Mechanisms of Parenteral Nutrition–Associated Liver and Gut Injury
Himani MadnawatAdam WeluE. GilbertDerian B. TaylorSonali JainChandrashekhara ManithodyKeith BlomenkampAjay K. Jain
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Abstract Parenteral nutrition (PN) has revolutionized the care of patients with intestinal failure by providing nutrition intravenously. Worldwide, PN remains a standard tool of nutrition delivery in neonatal, pediatric, and adult patients. Though the benefits are evident, patients receiving PN can suffer serious cholestasis due to lack of enteral feeding and sometimes have fatal complications from liver injury and gut atrophy, including PN‐associated liver disease or intestinal failure–associated liver disease. Recent studies into gut‐systemic cross talk via the bile acid–regulated farnesoid X receptor (FXR)–fibroblast growth factor 19 (FGF19) axis, gut microbial control of the TGR5–glucagon‐like peptide (GLP) axis, sepsis, and role of prematurity of hepatobiliary receptors are greatly broadening our understanding of PN‐associated injury. It has also been shown that the composition of ω‐6/ω‐3 polyunsaturated fatty acids given parenterally as lipid emulsions can variably drive damage to hepatocytes and cell integrity. This manuscript reviews the mechanisms for the multifactorial pathogenesis of liver disease and gut injury with PN and discusses novel ameliorative strategies.Keywords:
Farnesoid X receptor
Liver disease
Enteral administration
FGF19
Glucagon-like peptide-2
The nuclear receptor farnesoid X receptor (FXR) plays an important role in physiological bile acid synthesis, secretion and transport. Defects of FXR regulation in these processes can cause cholestasis and subsequent pathological changes. FXR regulates the synthesis and uptake of bile acid via enzymes. It also increases bile acid solubility and elimination by promoting conjugation reactions and exports pump expression in cholestasis. The changes in bile acid transporters are involved in cholestasis, which can result from the mutations of transporter genes or acquired dysfunction of transport systems, such as inflammation-induced intrahepatic cholestasis. The modulation function of FXR in extrahepatic cholestasis is not identical to that in intrahepatic cholestasis, but the discrepancy may be reduced over time. In extrahepatic cholestasis, increasing biliary pressure can induce bile duct proliferation and bile infarcts, but the absence of FXR may ameliorate them. This review provides an update on the function of FXR in the regulation of bile acid metabolism, its role in the pathophysiological process of cholestasis and the therapeutic use of FXR agonists.
Farnesoid X receptor
Ursodeoxycholic acid
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BACKGROUND: The bile acid-activated nuclear receptor Farnesoid X Receptor (FXR) is critical in maintaining intestinal barrier integrity and preventing bacterial overgrowth. Patients with Crohn's colitis (CC) exhibit reduced ileal FXR target gene expression. FXR agonists have been shown to ameliorate inflammation in murine colitis models. We here explore the feasibility of pharmacological FXR activation in CC.METHODS: Nine patients with quiescent CC and 12 disease controls were treated with the FXR ligand chenodeoxycholic acid (CDCA; 15 mg/kg/day) for 8 days. Ileal FXR activation was assessed in the fasting state during 6 hrs after the first CDCA dose and on day 8, by quantification of serum levels of fibroblast growth factor (FGF) 19. Since FGF19 induces gallbladder (GB) refilling in murine models, we also determined concurrent GB volumes by ultrasound. On day 8 ileal and cecal biopsies were obtained and FXR target gene expression was determined.RESULTS: At baseline, FGF19 levels were not different between CC and disease controls. After the first CDCA dose, there were progressive increases of FGF19 levels and GB volumes during the next 6 hours in CC patients and disease controls (FGF19: 576 resp. 537% of basal; GB volumes: 190 resp. 178% of basal) without differences between both groups, and a further increase at day 8. In comparison with a separate untreated control group, CDCA affected FXR target gene expression in both CC and disease controls, without differences between both groups.CONCLUSIONS: Pharmacological activation of FXR is feasible in patients with CC. These data provide a rationale to explore the anti-inflammatory properties of pharmacological activation of FXR in these patients.TRIAL REGISTRATION: TrialRegister.nl NTR2009. PMID: 23189156
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FGF19
Chenodeoxycholic acid
Basal (medicine)
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BackgroundDisruption of bile acid (BA) homeostasis plays a key role in intestinal inflammation. The gut-liver axis is the main site for the regulation of BA synthesis and BA pool size via the combined action of the nuclear Farnesoid X Receptor (FXR) and the enterokine Fibroblast Growth Factor 19 (FGF19). Increasing evidence have linked derangement of BA metabolism with dysbiosis and mucosal inflammation. Thus, here we aimed to investigate the potential action of an FGF19 analogue on intestinal microbiota and inflammation.MethodsA novel engineered non-tumorigenic variant of the FGF19 protein, M52-WO 2016/0168219 was generated. WT and FXRnull mice were injected with AAV-FGF19-M52 or the control AAV-GFP and subjected to Sodium Dextran Sulphate-induced colitis.FindingsFGF19-M52 reduced BA synthesis and pool size, modulated its composition and protected mice from intestinal inflammation. These events were coupled with preservation of the intestinal epithelial barrier integrity, inhibition of inflammatory immune response and modulation of microbiota composition. Interestingly, FGF19-M52-driven systemic and local anti-inflammatory activity was completely abolished in Farnesoid X Receptor (FXR)null mice, thus underscoring the need of FXR to guarantee enterocytes' fitness and complement FGF19 anti-inflammatory activity. To provide a translational perspective, we also show that circulating FGF19 levels are reduced in patients with Crohn's disease.InterpretationReactivation of the FXR-FGF19 axis in a murine model of intestinal inflammation could bona fide provide positive changes in BA metabolism with consequent reduction of intestinal inflammation and modulation of microbiota. These results point to the therapeutic potential of FGF19 in the treatment of intestinal inflammation with concomitant derangement of BA homeostasis.FundingA. Moschetta is funded by MIUR-PRIN 2017 <- 2017J3E2W2; Italian Association for Cancer Research (AIRC, IG 23239); Interreg V-A Greece-Italy 2014-2020-SILVER WELLBEING, MIS5003627; HDHL-INTIMIC EuJPI-FATMAL; MIUR PON "R&I" 2014-2020-ARS01_01220. No money has been paid by NGM Biopharmaceuticals or any other agency to write this article.
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FGF19
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FGF19
Farnesoid X receptor
Enterohepatic circulation
Liver disease
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While it has long been recognized that bile acids are essential for solubilizing lipophilic nutrients in the small intestine, the discovery in 1999 that bile acids serve as ligands for the nuclear receptor farnesoid X receptor (FXR) opened the floodgates in terms of characterizing their actions as selective signaling molecules. Bile acids act on FXR in ileal enterocytes to induce the expression of fibroblast growth factor (FGF)15/19, an atypical FGF that functions as a hormone. FGF15/19 subsequently acts on a cell surface receptor complex in hepatocytes to repress bile acid synthesis and gluconeogenesis, and to stimulate glycogen and protein synthesis. FGF15/19 also stimulates gallbladder filling. Thus, the bile acid-FXR-FGF15/19 signaling pathway regulates diverse aspects of the postprandial enterohepatic response. Pharmacologically, this endocrine pathway provides exciting new opportunities for treating metabolic disease and bile acid-related disorders such as primary biliary cirrhosis and bile acid diarrhea. Both FXR agonists and FGF19 analogs are currently in clinical trials.
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Total parenteral nutrition (TPN), a lifesaving therapy, involves providing nutrition by bypassing the gut. Unfortunately it is associated with significant complications including gut atrophy and parenteral nutrition associated liver disease (PNALD). PNALD includes steatosis, cholestasis, disrupted glucose metabolism, disrupted lipid metabolism, cirrhosis, and liver failure. The etiopathogenesis remains poorly defined; however, an altered enterohepatic circulation, disrupting nuclear receptor signaling, is emerging as a promising mechanism. Rodent models and our piglet TPN model have shown that, during regular feeding, bile acids activate farnesoid X receptor (FXR) in the gut and enhance fibroblast growth factor 19 (FGF19) level. FGF19 regulates bile acid, lipid, and glucose metabolism. We noted reduced FGF19 with TPN use and substantial improvement in FGF19, bilirubin, and metabolic profiles with the FXR agonist chenodeoxycholic acid (CDCA). Additionally, CDCA caused gut growth and enhanced expression of glucagon like peptides (GLPs). GLPs regulate gut trophic effects, insulin, glucose homeostasis, and hepatic steatosis. GLP secretion is regulated by the CDCA activated receptor TGR5. This leads to an important conclusion that, in addition to a disrupted FXR-FGF19 axis, a disrupted TGR5-GLP axis may contribute to TPN related pathologies. Thus modulators of FXR-FGF19 and the TGR5-GLP axis could help bring forward novel treatment strategies.
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Enterohepatic circulation
Chenodeoxycholic acid
Steatosis
Liver disease
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The objective of this study was to investigate whether the impairment of farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling in juvenile pigs with non-alcoholic fatty liver disease (NAFLD) is associated with changes in the composition of the enterohepatic bile acid pool. Eighteen 15-day-old Iberian pigs, pair-housed in pens, were allocated to receive either a control (CON) or high-fructose, high-fat (HFF) diet. Animals were euthanized in week 10, and liver, blood, and distal ileum (DI) samples were collected. HFF-fed pigs developed NAFLD and had decreased FGF19 expression in the DI and lower FGF19 levels in the blood. Compared with the CON, the HFF diet increased the total cholic acid (CA) and the CA to chenodeoxycholic acid (CDCA) ratio in the liver, DI, and blood. CA and CDCA levels in the DI were negatively and positively correlated with ileal FGF19 expression, respectively, and blood levels of FGF19 decreased with an increasing ileal CA to CDCA ratio. Compared with the CON, the HFF diet increased the gene expression of hepatic 12-alpha-hydrolase, which catalyzes the synthesis of CA in the liver. Since CA species are weaker FXR ligands than CDCA, our results suggest that impairment of FXR-FGF19 signaling in NAFLD pigs is associated with a decrease in FXR agonism in the bile acid pool.
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Prematurity and postnatal development regulate the expression of the FXR‐FGF19 axis in neonatal pigs
The farnesoid X receptor (FXR) is a nuclear bile acid receptor that regulates bile acid homeostasis. A key FXR target is fibroblast growth factor 19 (FGF19), which functions as an endocrine hormone. FGF19 is produced in both the intestine and liver in humans and pigs, whereas mice and rats express the human ortholog FGF15 only in the intestine, thus making pigs a more relevant model of human FGF19 biology. Gut bile acids activate small intestinal FXR triggering FGF19 secretion which circulates via the portal blood to inhibit hepatic bile acid synthesis by suppressing the rate limiting enzyme in bile acid synthesis, CYP7A1, via activation of extracellular‐signal‐regulated kinases (ERK) and c‐Jun N‐terminal kinase (JNK‐1) MAP kinase pathways and the orphan nuclear receptor, small heterodimer partner (SHP). Thus, enterohepatic FXR‐FGF19 signaling functions as a negative feedback signal to regulate bile acid homeostasis. Bile acid secretion has been shown to increase with gestational age. We hypothesized that expression and activation of the intestinal FXR‐FGF19 axis would be diminished in premature vs. term pigs and increased with postnatal age. We studied piglets delivered by cesarean‐section at 10 days preterm and full term. All pigs were fitted with orogastric and umbilical arterial catheters and fed minimal enteral nutrition with bovine colostrum for 5 d and then bovine mature milk until 26 d‐of‐age. Plasma and tissue samples were collected at days 0, 5, 11, and 26 d. We developed a porcine FGF19 specific sandwich ELISA assay by cloning the porcine FGF19 gene, overexpressing the protein using a baculovirus expression system, and developing monoclonal antibodies. We quantified the plasma FGF19 concentration using the ELISA and assayed distal intestinal gene expression of FGF19 and FXR by RT qPCR. We found that plasma FGF19 levels are strikingly lower (P<0.05) in premature vs. term newborn pigs. In addition, postnatal age markedly altered activity of the FXR‐FGF19 axis, where plasma FGF19 levels increased significantly 5 d after birth in preterm, but not term pigs. Plasma FGF19 levels then decreased (P<0.05) significantly between 5 and 26 d‐of‐age in both preterm and term pigs. Intestinal FXR and FGF19 expression were lower (P<0.05) in premature vs term newborn pigs and decreased (P<0.05) between day 5 and 26 d‐of‐age. We conclude that both prematurity and postnatal age regulate the FXR‐FGF19 axis in neonatal pigs. These findings have implications for the bile acid homeostasis, FGF19 function and growth of preterm and term infants during early postnatal life. Support or Funding Information Agricultural Research Institute, USDA‐ARS, NIH, CalPoly Summer Undergraduate Research Program (SURP), NEOMUNE This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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Farnesoid-X-Receptor (FXR) plays a central role in maintaining bile acid (BA) homeostasis by transcriptional control of numerous enterohepatic genes, including intestinal FGF19, a hormone that strongly represses hepatic BA synthesis. How activation of the FGF19 receptor at the membrane is transmitted to the nucleus for transcriptional regulation of BA levels and whether FGF19 signaling posttranslationally modulates FXR function remain largely unknown. Here we show that FXR is phosphorylated at Y67 by non-receptor tyrosine kinase, Src, in response to postprandial FGF19, which is critical for its nuclear localization and transcriptional regulation of BA levels. Liver-specific expression of phospho-defective Y67F-FXR or Src downregulation in mice results in impaired homeostatic responses to acute BA feeding, and exacerbates cholestatic pathologies upon drug-induced hepatobiliary insults. Also, the hepatic FGF19-Src-FXR pathway is defective in primary biliary cirrhosis (PBC) patients. This study identifies Src-mediated FXR phosphorylation as a potential therapeutic target and biomarker for BA-related enterohepatic diseases.
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Small heterodimer partner
Enterohepatic circulation
Homeostasis
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