Journal
BIOCHEMICAL PHARMACOLOGY
Volume 91, Issue 1, Pages 74-86Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2014.07.002
Keywords
Troxerutin; NAD(+); SirT1; Lipin 1; Hepatic lipid homeostasis; NAFLD
Categories
Funding
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- National Natural Science Foundation of China [81171012]
- Natural Science Foundation of Jiangsu Province [BK20131127]
- Qinglan Project Scientific and Technological Innovation Team Training Program of Jiangsu College and University
- Major Fundamental Research Program of the Natural Science Foundation of the Jiangsu Higher Education Institutions of China [07KJA36029]
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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 homologl (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 I localization and the ratio of hepatic Lpin 1 beta/alpha. 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. (C) 2014 Elsevier Inc. All rights reserved.
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