Natural Antioxidants for Non-alcoholic Fatty Liver Disease

Molecular Targets and Clinical Perspectives

Federico Salomone; Justyna Godos; Shira Zelber-Sagi

Disclosures

Liver International. 2016;36(1):5-20. 

In This Article

Abstract and Introduction

Abstract

Non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD), is emerging as a main health problem in industrialized countries. Lifestyle modifications are effective in the treatment of NAFLD; however, the long-term compliance is low. Therefore, several pharmacological treatments have been proposed but none has shown significant efficacy or long-term safety. Natural polyphenols are a heterogeneous class of polyphenolic compounds contained in vegetables, which are being proposed for the treatment of different metabolic disorders. Although the beneficial effect of these compounds has traditionally related to their antioxidant properties, they also exert several beneficial effects on hepatic and extra-hepatic glucose and lipid homeostasis. Furthermore, natural polyphenols exert antifibrogenic and antitumoural effects in animal models, which appear relevant from a clinical point of view because of the association of NASH with cirrhosis and hepatocellular carcinoma. Several polyphenols, such anthocyanins, curcumin and resveratrol and those present in coffee, tea, soy are available in the diet and their consumption can be proposed as part of a healthy diet for the treatment of NAFLD. Other phenolic compounds, such as silymarin, are commonly consumed worldwide as nutraceuticals or food supplements. Natural antioxidants are reported to have beneficial effects in preclinical models of NAFLD and in pilot clinical trials, and thus need clinical evaluation. In this review, we summarize the existing evidence regarding the potential role of natural antioxidants in the treatment of NAFLD and examine possible future clinical applications.

Introduction

Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder diffused in both western and eastern countries associated with increased cardiovascular and liver-related morbidity and mortality such as high levels of free fatty acids.[1] Metabolic alterations in lipid homeostasis, such as an of free fatty acids (FFA) and non-HDL cholesterol, have been reported to precede fatty liver onset.[2] In some patients, high liver FFA and cholesterol trigger hepatocyte damage and activation of inflammation and fibrogenesis through multiple cellular signalling pathways, which in turn lead to NASH.[3] Among the several molecular events leading to fibrogenesis, the initiation and perpetuation of oxidative stress in the liver appear to play a crucial role. In fact, patients with fibrogenic NASH display both an increase in radical oxygen and nitrogen species production[4] and a lack of endogenous antioxidant defenses.[5]

Both genetic[6] and environmental factors, especially dietary habits,[7] have been implicated in modulating the complex network of molecular signals leading to NASH. Lifestyle modification is effective in the treatment of liver steatosis and inflammation[7] though evidence on the effects of lifestyle changes on fibrosis is lacking. However, as most of patients are not compliant with healthy diet and physical activity, several drug treatments for the management of NAFLD have been proposed, but none has shown considerable efficacy on the whole spectrum of liver damage.[8]

Natural polyphenols are a wide class of phytochemicals sharing a common phenolic structure and classified as flavonoids and non-flavonoids.[9] Polyphenols are active plant metabolites with various functions including protection from microbial infections, attraction for pollinators and seed-dispersing animals.[9] Although not essential for life as vitamins in the short-term, dietary flavonoids and non-flavonoids are considered responsible for the health promoting effects of fruits and vegetables.[10] Flavonoids are formed by two phenolic rings connected by a three carbon bridge (Fig. 1) indicated as C6-C3-C6; on the basis of specific chemical sub-groups linked to the flavonoid skeleton, dietary flavonoids are classified in six main subclasses: flavones, isoflavones, flavonols, flavanols (or flavan-3-ols), flavanones and anthocyanins.[9] The diversity in functional groups leads to the differences in biological properties of flavonoids. Non-flavonoids do not have the C6-C3-C6 structure and can be formed by a single phenolic ring linked to one or three carbons such in phenolic acids or hydroxycinnamic acids; another subclass of non-flavonoids is represented by stilbenes, such as resveratrol, which display a C6-C2-C6 structure.[9] Natural polyphenols have been historically characterized for their potent antioxidants properties. However, several lines of evidence in vitro, and in animal models and emerging clinical trials reported beneficial effects on liver steatogenesis and related molecular pathways; some polyphenols have also revealed antifibrogenic effects both in preclinical and clinical setting. In this review, we aimed to summarize the existing experimental and clinical evidences regarding natural polyphenols and NAFLD and the potential future clinical applications.

Figure 1.

Chemical structure of polyphenols. Natural polyphenols are a wide class of phytochemicals sharing a common phenolic structure and classified as flavonoids and non-flavonoids. Flavonoids are formed by two phenolic rings connected by a three carbon bridge indicated as C6-C3-C6; on the basis of specific chemical sub-groups linked to the flavonoid skeleton, dietary flavonoids are classified in subclasses: flavones/isoflavones, flavonols, flavanols (or flavan-3-ols), flavanones and anthocyanins. Non-flavonoids do not have the C6-C3-C6 structure and can be formed by a single phenolic ring linked to one or three carbons such in phenolic acids or hydroxycinnamic acids; another subclass of non-flavonoids is represented by stilbenes, such as resveratrol, which display a C6-C2-C6 structure.

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