ANTIOXIDANT AND ANTI-INFLAMMATORY PROPERTIES OF BIOTRANSFORMED PROANTHOCYANIDINS IN RELATION TO NONALCOHOLIC FATTY LIVER DISEASE

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Despite the number of new NAFLD cases predicted to increase, there are no United States Food and Drug Administration-approved drugs for NAFLD. Bioactive dietary polyphenols such as proanthocyanidins (PAC) are potent in reducing the risk of NAFLD. The majority of dietary PAC are oligomeric PAC (OPAC) and polymeric PAC (PPAC), which are low in bioavailability. The biotransformation of OPAC and PPAC into bioavailable metabolites using probiotics can enhance their physiological benefits. Initially, an ultrasonication-assisted aqueous-ethanol-based PAC extraction method was developed to obtain food-grade PAC suitable for use in the development of synbiotics. The optimum conditions to extract PAC from grape seeds were by using 47% aqueous-ethanol at 60 °C temperature, 10.14:1 solvent to solid ratio, and 53 min of sonication time. The ability of a mixture of Lactobacillus and Bifidobacterium probiotic bacteria (PB) together with novel PB Akkermansia muciniphila to biotransform PPAC was evaluated in the C57BL/6 mice. PB could biotransform PAC into bioavailable metabolites and improve the PPAC biotransformation in the mice. Oral supplementation of isolated PPAC indirectly induced nonalcoholic steatohepatitis (NASH) in the mice by impairing the gut epithelial barrier function and subsequently enabling bacterial lipopolysaccharides translocation into the liver. OPAC and PPAC were biotransformed in vitro by using Saccharomyces cerevisiae to obtain bioactive metabolites while reducing the toxicity of PPAC. The biotransformed (BT)-OPAC and BT-PPAC significantly reduced the palmitic acid (PA)-induced lipid accumulation in mouse hepatocytes (AML12) by suppressing the de novo lipogenesis and promoting the fatty acid β-oxidation. Also, BT-PAC ameliorated PA-induced oxidative stress by activating the nuclear factor erythroid 2-related factor 2 antioxidant pathway and upregulating the expressions of antioxidant enzymes. Moreover, BT-PAC significantly reduced PA and LPS-induced inflammation in AML12 cells by suppressing the activation of toll-like receptor 4-mediated inflammatory signaling pathways. Taken together, these results suggest the potential to develop PAC-based synbiotics to mitigate the risk of NAFLD and NASH. However, such synbiotics must be critically evaluated for their safety for human consumption.