Troxerutin Attenuates Enhancement of Hepatic Gluconeogenesis by Inhibiting NOD Activation-Mediated Inflammation in High-Fat Diet-Treated Mice

Abstract

Recent evidence suggests that troxerutin, a trihydroxyethylated derivative of natural bioflavonoid rutin, exhibits beneficial effects on diabetes-related symptoms. Here we investigated the effects of troxerutin on the enhancement of hepatic gluconeogenesis in high-fat diet (HFD)-treated mice and the mechanisms underlying these effects. Mice were divided into four groups: Control group, HFD group, HFD + Troxerutin group, and Troxerutin group. Troxerutin was treated by daily oral administration at doses of 150 mg/kg/day for 20 weeks. Tauroursodeoxycholic acid (TUDCA) was used to inhibit endoplasmic reticulum stress (ER stress). Our results showed that troxerutin effectively improved obesity and related metabolic parameters, and liver injuries in HFD-treated mouse. Furthermore, troxerutin significantly attenuated enhancement of hepatic gluconeogenesis in HFD-fed mouse. Moreover, troxerutin notably suppressed nuclear factor-κB (NF-κB) p65 transcriptional activation and release of inflammatory cytokines in HFD-treated mouse livers. Mechanismly, troxerutin dramatically decreased Nucleotide oligomerization domain (NOD) expression, as well as interaction between NOD1/2 with interacting protein-2 (RIP2), by abating oxidative stress-induced ER stress in HFD-treated mouse livers, which was confirmed by TUDCA treatment. These improvement effects of troxerutin on hepatic glucose disorders might be mediated by its anti-obesity effect. In conclusion, troxerutin markedly diminished HFD-induced enhancement of hepatic gluconeogenesis via its inhibitory effects on ER stress-mediated NOD activation and consequent inflammation, which might be mediated by its anti-obesity effect.

Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

“…Moreover, they were suggested to decrease the energy barrier between conformational states during protein maturation to promote proper protein folding and to bind the surface-exposed hydrophobic elements of misfolded/unfolded proteins to prevent aggregate formation and degradation in ERAD pathway [87,91,92]. Although the exact mechanism of chaperoning activity of TUDCA is still unclear, it has been shown to prevent UPR malfunction and ameliorate ER stress in various cell types [21,22,[93][94][95]. TUDCA exerts these effects partially by assisting in the transfer of mutant proteins and partially by improving protein folding capacity through the activation of ATF6 [93].…”

“…TUDCA is one such compound that is known for its chaperoning activity [12][13][14][15]. Until now, various studies have demonstrated good efficiency of TUDCA in alleviating or resolving ER stress, playing a role as a chemical chaperone; however, the exact chemical interactions involved in such activity are still debatable [18][19][20][21][22][23].…”

Fusobacterium nucleatum Activates Endoplasmic Reticulum Stress to Promote Crohn’s Disease Development via the Upregulation of CARD3 Expression

“…Some studies have shown that CARD3 is a nucleotide oligomerization domain (NOD)-independent nodal point of gut inflammation (Panda and Gekara, 2018). Decreased expression of NOD1/2 and interaction between NOD1/2 and CARD3 can decrease the severity of ERS (Zhang et al, 2016). It is clear that NOD1/2 and CARD3 are important mediators of ERS-induced inflammation in mouse and human cells (Keestra-Gounder et al, 2016).…”

Inflammation promotes adipocyte lipolysis via IRE1 kinase

“…IRE1 kinase control of NF-κB is positioned to propagate lipolysis, but also a plethora of immune and stress responses related to NF-κB activation. It was important to define the role of IRE1-linked ER stress in regulating NF-κB and cytokines secretion because it was reported that the bacterial cell wall muropeptide sensors NOD1 and NOD2 are mediators of ER stress-induced cytokine secretion in macrophages (20,21) and in the liver (29). It was shown that thapsgargin-induced ER stress promoted macrophage secretion of Il6, which was dependent upon IRE1, NOD1/2, and RIPK2 (20,21).…”