# The Effects of Polyphenol-Rich Black Elderly on Oxidative Stress and Hepatic Cholesterol Metabolism
## 4 Discussion
SR-B1, a unique ligand membrane receptor, selectively uptakes HDL-associated cholesterol for the clearance in circulation and concomitant modulation of RCT [49; 50]. Overexpression of hepatic SR-B1 in the mouse decreased plasma HDL and increased biliary cholesterol concentration in the liver and gallbladder [51]. ABCA1, the transporter for hepatic cholesterol efflux, is required for nascent HDL biogenesis [52; 53]. There was a significant induction of SR-B1 and ABCA1 in BEE-treated HepG2 cells. Consistent with these results, polyphenol-abundant natural products induced hepatic SR-B1 and ABCA1 that are involved in HDL cholesterol metabolism. Quercetin, a polyphenic flavonoid, significantly increased the expression of SR-B1 in HepG2 cells and in the liver of C57 BL/6 mice [54]. Propolis and red wine concentrate increased hepatic ABCA1 expression in the mice and HepG2 cells [55; 56]. These observations support the possibility that the hypocholesterolemomic effects of BEE may be attributed to altering genes for cholesterol biosynthesis and uptake in the liver. The function of NPC1L1 is cholesterol absorption in the small intestine and liver [57]. Inhibitor of NPC1L1, exemitube, has been clinically used as an effective cholesterol-lowering medication [58; 59]. Hepatic NPC1L1 transports newly secreted biliary cholesterol back into hepatocytes to avoid excessive loss of cellular cholesterol [57; 60]. In contrast, ABCG5/G8 in the hepatocyte transports unmetabolized free cholesterol of the liver into bile for direct secretion [60; 61]. The expression of mRNA and protein of NPC1L1 was decreased, whereas ABCG5/G8 level was increased in BEE-treated HepG2 cells. Consistent with our findings, the expression of NPC1L1 was significantly decreased by _Opuntia focus indica_ high in phenolic compounds in HepG2 cells [62]. Coffea arabica pulp containing polyphenols alleviated hepatic lipid content by increasing cholesterol efflux transporter ABCG5/G8 in HepG2 cells [63]. CYP7A1 is the critical enzyme for the conversion of cholesterol to bile acids in the liver [64]. ABCB11, a bile salt export pump (BSEP), is present in the canalicular membrane of hepatocytes and mediates biliary secretion [65; 66; 67]. BEE altered the genes for bile acid synthesis and secretion in HepG2 cells. Consistent with our results, dietary resveratrol increased the mRNA and protein levels of hepatic CYP7A1, with a concomitant increase in CYP7A1 enzyme activity in high-fat-fed mice [37]. Polyphenols as a dietary antioxidant are reported to regulate cholesterol metabolism via bile acid biosynthesis [68]. Furthermore, cyanidin 3-glucoside, the major anthocyanin present in BEE with antioxidant properties, exerted hypocholesterolem activity by activating hepatic CYP7A1 for bile acid excretion [69]. In the present study, BEE significantly altered the genes involved in cholesterol transport in the direction of biliary cholesterol excretion. These results indicate that BEE can exert hypocholesterolemomic effects by facilitating the cholesterol from the liver into bile for secretion. Fatty acid metabolism is tightly associated with dyslipidemia. The genes for fatty acid synthesis and oxidation were measured in BEE-treated HepG2 cells. SREBPP1c preferentially activates the transcription of genes required for fatty acid and triglyceride synthesis, such as ACC, FAS, and SCD-1 [42; 44]. CPT1 is a mitochondrial enzyme required for the fatty acid \(\beta\)-oxidation process [70]. ACOX, the rate-limiting step of peroxisomal \(\beta\)-oxidation, catalyzes the very-long-chain saturated fatty acids (VLCFA). Accumulation of VLCFA in ACOX1 knockout mice confirmed the requirement for ACOX-1 for \(\beta\)-oxidation of these VLCFA [71; 72; 73]. In the present study, BEE altered the genes involved in fatty acid \(\beta\)-oxidation but not those involved in lipogenesis. Polypphenols from grape seed extract markedly increased CPT1 in HepG2 cells and human peripheral blood mononuclear cells [74].