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Bile Acids in the Pathogenesis of Necrotizing Enterocolitis
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Most BA reclamation occurs in the distal ileum via the apical sodium-dependent bile acid transporter (ASBT) (10). The intestinal bile acid–binding protein (IBABP, aka FABP6) is thought to shuttle internalized BAs to the basolateral surface of enterocytes (11, 12), where the heteromeric organic solute transporter (OSTα-OSTβ) effluxes BAs into portal circulation (13). On hepatocytes, the sodium-dependent taurocholate-transporting polypeptide (NTCP) and members of the organic anion-transporting polypeptide (OATP) family mediate the completion of enterohepatic circulation. The farnesoid X receptor (FXR) is a nuclear receptor for which BAs are endogenous ligands (14, 15). When BAs bind to FXR in the liver, a cascade of events occurs, eventually leading to suppression of CYP7A1 and NTCP with up-regulation of BSEP. In the intestine, activation of FXR by BAs down-regulates ASBT and up-regulates IBABP and OSTα-OSTβ (16, 17). Binding of BAs to FXR also activates fibroblast growth factor 19 (FGF19) in humans and FGF15 in mice. FGF15/19, an intestinal hormone, is secreted into portal circulation and in the liver and suppresses CYP7A1 and BA synthesis after binding to FGF receptor 4 (FGFR4) complexed with β-Klotho (18). This highly regulated process provides an effective mechanism for recycling BAs and preventing toxic accumulation in enterocytes and hepatocytes (19, 20).
Insulin Resistance and Glucose Regulation
Published in Awanish Kumar, Ashwini Kumar, Diabetes, 2020
Another important recent marker proposed that has shown considerable association with insulin resistance and diabetes is a new member of the fibroblast growth factor family – FGF21. Fibroblast growth factors (FGFs) are a class of glycoproteins responsible mainly for growth and metabolism. FGFs are autocrine, paracrine or endocrine in their action. Endocrine FGFs mainly work like hormone and affect metabolism. The human FGF family consists of 22 members with the majority functioning in growth, development and cellular differentiation, but the FGF19 subfamily members, comprising FGF15/19, FGF21 and FGF23, exert metabolic effect by endocrine action. While most other FGFs show their FGF receptor (FGFR) binding through binding to heparin sulphate of extracellular matrix (ECM), FGF21 binds to heparin sulphate very weakly and thus works in an endocrine manner. Another important feature of FGF21 activity is that the FGFRs that it binds to are combined to another transmembrane protein β-klotho which is primarily expressed in adipocytes, hepatocytes and the pancreas. Thus these organs are the major sites of action of FGF21. Thus, from the sites of action, it becomes apparent that FGF21 is involved in lipid, glucose and bile acid metabolism [42].
Luminally Active Therapies
Published in John K. DiBaise, Carol Rees Parrish, Jon S. Thompson, Short Bowel Syndrome Practical Approach to Management, 2017
FGF15/19 also stimulates gallbladder filling, and FXR activation has been shown to protect against cholestasis-induced liver injury; these effects are of great relevance to SBS given the occur-rence of cholestasis as a component of intestinal failure-associated liver disease (IFALD). Indeed, altered FXR signaling has been demonstrated in a pig model of IFALD [19], and in a much earlier study, Al-Ansari and colleagues [20] found that the IBAT was paradoxically down-regulated after massive intestinal resection.
The identification of farnesoid X receptor modulators as treatment options for nonalcoholic fatty liver disease
Published in Expert Opinion on Drug Discovery, 2021
Stefano Fiorucci, Michele Biagioli, Monia Baldoni, Patrizia Ricci, Valentina Sepe, Angela Zampella, Eleonora Distrutti
Another mechanism of regulation of cholesterol absorption by iFXR involves an SHP-dependent regulation of NPC1L1 in the proximal ileum [84]. In wild type mice exposure to FGF19 negatively regulated the expression of NPC1L1, decreased cholesterol absorption, while increased levels of hydrophilic bile acids, including tauro-α- and -β-MCAs. These effects were lost in Shp−/- mice [84]. Mechanistically, FGF19 signaling in IEC led to phosphorylation of SHP, which inhibited the activity of SREBF2 (sterol regulatory element-binding transcription factor 2), which, in turn, regulates cholesterol absorption by inducing the transcription of NPC1L1 in the upper small intestine [84]. Thus, FGF15/19 released from the terminal ileum functions as a negative feedback regulator of the expression of the cholesterol transporter in the proximal ileum. It is unclear whether this observation as a relevance to human pharmacology [57,85].
Effect of the Ileum and Colon on Liver Regeneration
Published in Journal of Investigative Surgery, 2021
Cláudia Nunes Oliveira, Ítalo Medeiros Azevedo, Keyla Borges Ferreira Rocha, Eryvaldo Sócrates Tabosa Egito, Aldo Cunha Medeiros
Ileal resection likely altered bile acid homeostasis, which was important for liver regeneration, in the 70% hepatectomy + ileal resection group. Zhang et al (2013) demonstrated that farnesoid X receptor (FXR) expressed in the liver and intestine activates the expression of fibroblast growth factor 15 (FGF15) in the ileum [13]. This contributes to suppressing CYP7a1 transcription, decreasing bile acid synthesis, and enhancing liver regeneration. It has been demonstrated that FGF15 released from the ileum has important effects on the enterohepatic cycle [14]. In addition to controlling bile acid synthesis, FXR stimulation activates pro-mitogenic mechanisms [15]. In the present study, we used ileal resection as a possible factor influencing liver regeneration, based on these mechanisms and other regulatory molecular factors of the enterohepatic cycle [16]. Qiu et al (2009) reported a change in functional liver mass, autophagy and apoptosis after small bowel resection in mice [12]. In our laboratory we have evaluated functional liver mass, using aspartate aminotransferase, alanine aminotransferase, gamaglutamiltransferase and biodistribution of pertechnetate labeled phytate (99 m-Tc-phytate), a radiocolloid used to validate the assessment of liver function in postoperative period of ileal resection in an animal model. We observed a significant reduction of functional liver capacity in rats subjected to 50 cm ileum resection [17].
Anti-diabetic drugs and NASH: from current options to promising perspectives
Published in Expert Opinion on Investigational Drugs, 2021
Sarra Smati, Clémence M Canivet, Jérôme Boursier, Bertrand Cariou
FGF19 (FGF15 in the mouse), another member of the FGF family, is a gastrointestinal endocrine hormone that regulates bile acid and glucose metabolism. FGF19 is induced in the intestine by the nuclear receptor farnesoid X receptor (FXR) that is activated by bile acids [101]. Through portal circulation, FGF19 travels to the liver and activates the receptor FGFR4 in association with the coreceptor βKLOTHO on hepatocytes and inhibits bile acid synthesis via CYP7A1 regulation. Aldafermin (NGM 282), an FGF19 analog devoid of hepatocyte proliferative effect of native FGF19, was evaluated in phase 2 trials. Administration of aldafermin in patients with NASH for 12 and 24 weeks led to a significant reduction in absolute liver fat content and in ALT levels [102,103]. In addition, in the 24-week study, there was a trend toward fibrosis improvement in aldafermin arm. Indeed, NASH resolution with no worsening of fibrosis was observed in 24% of patients under aldafermin compared to 9% of patients under placebo (p = 0.20) [103]. Effects of aldafermin on NASH histological features are currently further investigated in a phase 2 trial (NCT04210245) (Table 1). There was no significant change in metabolic parameters (HbA1C and plasma lipids) in aldafermin group compared to placebo [103].