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  • Liver disease is the third

    2019-07-30

    Liver disease is the third most common cause of premature death in the UK [26]. Due to the increased incidence of obesity, NAFLD is now more prevalent than alcohol-induced liver disease [2] with 67% of overweight and 94% of obese individuals presenting this condition [27]. The HF/HFr regime was selected as a physiologically relevant model for human NAFLD development and resulted in steatosis and hepatocyte ballooning indicative of early NASH. In this study we demonstrate that combined supplementation with FLAVn-3 prevented steatosis and hepatocyte ballooning, lowered weight and adipose tissue gain and improved insulin sensitivity. Individual feeding of FLAV and n-3 identified numerous physiological and molecular mechanisms which are likely to have acted synergistically to prevent NASH in the FLAVn-3 group. FLAV ameliorated the HF/HFr induced obesity, the aetiology of which is likely related to changes in lipid Cell Counting Kit-8 (CCK-8) and bile acid metabolism [34]. Our impact on weight gain is consistent with previous data demonstrating that 8% cocoa powder for 10weeks significantly reduced the rate of body weight gain, as well as final body weight and retroperitoneal WAT weight compared to HFD-fed controls [28]. Such effects may be related to increased faecal fat excretion [29], with cocoa extracts and their component polyphenols shown to inhibit the activity of pancreatic lipase and secreted phospholipase A2, which may reduce dietary fat absorption [30]. Previous studies have reported the hypoglycemic and insulin sensitising effects of cocoa polyphenols. For example, a proanthocyanidin-rich cocoa liquor extract suppressed a HFD-induced hyperglycemia through the activation of AMP-activated protein kinase α, and the translocation of glucose transporter 4 in mice [20]. In addition, short-term administration of dark chocolate improved insulin resistance in terms of improved HOMA-IR and quantitative insulin sensitivity check index (QUICKI) in healthy subjects [31]. While cocoa polyphenols may play a large part in the observed effects, emerging evidence is also suggestive that caffeine contribute to the weight loss [32] although its intake could explain some but not all of the diabetes-risk reduction and weight change in humans [33]. While most bile acids enter the gut conjugated to taurine or glycine, these are deamidated by microbial bile salt hydrolases (BSH) in the distal small intestine and, if not absorbed and transported back to the liver, are further metabolized by the gut microbiota [35]. Recent studies in obese mice showed that partial inhibition of BSH by antibiotics [36] results in the intestinal accumulation of conjugated bile acids, and in particular of the FXR antagonists tauro-muricholic acid (T-MCA) [37] and tauro-ursodeoxycholic acid (TUDCA) [38], therefore reducing steatosis and body weight gain partly via repressed expression of hepatic Srebf1 [36]. Recent evidence suggests that elevated FXR antagonistic bile acids along with FXR antagonist that specifically inhibit intestine FXR, play a role in the treatment of NAFLD [39]. The role of intestinal FXR in body weight reduction, insulin resistance and fatty livers was firmly established in mice lacking FXR that are metabolicaly resistant to HFD-induced metabolic disease [40]. Furthermore, liver-specific Shp deletion, a target of Fxr, prevented hepatic steatosis in animal fed a HFD and Western diet while the global double knockdown of Shp and Fxr protected against weight gain, glucose intolerance and hepatic steatosis [41]. Accordingly, our results indicate that FLAV, and in particular when combined with n-3, partially suppressed bile salt deconjugation and the subsequent microbial conversion of MCA into HDCA resulting in an increase of FXR bile acids antagonist which favoured its signalling inhibition in the intestine and liver. More precisely, we demonstrate that the FLAV-triggered repression of hepatic Shp translated into enhanced expression of Cyp7a1, the rate-limiting enzyme in the bile acid synthesis pathway, whose overexpression in the liver of mice counteracted diet-induced obesity, steatosis, and insulin resistance [42]. In support of this statement, the finding that FLAV suppressed the expression of Tgr5 and Gcg mRNA levels in the small intestine, suggests that the secretion of glucagon-like peptide-1 via intestinal Tgr5 did not account for the metabolic improvements caused by FLAV. Additionally, FLAV resulted in lower fasting insulin and insulin concentrations following the IPGTT, which along with the increased expression of Cyp7a1 is thought to underlie the impact on steatosis and hepatocyte ballooning evident following the FLAVn-3 treatment.