The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance

Abstract

Intestinal FGF19 has emerged as a novel endocrine regulator of hepatic bile salt and lipid metabolism. In patients with nonalcoholic fatty liver disease (NAFLD) hepatic lipid metabolism is deranged. A possible role of FGF19 in NAFLD has not been reported yet. In this study, we assessed intestinal FGF19 production and the hepatic response to FGF19 in NAFLD patients with and without insulin resistance [homeostasis model of assessment (HOMA) score > or =2.5 (n = 12) and HOMA score <2.5 (n = 8), respectively]. To this end, NAFLD patients received a standardized oral fat challenge. Postprandial excursions of triglycerides, bile salts, and FGF19 were monitored, and plasma levels of a marker for bile salt synthesis (7alpha-hydroxy-4-cholesten-3-one) were determined. Fasted FGF19 levels were comparable in a control group of healthy volunteers (n = 15) and in NAFLD patients (0.26 +/- 0.28 vs. 0.18 +/- 0.09 ng/ml, respectively, P = 0.94). Postprandial FGF19 levels in both controls and NAFLD patients peaked between 3-4 h and were three times higher than baseline levels. The areas under the postprandial FGF19 curve were similar in controls and in the HOMA score-based NAFLD subgroups. In NAFLD patients with HOMA score <2.5, the postprandial increase in plasma FGF19 was accompanied by a lowering of plasma levels of 7alpha-hydroxy-4-cholesten-3-one (-30%, P = 0.015). This anticipated decline was not observed in insulin-resistant NAFLD patients (+10%, P = 0.22). In conclusion, patients with NAFLD show an unimpaired intestinal FGF19 production. However, the hepatic response to FGF19 is impaired in NAFLD patients with insulin resistance (HOMA score > or =2.5). This impaired hepatic response to FGF19 may contribute to the dysregulation of lipid homeostasis in NAFLD.

Bile Acid Signaling in Metabolic Disease and Drug Therapy

“…Fgf15 knockout mice showed glucose intolerance, increased hepatic gluconeogenesis, and reduced hepatic glycogen storage but unaltered overall insulin sensitivity. Decreased fasting FGF19 levels or impaired hepatic response to FGF19 have been reported in humans with fatty liver and insulin resistance (Schreuder et al, 2010;Wojcik et al, 2012). These studies suggest that bile acid regulation of hepatic glucose metabolism involves complex cross-talk between FXR-dependent pathways and FXR-independent signaling pathways.…”

Aberrantly elevated microRNA-34a in obesity attenuates hepatic responses to FGF19 by targeting a membrane coreceptor β-Klotho

“…Secreted FGF19 binds to a hepatic membrane receptor complex, FGF19 receptor 4 (FGFR4), and its coreceptor β-Klotho (βKL) (3)(4)(5)(6), and it then triggers the activation of cellular kinases, including ERK and glycogen synthase kinase (GSK), to mediate postprandial metabolic responses (7,8). Interestingly, a recent study showed that the hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease (NAFLD) and insulin resistance (9). Despite the functional importance of βKL in transmitting FGF19 signaling, little is known about how the expression of βKL is regulated and why FGF19 signaling is impaired in patients who have fatty liver.…”

“…Hepatic miR-34a levels are substantially elevated in human patients with fatty liver (16,17) and in obese mice (14,15). Moreover, hepatic responses to FGF19 are impaired in patients with fatty liver disease (9). Therefore, to test if aberrantly elevated miR-34a in obesity correlates inversely with βKL levels, we determined the miR-34a and βKL levels in two mouse models of obesity.…”

The FGF Family in Humans, Mice, and Zebrafish: Development, Physiology, and Pathophysiology

“…The hepatic response to FGF15/19 is impaired in NAFLD patients with insulin resistance. This impaired response may contribute to the disturbance of lipid homeostasis in NAFLD (Schreuder et al, 2010). Serum FGF21 levels are significantly increased in NAFLD (Yilmaz et al, 2010;Dushay et al, 2010;Li et al, 2010).…”