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Inhibition of NAMPT aggravates high fat diet-induced hepatic steatosis in mice through regulating Sirt1/AMPKα/SREBP1 signaling pathway.
Lipids Health Dis 2017; 16(1):82LH

Abstract

BACKGROUND

Nonalcoholic 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.

METHODS

Hepatic 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.

RESULTS

FK866 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.

CONCLUSION

Our 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.

Authors+Show Affiliations

Institute of Translational Medicine, Nanchang University, 999 Xuefu Load, Honggutan District, Nanchang, 330031, China. School of Life Sciences, Nanchang University, Nanchang, 330031, China.Institute of Translational Medicine, Nanchang University, 999 Xuefu Load, Honggutan District, Nanchang, 330031, China.Institute of Translational Medicine, Nanchang University, 999 Xuefu Load, Honggutan District, Nanchang, 330031, China.Institute of Translational Medicine, Nanchang University, 999 Xuefu Load, Honggutan District, Nanchang, 330031, China.Institute of Translational Medicine, Nanchang University, 999 Xuefu Load, Honggutan District, Nanchang, 330031, China. School of Life Sciences, Nanchang University, Nanchang, 330031, China.Institute of Translational Medicine, Nanchang University, 999 Xuefu Load, Honggutan District, Nanchang, 330031, China.Institute of Translational Medicine, Nanchang University, 999 Xuefu Load, Honggutan District, Nanchang, 330031, China.Institute of Translational Medicine, Nanchang University, 999 Xuefu Load, Honggutan District, Nanchang, 330031, China. dengk26@gmail.com.Institute of Translational Medicine, Nanchang University, 999 Xuefu Load, Honggutan District, Nanchang, 330031, China. hongboxin@yahoo.com. School of Life Sciences, Nanchang University, Nanchang, 330031, China. hongboxin@yahoo.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28449683

Citation

Wang, Ling-Fang, et al. "Inhibition of NAMPT Aggravates High Fat Diet-induced Hepatic Steatosis in Mice Through Regulating Sirt1/AMPKα/SREBP1 Signaling Pathway." Lipids in Health and Disease, vol. 16, no. 1, 2017, p. 82.
Wang LF, Wang XN, Huang CC, et al. Inhibition of NAMPT aggravates high fat diet-induced hepatic steatosis in mice through regulating Sirt1/AMPKα/SREBP1 signaling pathway. Lipids Health Dis. 2017;16(1):82.
Wang, L. F., Wang, X. N., Huang, C. C., Hu, L., Xiao, Y. F., Guan, X. H., ... Xin, H. B. (2017). Inhibition of NAMPT aggravates high fat diet-induced hepatic steatosis in mice through regulating Sirt1/AMPKα/SREBP1 signaling pathway. Lipids in Health and Disease, 16(1), p. 82. doi:10.1186/s12944-017-0464-z.
Wang LF, et al. Inhibition of NAMPT Aggravates High Fat Diet-induced Hepatic Steatosis in Mice Through Regulating Sirt1/AMPKα/SREBP1 Signaling Pathway. Lipids Health Dis. 2017 Apr 27;16(1):82. PubMed PMID: 28449683.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of NAMPT aggravates high fat diet-induced hepatic steatosis in mice through regulating Sirt1/AMPKα/SREBP1 signaling pathway. AU - Wang,Ling-Fang, AU - Wang,Xiao-Nv, AU - Huang,Cong-Cong, AU - Hu,Long, AU - Xiao,Yun-Fei, AU - Guan,Xiao-Hui, AU - Qian,Yi-Song, AU - Deng,Ke-Yu, AU - Xin,Hong-Bo, Y1 - 2017/04/27/ PY - 2016/12/04/received PY - 2017/03/30/accepted PY - 2017/4/29/entrez PY - 2017/4/30/pubmed PY - 2018/2/20/medline KW - AMPKα KW - FK866 KW - Mouse KW - Nad+ KW - Nafld KW - Nampt KW - Sirt1 SP - 82 EP - 82 JF - Lipids in health and disease JO - Lipids Health Dis VL - 16 IS - 1 N2 - BACKGROUND: Nonalcoholic 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. METHODS: Hepatic 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. RESULTS: FK866 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. CONCLUSION: Our 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. SN - 1476-511X UR - https://www.unboundmedicine.com/medline/citation/28449683/Inhibition_of_NAMPT_aggravates_high_fat_diet_induced_hepatic_steatosis_in_mice_through_regulating_Sirt1/AMPKα/SREBP1_signaling_pathway_ L2 - https://lipidworld.biomedcentral.com/articles/10.1186/s12944-017-0464-z DB - PRIME DP - Unbound Medicine ER -