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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].
Irritable Bowel Syndrome
Published in Peter Sagar, Andrew G. Hill, Charles H. Knowles, Stefan Post, Willem A. Bemelman, Patricia L. Roberts, Susan Galandiuk, John R.T. Monson, Michael R.B. Keighley, Norman S. Williams, Keighley & Williams’ Surgery of the Anus, Rectum and Colon, 2019
Recent evidence indicates that about 28% of patients with IBS-D may have bile acid diarrhoea (BAD).31 The most common cause of BAD is believed to be overproduction of bile acids, leading to a larger than normal pool of bile acids that saturate the transport capacity for bile acids in the distal ileum and leads to increased spill-over of bile acids to the colon. An increased amount of bile acids in the colon will stimulate electrolyte and water secretion and give rise to diarrhoea. The loss of bile acids can be measured using a radiolabelled synthetic bile acid 75Se-homocholic acid-taurine (SeHCAT). The measured entity with the SeHCAT-test is whole body retention of the tracer after seven days. Retention of <10% indicates significant loss of bile acids to faeces. The exact fraction of tracer that should remain after normal losses of bile acids is somewhat controversial, but >15% is often considered normal. Newer methods for assessment of bile acid diarrhoea include measurements of the serum level of 7α-hydroxy-4-cholesten-3-one, which reflects the rate of bile acid synthesis, and the serum level of the protein-hormone fibroblast growth factor 19 (FGF19), which is secreted by enterocytes of the small bowel for the control of bile acid synthesis in the liver.
Lower systemic inflammation is associated with gut firmicutes dominance and reduced liver injury in a novel ambulatory model of parenteral nutrition
Published in Annals of Medicine, 2022
Ashish Samaddar, Johan van Nispen, Austin Armstrong, Eric Song, Marcus Voigt, Vidul Murali, Joseph Krebs, Chandra Manithody, Christine Denton, Aaron C. Ericsson, Ajay Kumar Jain
In our model, the prevalence of inflammatory mediators had adverse systemic effects. In both the control and TPN groups, as the level of LPS and inflammatory cytokines increased, the weight of the neonatal pigs on the day of the sac was decreased. For these neonatal pigs, the ability to gain weight is an indicator of the ability to thrive. Several studies have correlated TNF-A with hepatic inflammation and injury [39,40]. In the EN control group, TNF-A levels had the strongest correlation with the serum GGT levels, a marker of liver injury. In the TPN piglets, this trend was not as strong, but inflammatory cytokines had a positive correlation with GGT. In both EN and TPN animals, there was a statistically significant association between portal LPS levels and bile acid levels. In animals on TPN, serum Fibroblast Growth Factor 19 (FGF19) levels are decreased due to a lack of luminal Farnesoid X Receptor (FXR) activation [6,24]. FGF19 regulates CyP7A1, the rate-limiting step of bile acid synthesis, and is known to suppress CyP7A1. Thus, while LPS is known to suppress CyP7A1, the plausible explanation for the higher bile acid levels is due to the lack of the inhibition of CyP7A1 by FGF19 which is not offset by the LPS action.
FGFR4 inhibitors for the treatment of hepatocellular carcinoma: a synopsis of therapeutic potential
Published in Expert Opinion on Investigational Drugs, 2022
Hao Xie, Diego M Alem Glison, Richard D. Kim
Fibroblast growth factors (FGFs), a family of ligands that bind the corresponding FGF receptor FGFR1-4, involve in various physiologic processes including early embryogenesis, wound repair, angiogenesis, bile acid synthesis, and metabolism [12,13]. Aberrant FGF/FGFR signaling pathways are present in multiple types of cancers including HCC, which lead to significantly increased cell proliferation and survival [14–16]. Among them, FGF19 and its counterpart receptor FGFR4 were shown as a potential driver in advanced HCC [17]. In normal physiology, FGF19 regulates hepatocyte proliferation and bile acid synthesis by binding to FGFR4 [18]. However, a subset of advanced HCCs has aberrant FGF19 expression, which implicates that FGF19 is a potential driver of hepatocarcinogenesis [19]. Amplification of FGF19/CCND1 locus is present in approximately 6% of HCC cases [20,21]. In addition, epigenetic alterations are also responsible for the upregulation of FGF19 in up to 23% of HCC cases [22]. Overexpression of FGF19 in patients with HCC creates autocrine–paracrine signaling where FGF19 binds to FGFR4 with βklotho (KLB) as a coreceptor. This interaction activates downstream effector proteins for HCC proliferation [17].
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].