa B (NFκB) activation [13]. Wu et al demonstrated that ISL inhibits interferon γ induced inflammation in hepatocytes by influencing the activation of JAK1/STAT1, IRF3/MyD88, ERK/MAPK, JNK/MAPK, and PI3K/Akt signaling pathways [14].…”