Abstract
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.
Highlights
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
The inhibition of Nicotinamide phosphoribosyltransferase (NAMPT) reduced the production of NAD+ through inhibiting the NAD+ salvage pathway, resulting in the decrease of Sirt1 activity, and attenuated the deacetylation of sterol regulatory elementbinding protein 1 (SREBP1) in which the inhibition of SREBP1 activity promoted the expressions of fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC)
Real-time PCR analysis indicated that the expressions of the lipogenic genes such as SREBP1, FASN, ACC and Stearoyl-CoA desaturase (SCD1) were increased in the high fat diet (HFD)-fed mice treated with FK866 (Fig. 1f )
Summary
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. The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing globally, and it has become the predominant cause of chronic liver disease in the world [1]. Hepatic lipid synthesis is regulated by many important transcription factors such as liver X receptor (LXR), carbohydrate response element binding protein (ChREBP) and sterol regulatory element–binding protein 1C (SREBP1C) [8,9,10]. It has been found that the phosphorylation of AMPKα at its Ser372 suppressed the cleavage and nuclear translocation of SREBP-1c and further repressed the expressions of the SREBP1C-mediated target genes in hepatocytes when the cells were treated with high glucose, leading to reduction of lipogenesis and lipid accumulation [13]
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