The hepatic response to FGF 19 is impaired in patients with non - alcoholic 1 fatty liver disease and insulin resistance

30 Intestinal FGF19 has emerged as a novel endocrine regulator of hepatic bile salt and lipid 31 metabolism. In patients with non-alcoholic fatty liver disease (NAFLD) hepatic lipid 32 metabolism is deranged. A possible role of FGF19 in NAFLD has not been reported yet. In this 33 study, we assessed intestinal FGF19 production and the hepatic response to FGF19 in NAFLD 34 patients with and without insulin resistance (HOMA score ≥2.5 [n=12] and HOMA score <2.5 35 [n=8], respectively). To this end, NAFLD patients received a standardized oral fat challenge. 36 Postprandial excursions of triglycerides, bile salts and FGF19 were monitored, and plasma 37 levels of a marker for bile salt synthesis (7α-hydroxy-4-cholesten-3-one) were determined. 38 Fasted FGF19 levels were comparable in a control group of healthy volunteers (n=15) and in 39 NAFLD patients (0.26±0.28 ng/mL vs. 0.18±0.09 ng/mL, resp., P=0.94). Postprandial FGF19 40 levels in both controls and NAFLD patients peaked between 3-4 hrs and were three times 41 higher than baseline levels. The areas under the postprandial FGF19 curve were similar in 42 controls and in the HOMA score-based NAFLD subgroups. In NAFLD patients with HOMA 43 score <2.5, the postprandial increase in plasma FGF19 was accompanied by a lowering of 44 plasma levels of 7α-hydroxy-4-cholesten-3-one (-30%, P=0.015). This anticipated decline was 45 not observed in insulin-resistant NAFLD patients (+10%, P=0.22). In conclusion, patients with 46 NAFLD show an unimpaired intestinal FGF19 production. However, the hepatic response to 47 FGF19 is impaired in NAFLD patients with insulin resistance (HOMA score ≥2.5). This 48 impaired hepatic response to FGF19 may contribute to the dysregulation of lipid homeostasis 49 in NAFLD. 50 51 52