title: Troxerutin improves hepatic lipid homeostasis by restoring NAD(+)-depletion-mediated dysfunction of lipin 1 signaling in high-fat diet-treated mice.
abstract: Recent evidences suggest that NAD(+) depletion leads to abnormal hepatic lipid metabolism in high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD); however, the contributing mechanism is not well understood. Our previous study showed that troxerutin, a trihydroxyethylated derivative of natural bioflavonoid rutin, effectively inhibited obesity, and normalized hyperglycemia and hyperlipidemia in high-cholesterol diet-induced diabetic mice. Here we investigated whether troxerutin improved hepatic lipid metabolism via preventing NAD(+) depletion in HFD-induced NAFLD mouse model and the mechanisms underlying these effects. Our results showed that troxerutin markedly prevented obesity, liver steatosis and injury in HFD-fed mice. Troxerutin largely suppressed oxidative stress-mediated NAD(+)-depletion by increasing nicotinamide phosphoribosyltransferase (NAMPT) protein expression and decreasing poly (ADP-ribose) polymerase-1 (PARP1) protein expression and activity in HFD-treated mouse livers. Consequently, troxerutin remarkably restored Silent mating type information regulation 2 homolog1 (SirT1) protein expression and activity in HFD-treated mouse livers. Therefore, troxerutin promoted SirT1-mediated AMP-activated protein kinase (AMPK) activation to inhibit mammalian target of rapamycin complex 1 (mTORC1) signaling, which enhanced nuclear lipin 1 localization, lowered cytoplasmic lipin 1 localization and the ratio of hepatic Lpin 1β/α. Ultimately, troxerutin improved lipid homeostasis by enhancing fatty acid oxidation and triglyceride secretion, and suppressing lipogenesis in HFD-fed mouse livers. In conclusion, troxerutin displayed beneficial effects on hepatic lipid homeostasis in HFD-induced NAFLD by blocking oxidative stress to restore NAD(+)-depletion-mediated dysfunction of lipin 1 signaling. This study provides novel mechanistic insights into NAFLD pathogenesis and indicates that troxerutin is a candidate for pharmacological intervention of NAFLD via restoring NAD(+) levels.
authors.affiliation: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu, PR China.
authors.forename: Zi-Feng
authors.initials: ZF
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu, PR China.
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Fan
authors.affiliation: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu, PR China. Electronic address: ylzheng@jsnu.edu.cn.
authors.forename: Yuan-Lin
authors.initials: YL
authors.lastname: Zheng
authors.affiliation: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu, PR China.
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Wu
authors.affiliation: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu, PR China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Shan
authors.affiliation: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D005234:Fatty Liver / Q000209:etiology / Q000517:prevention & control; D006896:Hydroxyethylrutoside / Q000031:analogs & derivatives* / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009243:NAD / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000517:prevention & control; D018384:Oxidative Stress / Q000187:drug effects; D010711:Phosphatidate Phosphatase / Q000378:metabolism*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D006896:Hydroxyethylrutoside; D009687:Nuclear Proteins; D009243:NAD; C005865:troxerutin; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: EX527 (PubChem CID 5113032); Hepatic lipid homeostasis; Lipin 1; NAD(+); NAFLD; SirT1; Troxerutin; Troxerutin (PubChem CID 9896814)