A novel fibroblast growth factor 15-dependent and bile acid-independent promotion of liver regeneration in mice

Objective:The role of intestine-derived factors in promoting liver regeneration after partial hepatectomy(PHx)are not entirely known,but bile acids(BAs)and fibroblast growth factor 15(Fgf15)that are highly expressed in the mouse ileum could promote hepatocyte proliferation.Fgf15 strongly suppresses the synthesis of BAs,and emerging evidence indicates that Fgf15 is important for liver regeneration.

Fatty liver diseases,bile acids,and FXR

The prevalence of nonalcoholic fatty liver disease(NAFLD) worldwide has increased at an alarming rate,which will likely result in enormous medical and economic burden.NAFLD presents as a spectrum of liver diseases ranging from simple steatosis,nonalcoholic steatohepatitis(NASH),fibrosis,cirrhosis,and even to hepatocellular carcinoma(HCC).A comprehensive understanding of the mechanism(s) of NAFLD-to-NASH transition remains elusive with various genetic and environmental susceptibility factors possibly involved.An understanding of the mechanism may provide novel strategies in the prevention and treatment to NASH.Abnormal regulation of bile acid homeostasis emerges as an important mechanism to liver injury.The bile acid homeostasis is critically regulated by the farnesoid X receptor(FXR) that is activated by bile acids.FXR has been known to exert tissue-specific effects in regulating bile acid synthesis and transport.Current investigations demonstrate FXR also plays a principle role in regulating lipid metabolism and suppressing inflammation in the liver.Therefore,the future determination of the molecular mechanism by which FXR protects the liver from developing NAFLD may shed light to the prevention and treatment of NAFLD.

Farnesoid X receptor,the bile acid sensing nuclear receptor,in liver regeneration

The liver is unique in regenerative potential, which could recover the lost mass and function after injury from ischemia and resection. The underlying molecular mechanisms of liver regeneration have been extensively studied in the past using the partial hepatectomy(PH) model in rodents, where 2/3 PH is carried out by removing two lobes. The whole process of liver regeneration is complicated, orchestrated event involving a network of connected interactions, which still remain fully elusive. Bile acids(BAs) are ligands of farnesoid X receptor(FXR), a nuclear receptor of ligand-activated transcription factor. FXR has been shown to be highly involved in liver regeneration. BAs and FXR not only interact with each other but also regulate various downstream targets independently during liver regeneration. Moreover, recent findings suggest that tissue-specific FXR also contributes to liver regeneration significantly. These novel findings suggest that FXR has much broader role than regulating BA, cholesterol, lipid and glucose metabolism. Therefore, these researches highlight FXR as an important pharmaceutical target for potentialuse of FXR ligands to regulate liver regeneration in clinic. This review focuses on the roles of BAs and FXR in liver regeneration and the current underlying molecular mechanisms which contribute to liver regeneration.

Role of farnesoid X receptor in establishment of ontogeny of phase-I drug metabolizing enzyme genes in mouse liver

The expression of phase-I drug metabolizing enzymes in liver changes dramatically during postnatal liver maturation.Farnesoid X receptor(FXR) is critical for bile acid and lipid homeostasis in liver.However,the role of FXR in regulating ontogeny of phase-I drug metabolizing genes is not clear.Hence,we applied RNA-sequencing to quantify the developmental expression of phase-I genes in both Fxr-null and control(C57BL/6) mouse livers during development.Liver samples of male C57BL/6 and Fxr-null mice at6 different ages from prenatal to adult were used.The Fxr-null showed an overall effect to diminish the "day-1 surge" of phase-I gene expression,including cytochrome P450 s at neonatal ages.Among the 185 phase-I genes from 12 different families,136 were expressed,and differential expression during development occurred in genes from all 12 phase-I families,including hydrolysis: carboxylesterase(Ces),paraoxonase(Pon),and epoxide hydrolase(Ephx); reduction: aldoketo reductase(Akr),quinone oxidoreductase(Nqo),and dihydropyrimidine dehydrogenase(Dpyd); and oxidation: alcohol dehydrogenase(Adh),aldehyde dehydrogenase(Aldh),flavin monooxygenases(Fmo),molybdenum hydroxylase(Aox and Xdh),cytochrome P450(P450),and cytochrome P450 oxidoreductase(Por).The data also suggested new phase-I genes potentially targeted by FXR.These results revealed an important role of FXR in regulation of ontogeny of phase-I genes.

Bile acid homeostasis in female mice deficient in Cyp7a1 and Cyp27a1

Bile acids(BAs) are amphipathic molecules important for metabolism of cholesterol,absorption of lipids and lipid soluble vitamins,bile flow,and regulation of gut microbiome.There are over 30 different BA species known to exist in humans and mice,which are endogenous modulators of at least 6 different membrane or nuclear receptors.This diversity of ligands and receptors play important roles in health and disease;however,the full functions of each individual BA in vivo remain unclear.We generated a mouse model lacking the initiating enzymes,CYP7 A1 and CYP27 A1,in the two main pathways of BA synthesis.Because females are more susceptible to BA related diseases,such as intrahepatic cholestasis of pregnancy,we expanded this model into female mice.The null mice of Cyp7 a1 and Cyp27 a1 were crossbred to create double knockout(DKO) mice.BA concentrations in female DKO mice had reductions in serum(63%),liver(83%),gallbladder(94%),and small intestine(85%),as compared to WT mice.Despite low BA levels,DKO mice had a similar expression pattern to that of WT mice for genes involved in BA regulation,synthesis,conjugation,and transport.Additionally,through treatment with a synthetic FXR agonist,GW4064,female DKO mice responded to FXR activation similarly to WT mice.

Effects of total parenteral nutrition on drug metabolism gene expression in mice

Parenteral nutrition-associated liver disease(PNALD)is a liver dysfunction caused by various risk factors presented in patients receiving total parenteral nutrition(TPN).Omega-6 rich Intralipid?and omega-3 rich Omegaven?are two intravenous lipid emulsions used in TPN.TPN could affect the hepatic expression of genes in anti-oxidative stress,but it’s unknown whether TPN affects genes in drug metabolism.In this study,either Intralipid?-or Omegaven?-based TPN was administered to mice and the expression of a cohort of genes involved in anti-oxidative stress or drug metabolism was analyzed,glutathione(GSH)levels were measured,and protein levels for two key drug metabolism geneswere determined.Overall,the expression of most genes was downregulated by Intralipid?-based TPN(Gstpl,Gstml,3,6,Nqol,Ho-1,Mt-1,Gclc,Gclm,Cyp2d9,2f2,2b 10,and 3a11).Omegaven?showed similar results as Intralipid?except for preserving the expression of Gstml and Cyp3a11,and increasing Ho-1.Total GSH levels were decreased by Intralipid?,but increased by Omegaven?.CYP3A11 protein levels were increased by Omegaven?.In conclusion,TPN reduced the expression of many genes involved in anti-oxidative stress and drug metabolism in mice.However,Omegaven?preserved expression of Cyp3a11,suggesting another beneficial effect of Omegaven?in protecting liver functions.

Effects of intestine-specific deletion of fibroblast growth factor 15 on alcoholic liver disease development in mice

Background and aims:Alcoholic liver disease(ALD)is an important and growing cause for the development of chronic liver diseases in the world.Bile acid(BA)levels are increased in patients with ALD anddysregulation of BA homeostasis worsens ALD.BA synthesis is critically regulated by fibroblast growthfactor(FGF)15 in mice and FGF19 in humans.FGF15/19 are mainly produced in the ileum and their mainfunction is to suppress BA synthesis in the liver through the activation of fibroblast growth factor receptor 4(FGFR4)on hepatocytes.The effects of intestine-specific Fgf15 deficiency on the development ofALD were determined in the current study.Methods:Enterocyte-specific Fgf15 knockout mice(Fgf15intint^(-/-))and the established mouse model bychronic and binge ethanol feeding(NIAAA model)were adapted in this study.Results:The Fgf15intint^(-/-)mice had increased BA pool size,consistent with negative effects of FGF15-FGFR4signaling on BA synthesis.There were not obviously physical and hepatic histological abnormalitiespresented in Fgf15intint^(-/-)mice compared to wild-type mice.Following alcohol treatment,the Fgf15intint^(-/-)mice exhibited a higher degree of liver injury,increased hepatic expression of Cd14,a receptor forlipopolysaccharide expressed in the liver,and increased hepatic lipid levels.We did not observe alterations in the levels of fibrosis in the liver or expression of genes involved in hepatic fibrosis,regardless ofgenotypes or following the alcohol treatment.Conclusions:FGF15 may prevent hepatic steatosis in the development of ALD in mice,and maintainingFGF19/FGFR4 signaling may be critical in the prevention and/or treatment of ALD in humans in thefuture.

Farnesoid X receptor and fibroblast growth factor 15/19 as pharmacological targets

The farnesoid X receptor(FXR)is a nuclear receptor and transcriptional regulator activated by bile acids or synthetic FXR agonists.FXR is expressed highly in the liver and intestine where modulation of FXR critically regulates the expression of genes involved in cholesterol and bile acid homeostasis,hepatic gluconeogenesis/lipogenesis,and inflammation.We review the roles of FXR and one of its intestinal target genes,fibroblast growth factor(FGF)15 in mice/FGF19 in humans,play in regulating these important pathways in health and diseases.The main purpose of this review is to review therapeutics that target bile acid signaling to treat non-alcoholic steatohepatitis(NASH),a stage of disease within the spectrum of non-alcoholic fatty liver disease(NAFLD)with a focus on current preclinical studies in mice and clinical research.NASH is a huge medical burden and characterized by hepatic steatosis,inflam-mation,and progressive development of liver fibrosis.However,there is currently no Food and Drug Administration approved treatment option for NASH.While there are multiple factors contributing to NASH pathophysiology,bile acid regulation is proposed to have a major role in NASH pathogenesis.Synthetic FXR agonists and FGF19 protein may be promising agents to treat NASH,with obeticholic acid(OCA),cilofexor,tropifexor,nidufexor,EDP-305,and NGM282 currently in phase II or III clinical trials of NASH.FXR antagonism has also emerged,and antagonists like ursodeoxycholic acid(UDCA)and glycine-beta-muricholic acid(Gly-MCA)are in pre-clinical stage development for NASH treatment.This mini review seeks to evaluate and organize the literature available on FXR ligands and pathways for the treatment of NASH.

Editorial

Bile acids have been traditionally viewed as detergent molecules involved in the solubilization and absorption of lipids and lipidsoluble vitamins from the intestines.However,as a result of intensive research over the past two decades,bile acids are now viewed as endocrine signaling molecules that activate specific nuclear receptors and G-protein coupled receptors regulating nutrient metabolism in the liver and intestines.The year

Altered gut-liver axis in liver diseases

Chronic liver diseases have become a major global health prob-lem and its prevalence has been rapidly rising during the last decade.Extensive studies have identified the major causes for the progression of these diseases including chronic viral infections,ge-netic mutations,excessive alcohol consumption,metabolic dis-eases,cholestatic liver injury and toxic effects of medications.1e3 Regardless of the aetiology,multiple common mechanisms,espe-cially the gut-liver-axis,are associated with the pathogenesis and fibrotic disease progression of chronic liver injury.However,it re-mains challenging to develop effective therapeutics due to our limited understanding of these mechanisms.In this special issue,we are excited to present seven review articles and one original research paper.With this collection,we have provided the recent advances in understanding the roles of the gut-liver-axis in the development of a variety of liver diseases.