To obviate the mitogenic FGF activity several engineered FGF
To obviate the mitogenic FGF19 activity, several engineered FGF19 variants have been generated aiming to maintain the metabolic activity excluding the protumorigenic ones. One variant, M70, that differs from wild-type FGF19 by 5-amino acids deletion at the N-terminus and the substitution of 3-amino acids [,45], fully retains BA regulatory activity but is devoid of pro-tumoral activity in mouse models . In Abcb4−/− mice, M70 reduces hepatic inflammation and biliary fibrosis through CYP7A1 inhibition decreasing BA pool size . Moreover, in a mouse model of NASH, M70 decreases liver injury and ameliorates histological features of NASH, glucose and lipid metabolism representing a promising approach to treat this pathology . A phase II clinical trial has tested the safety and efficacy of NGM282 (M70) for the treatment of NASH. In these patients, the administration of 3 mg or 6 mg of NGM282 was well tolerated and reduced liver fat content as well as liver inflammation and fibrosis . Further studies are needed to evaluate the impact of M70 or others FGF19 engineered variants in the management of gut–liver axis diseases.
In conclusion, the gut–liver FXR–FGF19 duo represents the paradigm of physiological BA negative feedback regulation of their synthesis. The activation of this pathway could be a putative antifibrotic therapy in NASH. Here we presented a novel and intriguing view on the possibility to target this FXR–FGF19 duo in order to offer a bona fide promising therapeutic approach to bile CGP 3466B maleate australia promoted hepatocarcinoma. Future studies are needed to prove this hypothesis correct.
Grant support Moschetta is funded by Italian Association for Cancer Research (AIRC, IG 18987), NR-NET FP7 Marie Curie ITN, Italian Ministry of Health (Young Researchers Grant GR-2010-2314703).
Conflict of interest statement
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Main Text Sepsis is a life-threatening condition caused by a dysregulated host response to infection. The liver is an essential organ that acts as a guardian, modifier, and target of sepsis (Strnad et al., 2017). Any condition of impaired hepatic BA flow is defined as cholestasis, which is a common co-morbidity of sepsis; therefore, measurement of plasmatic BA level is routinely used as a sepsis prognostic marker. BAs are synthesized from cholesterol in the liver, stored in the gallbladder, and post-prandially released into the intestine in order to facilitate the absorption of dietary lipids and liposoluble vitamins. These amphipathic molecules travel along the intestine and once in the distal ileum 95% of them are actively absorbed and return to the liver via the portal vein in the so-called enterohepatic circulation. BAs are crucial metabolic players and important signaling molecules (Thomas et al., 2008); thus, the physiologic orchestration of BA enterohepatic circulation is essential. The nuclear Farnesoid X receptor (FXR) is the master regulator of BA homeostasis, governing their synthesis, transport, and metabolism (Modica et al., 2010). BA circulation is tightly controlled by a number of membrane transport systems. The organic anion transporting polypeptides (Oatps) and the Na+ taurocholate cotransport protein (Ntcp) mediate hepatic BA uptake at the basolateral membrane of hepatocytes. After conjugation, BAs are secreted into the bile via the canalicular membrane ATP-binding cassette (ABC) transporters, mainly the bile salt export pump (Bsep) and the multidrug related protein 2 (Mrp2). On the contrary, the basolateral membrane ABC transporters, such as Mrp3 and Mrp4, and the organic anion transporters α and β (OSTα/β) drive an alternative route to drain the BAs from the liver to the systemic circulation in case of obstruction to bile flow. Alterations of the equilibrium of these transport systems may lead to a cholestatic disorder.