Inhibition of NAMPT aggravates high fat diet-induced hepatic steatosis in mice through regulating Sirt1-AMPKα-SREBP1 signaling pathwayReportar como inadecuado

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Lipids in Health and Disease

, 16:82

First Online: 27 April 2017Received: 04 December 2016Accepted: 30 March 2017DOI: 10.1186-s12944-017-0464-z

Cite this article as: Wang, LF., Wang, XN., Huang, CC. et al. Lipids Health Dis 2017 16: 82. doi:10.1186-s12944-017-0464-z


BackgroundNonalcoholic fatty liver disease is one of the most common liver diseases in the world and is a typical hepatic manifestation of metabolic syndrome which is characterized with lipid accumulation in liver. Nicotinamide phosphoribosyltransferase NAMPT has been recently identified as an enzyme involved in nicotinamide adenine dinucleotide NAD biosynthesis and plays an important role in cellular metabolism in variety of organs in mammals. The aim of this study was to investigate the effects of NAMPT on high fat diet-induced hepatic steatosis.

MethodsHepatic steatosis model was induced by high fat diet HFD in C57BL-6 mice in vivo. HepG2 and Hep1-6 hepatocytes were transfected with NAMPT vector plasmid or treated with NAMPT inhibitor FK866 and then incubated with oleic acid. Lipids accumulation was examined by HE staining or oil red staining. Quantitative RT-PCR and Western blot were used to measure expressions of the genes involved in lipogenic synthesis.

ResultsFK866 significantly promoted liver steatosis in the mice fed with HFD and hepatic lipid accumulation in vitro, accompanied by the increases of the expressions of lipogenic genes such as sterol regulatory element-binding protein 1 SREBP1 and fatty acid synthase FASN. Nicotinamide mononucleotide NMN and NAD significantly rescued the actions of FK866 in vitro. In contrast, overexpression of NAMPT in HepG2 and Hep1-6 hepatocytes ameliorated hepatic lipid accumulation. In addition, FK866 decreased the protein levels of Sirt1 and phospho-AMPKα in liver of the HFD fed mice. Furthermore, Resveratrol, a Sirt1 activator, significantly reduced lipogenic gene expressions, while EX-527, a Sirt1 specific inhibitor, had the opposite effects.

ConclusionOur results demonstrated that inhibition of NAMPT aggravated the HFD- or oleic acid-induced hepatic steatosis through suppressing Sirt1-mediated signaling pathway. On the one hand, the inhibition of NAMPT reduced the production of NAD through inhibiting the NAD salvage pathway, resulting in the decrease of Sirt1 activity, and then attenuated the deacetylation of SREBP1 in which the inhibition of SREBP1 activity promoted the expressions of FASN and ACC. On the other hand, the reduced Sirt1 activity alleviated the activation of AMPKα to further enhance SREBP1 activities.

KeywordsNampt Nad Nafld FK866 Sirt1 AMPKα Mouse AbbreviationsACCAcetyl-CoA carboxylase

AMPKαAMP-activated protein kinase

FASNFatty acid synthase

HFDHigh fat diet

NADNicotinamide adenine dinucleotide

NAFLDNonalcoholic fatty liver disease

NAMPTNicotinamide phosphoribosyltransferase

NDNormal diet

NMNNicotinamide mononucleotide

OAOleic acid

SCD1Stearoyl-CoA desaturase

SREBP1Sterol regulatory element-binding protein 1

Electronic supplementary materialThe online version of this article doi:10.1186-s12944-017-0464-z contains supplementary material, which is available to authorized users.

Autor: Ling-Fang Wang - Xiao-Nv Wang - Cong-Cong Huang - Long Hu - Yun-Fei Xiao - Xiao-Hui Guan - Yi-Song Qian - Ke-Yu Deng - Hon


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