Beneficial Effects of Dietary Polyphenols in the Prevention and Treatment of NAFLD: Cell-Signaling Pathways Underlying Health Effects

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic accretion of triacylglycerides in the absence of alcohol intake that may progress to steatohepatitis, fibrosis and cirrhosis, becoming the main cause of chronic liver disease. This article discusses recent data concerning the use of dietary polyphenols in the prevention and treatment of NAFLD in vitro, in vivo, and in clinical trials. Methods: Study searches were performed using the PubMed database from the National Library of Medicine-National Institutes of Health. Results: Polyphenols exert beneficial effects in NAFLD, with positive outcomes being related to body weight gain, insulin resistance, liver fat accumulation, oxidative stress, pro-inflammatory status, mitochondrial dysfunction and ER stress. Data reported for hydroxytyrosol suggest that the activation of the hepatic PPAR-α-FGF21-AMPK-PGC-1α signaling cascade is associated with fatty acid oxidation enhancement, de novo lipogenesis diminution and recovery of mitochondrial function, a contention that is supported by the actions of several polyphenols on specific components of this signaling pathway. Besides, polyphenols downregulate NF-κB, suppressing the pro-inflammatory state developed in NAFLD and upregulate liver Nrf2, increasing the cellular antioxidant potential. The latter feature of polyphenols is contributed by chelation of pro-oxidant trace elements, reduction of free radicals to stable forms and inhibition of free radical generating systems. Conclusion: Polyphenols are relevant bioactive compounds in terms of prevention and treatment of NAFLD, which exhibit low bioavailability and instability in biological systems that could limit their health effects. These drawbacks reinforce the necessity of further studies to improve the efficacy of polyphenol formulations for human interventions.

Perspectives in liver redox imbalance: Toxicological and pharmacological aspects underlying iron overloading, nonalcoholic fatty liver disease, and thyroid hormone action

“…61 These changes are prevented by antioxidant addition (N-acetyl cysteine, ascorbic acid, resveratrol), supporting the contention that TGs directly induce lipotoxicity through development of prolonged redox imbalance (Figure 2). 61 Studies in obese patients 62 and mice subjected to highfat diets (HFDs), 63 hepatic steatosis was associated with higher ROS production, as evidenced by the consequent alterations in redox imbalance-related parameters. These include GSH depletion and decreased SOD activity and in the ferric reducing activity of plasma (FRAP), increased protein carbonylation, 62 lipid peroxidation (higher 4-hydroxy-2 0 -nonenal [HNE] adduct levels) and DNA oxidation (higher content of 8-hydroxydeoxyguanosine) 64 in the liver of NAFLD patients.…”

“…77 In view that PPAR-α controls the hepatic expression of FGF21, 80 depressed PPAR-α activity is likely to diminished that of the energy sensing cascade FGF21-AMP-activated protein kinase (AMPK)-PPAR-γ coactivator 1α (PGC-1α), resulting in mitochondrial dysfunction (lower ATP and NAD + levels, complex I and II activities and the mRNA expression of β-ATP synthase). 81 (iii) Downregulation of transcription factor Nrf2 affording antioxidant protection is observed in the liver of mice after HFD feeding, 82 a finding that may be ascribed to the reduction in the production of n-3 LCPUFA-derived J3-isoprostanes, oxidation products that exert a potent activation of Nrf2. 83 In addition to the above n-3 LCPUFA-related prosteatotic mechanisms, protein oxidation by redox imbalance also contributes to fat accumulation in the liver, 62,65 considering that oxidized, F I G U R E 2 Diagram depicting the development of liver redox imbalance associated with overnutrition leading to nonalcoholic fatty liver disease (NAFLD) (A) and its exacerbation underlying the progression into nonalcoholic steatohepatitis (NASH) (B).…”

“…Loss of GSH and higher protein carbonylation and lipid peroxidation (greater content of thiobarbituric acid reactants [TBARs] and F-8 isoprostanes) were reported in the liver of HFD-fed mice. 63,65 Importantly, Kupffer cells from NAFLD patients with simple steatosis exhibit elevated levels of TBARs, O 2…”

Green Pea (Pisum sativum L.) Hull Polyphenol Extract Alleviates NAFLD through VB6/TLR4/NF-κB and PPAR Pathways

“…The large number of lipids in the liver, as reactive species, determine cellular homeostasis or dysfunctional biomolecules, and their oxidation leads to an imbalance of redox, which ultimately causes oxidative stress and more severe inflammation, thus increasing liver antioxidant capacity and reducing the inflammatory response to decrease ROS/RNS and inflammatory mediators is essential for prevention or treatment of NAFLD. , The above results demonstrate that HFD can induce inflammation that can be further exacerbated by DSS, but intervention by EGPH can alleviate the aggravated inflammatory status, which can be attributed to the polyphenols of EGPH. Various dietary polyphenols have been found to ameliorate inflammation and NAFLD …”

Diet and Gut Microbiota Interaction-Derived Metabolites and Intrahepatic Immune Response in NAFLD Development and Treatment

“…Natural polyphenols such as resveratrol with anti-inflammatory and antioxidant properties show potential efficiency against NAFLD [ 102 ]. Polyphenol showed multiple effects, including reduction in body weight gain and hepatic fat accumulation, improvement of insulin resistance, and amelioration of oxidative stress, mitochondrial dysfunction, and ER stress [ 103 ]. In addition, they can decrease both serum and liver proinflammatory cytokines that contribute to the fatty liver [ 104 ].…”