Spermidine Supplementation Protects the Liver Endothelium from Liver Damage in Mice.

Genís Campreciós,Virginia Hernández-Gea,Erica Lafoz,Maria Ruart,Héctor García-Calderó,Marta Magaz,Marina Vilaseca,Joan Carles García-Pagán,Mar Coll,Isabel Graupera,Aina Anton,Scott L Friedman,Natalia Jiménez,Nuria Suárez-Herrera,Carla Montironi,Celia Martínez

doi:10.3390/nu13113700

Abstract

Chronic liver diseases are multifactorial and the need to develop effective therapies is high. Recent studies have shown the potential of ameliorating liver disease progression through protection of the liver endothelium. Polyamine spermidine (SPD) is a caloric restriction mimetic with autophagy-enhancing properties capable of prolonging lifespan and with a proven beneficial effect in cardiovascular disease in mice and humans. We evaluated the use of dietary supplementation with SPD in two models of liver disease (CCl4 and CDAAH diet). We analyzed the effect of SPD on endothelial dysfunction in vitro and in vivo. C57BL/6J mice were supplemented with SPD in the drinking water prior and concomitantly with CCl4 and CDAAH treatments. Endothelial autophagy deficient (Atg7endo) mice were also evaluated. Liver tissue was used to evaluate the impact of SPD prophylaxis on liver damage, endothelial dysfunction, oxidative stress, mitochondrial status, inflammation and liver fibrosis. SPD improved the endothelial response to oxidative injury in vitro and improved the liver endothelial phenotype and protected against liver injury in vivo. SPD reduced the overall liver oxidative stress and improved mitochondrial fitness. The absence of benefits in the Atg7endo mice suggests an autophagy-dependent effect of SPD. This study suggests SPD diet supplementation in early phases of disease protects the liver endothelium from oxidative stress and may be an attractive approach to modify the chronic liver disease course and halt fibrosis progression.

Highlights

Chronic liver injury is a highly prevalent disease that affects 1.5 billion people worldwide and is responsible for 2 million deaths/year [1]
Low levels of SPD have been correlated with disease severity in patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) [11] and SPD is reduced in patients with acute on chronic liver failure (ACLF) [12]
Because liver sinusoidal endothelial cells (LSEC) rapidly lose their phenotype when cultured in vitro [5,6] and there are no reliable markers to evaluate endothelial function in immortalized cell lines, we evaluated the direct effect of SPD pretreatment on two liver endothelial cell lines of murine (TSEC) and human (SK-HEP1) origin following an oxidative injury

Summary

Introduction

Chronic liver injury is a highly prevalent disease that affects 1.5 billion people worldwide and is responsible for 2 million deaths/year [1]. Spermidine (SPD) is an evolutionary conserved polyamine shown to exert a protective and lifespan-extending effect in mammals [9]. It is considered a caloric restriction mimetic due to its substantial antiaging effects through anti-inflammatory and antioxidant properties, while enhancing mitochondrial metabolic function and improving proteostasis and chaperone activity [10]. Its bioavailability can be increased by dietary supplementation with enriched aliments such as soybeans, wheat germ, nuts and fermented products [13], and dietary intake of SPD has been inversely correlated with the risk of heart failure, acute coronary artery disease, stroke and death due to vascular diseases [14], suggesting a beneficial role of SPD in maintaining endothelial phenotype in different organs. No data regarding the specific effect of SPD on the liver endothelium have been reported

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Results

Conclusion