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    • In addition to the role of TGR the FXR FGF

    2021-11-19

    In addition to the role of TGR5, the FXR-FGF15/19 axis has been implicated in other aspects of glucose metabolism and metabolic disorders. In humans, both obesity and type 2 diabetes mellitus (T2DM) are associated with lower plasma FGF19 levels [67,68]. A derivative of the naturally occurring FXR agonist CDCA, 6α-ethyl-CDCA (obeticholic acid, OCA), was recently approved by the Food and Drug Administration (FDA) for the treatment of primary biliary cholangitis (PBC), and is in clinical trials for treatment of non-alcoholic steatohepatitis. Administration of OCA to patients with non-alcoholic fatty liver disease and T2DM increased plasma FGF19 levels, decreased liver enzymes (alanine aminotransferase and γ-glutamyltransferase) and improved insulin sensitivity [69]. In a phase 3 clinical trial, OCA ameliorated histology scores of non-alcoholic steatohepatitis patients [70]. Animal studies, however, have not generated unambiguous results regarding the effects of the FXR-FGF15/19 axis on metabolism. Transgenic mice with hepatic overexpression of FGF19 display an increased metabolic rate and decreased adiposity [71]. Kir et al. found that administration of FGF19 to WT mice improved glucose metabolism by inducing hepatic glycogen and protein synthesis [72]. Conversely, Fgf15 mice showed glucose intolerance and a reduced hepatic glycogen content. Administration of FGF19 was even found to reverse diabetes mellitus in ob/ob mice [73]. A direct involvement of Fxr-Fgf15 signaling was demonstrated by intestinal inactivation of Fxr or reducing intestinal Fxr signaling through remodeling the intestinal microbial profile by the anti-oxidant tempol, both of which reduced diet induced obesity and hepatic triglyceride accumulation in mice [74,75]. The metabolic improvements by tempol were explained by reduced species of Lactobacillus and their BSH activity resulting in increased levels of tauro-β-muricholic acid, a naturally occurring FXR antagonist. This claim was further supported by a study in which administration of glyco-β-muricholic AT9283 (Gly-MCA), a selective FXR inhibitor, reduced obesity and improved related metabolic abnormalities in mice [76]. On the other hand, intestine-specific FXR activation using the intestinally restricted FXR agonist fexaramine, reduced diet-induced obesity, insulin resistance and steatosis in mice fed a HFD [77]. However, a recent study explained the beneficial effects of fexaramine by an indirect effect on the microbiota and activation of TGR5 via pronounced alterations in BA composition [78].
    Bile acid homeostasis and its role in cystic fibrosis liver disease Cystic fibrosis liver disease (CFLD) is a severe complication of CF and an independent risk factor for mortality [79,80]. According to the 2016 CF patient registry report, CFLD accounted for 2.7% of mortality in CF patients [81]. CFLD is an umbrella term used to describe various types of liver dysfunction in CF of which the pathophysiology is often not completely understood [82]. In the liver, CFTR is expressed exclusively at the apical membrane of cholangiocytes lining the bile ducts [15,83]. One proposed mechanism for the development of CFLD is that loss of CFTR function leads to obstruction of the bile ducts by thickening of the mucus, eventually resulting in obstructive biliary cirrhosis. Murine CF models generally do not display CFLD except upon ageing [84,85]. The absence of CFLD in murine CF models might be partially explained by lower BA toxicity due to differences in biliary BA composition between mice and humans. Mice generally have a higher concentration of hydrophilic BAs which is regarded as less cytotoxic since hydrophilic BAs have a lower detergent capacity than hydrophobic BAs [86]. High concentrations of hydrophobic BAs, mainly DCA, have been associated with increased risk of cholesterol gallstone disease, colon cancer and liver cancer [53,87]. FXR-FGF15/19 signaling and hepatic FXR activation have been consistently shown to affect liver regeneration and proliferation [[88], [89], [90], [91]]. This regenerative/proliferative response, measured by hepatic staining of the proliferation marker Ki67, is absent in Cftr mice upon feeding cholic acid (CA), a strong FXR agonist [17]. This suggests that a CF liver might have reduced regenerative ability due to BA malabsorption. Interestingly, in humans the presence of CFLD is associated with normalization of fecal BA excretion which could be due to impaired production as declining liver function occurs but this has not been further investigated [2].