Abstract

Liver diseases affect millions of people worldwide. In most of the cases, severe hepatic dysfunction and liver cancer stem from mild and common clinical signs including hepatic steatosis, insulin resistance, liver inflammation, and oxidative stress, all together referred to as Nonalcoholic Fatty Liver Disease (NAFLD). Nutraceuticals endowed with antioxidant activity have been shown to reduce NAFLD risk factors and exert hepatoprotective effects. Here, we test the protective effect exerted on liver by the antioxidant Taurisolo, a nutraceutical formulation produced by grape pomace and enriched in Resveratrol and Polyphenols. We analyze the effect of Taurisolo on liver cells by profiling the metabolome of in vitro cultured hepatic HuH7 cells and of C57BL-6J mice fed a High Fat Diet and treated with the nutraceutical. Both in vitro and in vivo, we provide evidence that Taurisolo reduces risk factor markers associated with NAFLD. Taurisolo stimulates glucose uptake and reduces hepatic cholesterol and serum triglycerides. Furthermore, we give new insights into the mechanism of action of Taurisolo. The nutraceutical increases mitochondrial activity and promotes respiration and ATP production, fostering catabolic reactions like fatty acid β-oxidation and amino acid catabolism. On the contrary, Taurisolo reduces anabolic reactions like biosynthesis of cholesterol, bile acids, and plasma membrane lipids.

Highlights

  • With a global prevalence of 25%, Nonalcoholic Fatty Liver Disease (NAFLD) is a major cause of liver disease worldwide [1]

  • Drugs administered to prevent hypertriglyceridemia, hypercholesterolemia (statins, ezetimibe, Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lomitapide, and bile acid sequestrants) [12] and insulin resistance (IR) [13] have all shown to ameliorate hepatic dysfunctions caused by NAFLD [3,14]

  • Our results show that Taurisolo promotes glucose uptake, hepatic glycolysis, fatty acid beta-oxidation leading to an overall reduction of hepatic triglycerides and cholesterol levels and a better response to insulin

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Summary

Introduction

With a global prevalence of 25%, Nonalcoholic Fatty Liver Disease (NAFLD) is a major cause of liver disease worldwide [1]. While excessive fat consumption remains the leading cause of NAFLD, dysmetabolism, hypertriglyceridemia, and IR are emerging risk factors for liver dysfunction [6]. Due to the high prevalence of the disease, efforts have been made to control risk factors for the NAFLD to avoid the progression of the condition. Drugs administered to prevent hypertriglyceridemia (fibrates, omega-3-fatty acids), hypercholesterolemia (statins, ezetimibe, Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lomitapide, and bile acid sequestrants) [12] and IR (metformin, sulfonylureas and thiazolidinediones, dipeptidyl peptidase-4 inhibitors and incretins) [13] have all shown to ameliorate hepatic dysfunctions caused by NAFLD [3,14]

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