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

• Published in: International journal of molecular sciences Vol. 18; no. 1; p. 31
• Main Authors: Zhang, Zifeng, Wang, Xin, Zheng, Guihong, Shan, Qun, Lu, Jun, Fan, Shaohua, Sun, Chunhui, Wu, Dongmei, Zhang, Cheng, Su, Weitong, Sui, Junwen, Zheng, Yuanlin
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.01.2017; MDPI
• Subjects: Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Cytokines; Diabetes mellitus; Diet, High-Fat - adverse effects; Endoplasmic reticulum; Endoplasmic Reticulum Stress; fasting hyperglycemia; Gluconeogenesis; hepatic gluconeogenesis; High fat diet; Hydroxyethylrutoside - administration & dosage; Hydroxyethylrutoside - analogs & derivatives; Hydroxyethylrutoside - pharmacology; Hydroxyethylrutoside - therapeutic use; Hyperglycemia - drug therapy; Hyperglycemia - etiology; Hyperglycemia - metabolism; Inflammation; Liver; Liver - drug effects; Liver - metabolism; Male; Mice; Mice, Inbred ICR; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Nod Signaling Adaptor Proteins - metabolism; Nod1 protein; nucleotide oligomerization domain protein; Nucleotides; Obesity; Oligomerization; Oral administration; Oxidative Stress; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Rutin; Signs and symptoms; Tauroursodeoxycholic acid; Transcription activation; troxerutin; nucleotide oligomerization domain protein; hepatic gluconeogenesis; inflammation; fasting hyperglycemia; troxerutin; endoplasmic reticulum stress
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms18010031

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.