Annals of Hepatology (Jan 2022)

NAMPT INHIBITION AND INCREASED NAD-BIOAVAILABILITY ATENUATE LIVER DAMAGE IN CCl4-INDUCED MICE CHRONIC LIVER DISEASE

  • J.A. Gutiérrez buendía,
  • R. Pérez Cabeza de Vaca,
  • G.A. Domínguez Pérez,
  • E. Vera Gomez,
  • A. Hernández Patricio,
  • K. Moreno Vega,
  • M. Salamanca García,
  • J.I. Bustamante Santillan,
  • P. Mondragón Terán,
  • R. Hernández Muñoz,
  • J.A. Suárez Cuenca

Journal volume & issue
Vol. 27
p. 100630

Abstract

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Introduction and Objectives: Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme on the NAD+ salvage biosynthetic pathway and a cytokine regulator with an important role in inflammation and fibrogenesis modulation. Use of FK866 (NAMPT inhibitor) has been proposed as a treatment on inflammatory diseases and cancer. However, FK866-induced depletion of NAD may also cause major impairment of the redox and bioenergetics homeostasis of the cell within the liver, thus limiting a favorable outcome for Chronic Liver Disease (CLD), as low NAD levels have been associated with higher Oxidative Stress and increased metabolic risk. The aim of this study was to evaluate the effects of NAMPT inhibition and concomitant NAD restoration on experimental CLD in vivo. Methods and Results: NAMPT inhibition was evaluated within a CCl4-induced CLD model on male BALB/c mice and a mild improved outcome was observed on the histological and biochemical features. NAD restoration strategy was accomplished by the concomitant administration of its precursor, NMN, resulting in significant improve on the histological analysis; lower inflammatory infiltrate and fibrosis were measured by image analysis on digitalized micrographies. Lower levels of Direct Bilirubin were also observed. NAMPT inhibition and adequate NAD restoration were confirmed by a colorimetric assay of NADH and NAD+ and biochemical features were measured by routinary Liver Function Tests. Silymarin was used as a hepatoprotective control. Conclusion: This study shows that NAMPT inhibition concomitant to NAD restoration significantly attenuate experimental liver damage.The authors declare that there is no conflict of interest.