Bile acids not only play a cardinal role in the digestion and absorption of fat and fat-soluble vitamins, but also significantly affect gastrointestinal motor, sensory and secretory functions, intestinal barrier permeability and the regulation of the inflammatory response. The results of recent studies have revealed complex interactions between bile acids and the gut microbiota. In addition, bile acids also play a role of signaling molecules regulating the activity of lipid and glucose metabolic pathways, as well as a role of ligands for transcription <em>factors</em>. Genetic <em>factors</em> associated with the regulation of bile acid synthesis, transport and action may significantly influence gastrointestinal function and predispose to diarrhea resulting from bile acid malabsorption. Methods used in the diagnosis of bile acid malabsorption include 75selenium-homotaurocholic acid test, serum C4 and <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>), as well as fecal bile acid levels. The paper presents the latest data on the role of bile acid in the pathogenesis of irritable bowel syndrome, inflammatory bowel diseases and colorectal cancer. Advances in the treatment of disturbances in bile acids absorption and synthesis are also presented. A better understanding of molecular mechanisms regulating bile acid action may have implication for colorectal cancer prevention.

BACKGROUND

The process of pancreatic regeneration, well known and accepted, is less known than the hepatic and includes different mechanisms and factors. Pancreatic regeneration is better known in acute pancreatitis. After an extensive pancreatic necrosis, the morphological and functional regeneration is assessed by dynamic computed tomography associated with normalization of glycemia and the exocrine function. Different groups identified and evaluated experimentally and clinically the actions of multiple factors involved in the process of pancreatic regeneration. Even difficult to assess, pancreatic regeneration after partial pancreatectomy is well documented and of capital importance.

METHODS

A 57-year-old woman with discomfort in the upper-left abdominal quadrant. CT scans showed a tumor in the body and tail of the pancreas adherent to the spleen. Preoperative CA 19-9 was normal. She was operated on and the tumor resected en bloc with the spleen. Only the head of the pancreas was preserved. Intraoperative pathological examination of the specimen showed a mucinous cistoadenoma with no malignant degeneration. Postoperative course was uneventful and discharged at p.o. day 10, with ongoing diabetes. Four month later she presented pain in the upper-left quadrant with hyperamylasemia. CT scans showed a normal body and tail with an image of pseudocyst at the top of the pancreatic tail. One year after the initial surgery she remained asymptomatic, without diabetes and with no dietary restrictions. Further CT controls showed images of the entire regeneration of the body and tail of the pancreas.

CONCLUSIONS

Several phenomena are well known and accepted to be associated with the regeneration of the pancreas. In 1965, Tiscornia et al demonstrated the restoration of the pancreatic exocrine function after 6 weeks of selective occlusion of the pancreatic duct. The authors proposed pancreatic regeneration as responsible of morphological, histological and functional changes observed in operated patients where the pancreatic duct was decompressed by an anastomosis to the small bowel and constitutes the rational basis for surgical treatment of chronic pancreatitis. Several humoral factors seems to be involved in pancreatic regeneration acting by a specific receptors-mechanisms, like Bombesin, Octeotride, FGF (Fibroblast Growth Factor) and TGF (Transforming Growth Factor). Friess et al demonstrated increased levels of TGF in acute pancreatitis and considered it to be responsible of the pancreatic regeneration. Waguri et al experimentally demonstrated a double mechanism involved in the regeneration of B-cells: cellular and humoral ways could vary according to different situations. Less evident are the mechanisms involved after surgical pancreatic resection. Kato et al demonstrated the importance of zinc after partial pancreatic resection in dogs. Up to now, there are no other associations experimentally nor in humans. Our case showed in several CT scans control the presence of a normal pancreatic body and tails after a splenopancreatectomy, with restoration of endocrine and exocrine functions. Probably, several mechanisms were involved in this case. Further investigations will elucidate the answered.

CONCLUSIONS

Pancreatic regeneration was confirmed by CT scans images and also functionally after an extensive resection. Future similar findings could be of great clinical importance.

The endocrine action of human (h) intestine-derived <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (hFGF<em>19</em>) toward liver cells necessitates a highly specific recognition system. We previously reported that at physiological concentrations (~30 pM), hFGF<em>19</em> requires sulfated glycosaminoglycans (sGAGs) for its signaling via human FGF receptor 4 (hFGFR4) in the presence of a co-receptor, human βKlotho (hKLB), thus establishing specific targeting. Here we report that the specificity of hFGF<em>19</em> signaling is greatly altered in a mouse model system. In in vitro cellular systems, at concentrations achievable in transgenic animals and in pharmacologic animal experiments (1-100 nM), hFGF<em>19</em> activates mouse (m)FGFR1c, mFGFR2c, and mFGFR3c but not mFGFR4 in the presence of mKLB and nonheparin authentic sGAGs. Furthermore, in the presence of hepatic sGAGs or heparin, nanomolar hFGF<em>19</em> activates mFGFR4, even in the absence of co-expressed mKLB. Taken together, these results indicate that the sGAG-assisted receptor specificity of hFGF<em>19</em> signaling achieved in experimental mouse systems differs greatly from that in physiological human systems. This suggests the function and mechanism of hFGF<em>19</em> signaling identified using mouse systems should be reevaluated.

BACKGROUND

Enterohepatic bacterial infections have the potential to affect multiple physiological processes of the body. <em>Fibroblast</em> <em>growth</em> <em>factor</em> 15/<em>19</em> (FGF15 in mice, FGF<em>19</em> in humans) is a hormone that functions as a central regulator of glucose, lipid and bile acid metabolism. FGF15/<em>19</em> is produced in the intestine and exert its actions on the liver by signaling through the FGFR4-βKlotho receptor complex. Here, we examined the in vivo effects of enterohepatic bacterial infection over the FGF15 endocrine axis.

RESULTS

Infection triggered significant reductions in the intestinal expression of Fgf15 and its hepatic receptor components (Fgfr4 and Klb (βKlotho)). Infection also resulted in alterations of the expression pattern of genes involved in hepatobiliary function, marked reduction in gallbladder bile volumes and accumulation of hepatic cholesterol and triglycerides. The decrease in ileal Fgf15 expression was associated with liver bacterial colonization and hepatobiliary pathophysiology rather than with direct intestinal bacterial pathogenesis.

CONCLUSIONS

Bacterial pathogens of the enterohepatic system can disturb the homeostasis of the FGF15/<em>19</em>-FGFR4 endocrine axis. These results open up a possible link between FGF15/<em>19</em>-FGFR4 disruptions and the metabolic and nutritional disorders observed in infectious diseases.

Bile acid (BA) production in mice is regulated by hepatic farnesoid X receptors and by intestinal <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF)-15 (in humans, FGF-<em>19</em>), a suppressor of BA synthesis that also reduces serum triglycerides and glucose. Cholestyramine treatment reduces FGF-<em>19</em> and induces BA synthesis, whereas plasma triglycerides may increase from unclear reasons. We explored whether FGF-<em>19</em> may suppress BA synthesis and plasma triglycerides in humans by modulation of FGF-<em>19</em> levels through long-term cholestyramine treatment at increasing doses. In a second acute experiment, metabolic responses from 1 day of cholestyramine treatment were monitored. Long-term treatment reduced serum FGF-<em>19</em> by >90%; BA synthesis increased up to 17-fold, whereas serum BAs, triglycerides, glucose, and insulin were stable. After long-term treatment, serum BAs and FGF-<em>19</em> displayed rebound increases above baseline levels, and BA and cholesterol syntheses normalized after 1 wk without rebound reductions. Acute cholestyramine treatment decreased FGF-<em>19</em> by 95% overnight and serum BAs by 60%, while BA synthesis increased fourfold and triglycerides doubled. The results support that FGF-<em>19</em> represses BA synthesis but not serum triglycerides. However, after cessation of both long-term and 1-day cholestyramine treatment, circulating FGF-<em>19</em> levels were normalized within 2 days, whereas BA synthesis remained significantly induced in both situations, indicating that also other mechanisms than the FGF-<em>19</em> pathway are responsible for stimulation of BA synthesis elicited by cholestyramine. Several of the responses during cholestyramine treatment persisted at least 6 days after treatment, highlighting the importance of removing such treatment well before evaluating dynamics of the enterohepatic circulation in humans.

Although the appearance of hepatic foci in the pancreas has been described in animal experiments and in human pathology, evidence for the conversion of human pancreatic cells to liver cells is still lacking. We therefore investigated the developmental plasticity between human embryonic pancreatic cells and liver cells. Cells were isolated and expanded from 7-8-week-old human fetal pancreata (HFP) and were characterized for the absence and presence of pancreatic and hepatic markers. In vitro expanded HFP were treated with <em>fibroblast</em> <em>growth</em> <em>factor</em> 2 (FGF2) and dexamethasone (DX) to induce a liver phenotye in the cells. These treated cells in various passages were further studied for their capacity to be functional in hepatic parenchyma following retrorsine-induced injury in nude C57 black mice. Amylase- and EPCAM-positive-enriched cells isolated from HFP and treated with FGF2 and DX lost expression of pancreatic markers and gained a liver phenotype. Hepatic differentiation was based on the expression (both at the mRNA and protein level) of liver markers albumin and cytokeratin <em>19</em>. When transplanted in vivo into nude mice treated with retrorsine, both cell types successfully engrafted and functionally differentiated into hepatic cells expressing human albumin, glycogen, dipeptidyl peptidase, and gamma-glutamyltranspeptidase. These data indicate that human fetal pancreatic cells have a capacity to alter their gene expression profile in response to exogenous treatment with FGF2 and DX. It may be possible to generate an unlimited supply of hepatocytes in vitro for cell therapy.

Caudal appendage is a rare but reported finding seen in association with craniosynostosis. We report a newborn with caudal appendage secondary to sacrococcygeal eversion, a cloverleaf skull, choanal atresia, and a heterozygous mutation of Y375C in the juxtamembrane domain (exon 11) of <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor 2 (FGFR2). Further support of this association are 22 other cases of craniosynostosis with caudal appendage or sacrococcygeal eversion in the literature. Of these, <em>19</em> had detectable mutations in FGFR2; 5, the same mutation; and 5, a similar substitution of cysteine for serine. We hypothesize that the association of craniosynostosis and caudal appendage is due to abnormal expression of FGFR2 in the tail bud of a developing embryo based on animal models. Our case and those reported in the literature suggest that in patients with caudal appendage and craniosynostosis, FGRF2 analysis should include regions outside the commonly tested exons 8 and 10, particularly the juxtamembrane domain.

The contiguous gene syndrome involving 8p11.2 is recognized as a combined phenotype of both Kallmann syndrome and hereditary spherocytosis, because the genes responsible for these 2 clinical entities, the <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor 1 (FGFR1) and ankyrin 1 (ANK1) genes, respectively, are located in this region within a distance of 3.2Mb. We identified a 3.7Mb deletion of 8p11.2 in a <em>19</em>-month-old female patient with hereditary spherocytosis. The identified deletion included ANK1, but not FGFR1, which is consistent with the absence of any phenotype or laboratory findings of Kallmann syndrome. Compared with the previous studies, the deletion identified in this study was located on the proximal end of 8p, indicating a pure interstitial deletion of 8p11.21. This patient exhibited mild developmental delay and distinctive facial findings in addition to hereditary spherocytosis. Thus, some of the genes included in the deleted region would be related to these symptoms.

OBJECTIVE

To assess cytokine and chemokine levels in youth experiencing antipsychotic-induced weight gain (AIWG) compared to obese patients, hypothesizing a different "immune signature" between the two kinds of obesity.

METHODS

We compared a group of youth experiencing AIWG (N <em>19</em>, mean age 159 months, mean body mass index [BMI] z-score 1.81) and an age-, gender-, and BMI-matched group of untreated obese patients (N <em>19</em>, mean age 147 months, mean BMI z-score 2) for a wide range of cytokines and chemokines by using a multiplex ELISA test.

RESULTS

Platelet-derived growth factor (PDGF), interleukin (IL)1-β, IL4, IL8, IL9, IL12, IL 17, eotaxin, FGF, GMCSF, IP10, MIP1b, and vascular-endothelial growth factor (VEGF) were significantly lower in the AIWG group, whereas IL13 and RANTES were significantly higher. Controlling for age, sex, and BMI, PDGF, IL4, IL8, IL13, IL17, eotaxin, fibroblast growth factor (FGF), granulocyte-macrophage colony-stimulating factor (GMCSF), IP10, MIP1b, and VEGF remain significantly different.

CONCLUSIONS

A clearly different pattern of cytokines distinguishes the two kinds of obesity, suggesting a different immune signature. Interestingly, most of the cytokines and chemokines bearing proinflammatory effects resulted decreased in the AIWG group, whereas IL-13, which holds an immune-modulatory effect, resulted increased.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) promotes tumor <em>growth</em> in various types of cancer, but its function has not been investigated in the context of colorectal adenoma. Here, we report that FGF<em>19</em> expression was greater in colorectal adenoma than in normal tissues, as measured by an enzyme-linked immunosorbent assay, quantitative reverse-transcription PCR and immunohistochemistry. FGF<em>19</em> expression was also elevated in a subset of human colon cancer cell lines. Moreover, FGF receptor 4 (FGFR4), the cognate receptor for FGF<em>19</em>, was upregulated in colorectal adenoma tissues. Lipid levels and body mass index values strongly correlated with FGF<em>19</em> and FGFR4 levels in patients with colon adenomas. These observations indicate that the FGF<em>19</em>/FGFR4 pathway may be involved in the development of neoplasia, and that FGF<em>19</em> may be a valuable diagnostic marker for the identification of patients with colorectal adenomas.

The aim of the study was to determine the effect of occupational exposure to lead on the blood levels of pro-inflammatory cytokines and selected <em>factors</em> that influence angiogenesis. The study population was divided into two groups. The first group consisted of 56 male workers chronically exposed to lead. The second group (control) was comprised of 24 male administrative workers. The serum levels of interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis <em>factor</em> α (TNF-α) were significantly higher in the group of workers chronically exposed to lead compared to control values by 38%, 68%, and 57%, respectively. Similarly, the values of soluble vascular endothelial <em>growth</em> <em>factor</em> receptor-1 (sVEGFR-1) and <em>fibroblast</em> <em>growth</em> <em>factor</em>-basic (FGF-basic) were higher by <em>19</em>% and 63%, respectively. In the group of workers chronically exposed to lead, there were positive correlations between the levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and angiogenic <em>factors</em> (VEGF, FGF-basic, sVEGFR-1, and soluble angiopoietin receptor). In the control group, there were no correlations between the levels of the abovementioned parameters. Results of the present study indicate that chronic occupational lead exposure promotes inflammatory processes via induction of pro-inflammatory cytokines, modulates angiogenesis, and elicits interdependencies between the immune response and angiogenic <em>factors</em>.

OBJECTIVE

Parathyroid hormone (iPTH) and fibroblast growth factor 23 (FGF23) are elevated in secondary hyperparathyroidism. In hemodialysis, higher dialysate calcium (1.5 mmol/L) induces intradialytic suppression of iPTH, whereas its impact on FGF23 and markers of bone metabolism is unknown. We assessed the time course of FGF23 and markers of bone metabolism in relationship to dialysate calcium.

METHODS

In this prospective cohort study of 19 patients on maintenance hemodialysis, we measured serum calcium (sCa), inorganic phosphate (iP), blood urea nitrogen (BUN), β2-microglobulin (ßMG), iPTH, FGF23, aminoterminal propeptide type 1 procollagen (P1NP), C-telopeptide of type I collagen for bone degradation (CTX-I), osteocalcin (OC), bone specific alkaline phosphatase (BALP), and tartrate-resistant acid phosphatase (TRAP5b) during a single hemodialysis session at baseline, 1, 2, and 3h of dialysis. The time course of measured parameters was compared according to groups of prescribed dialysate calcium of 1.25 mmol/L and 1.5 mmol/L.

RESULTS

iPTH declined in the 1.5 mmol/L dialysis group as serum calcium increased whereas it tended to increase in the 1.25 mmol/L group without significant changes in serum calcium. Patients on long-term dialysate calcium of 1.5 mmol/L had significantly lower CTX-I levels and tended to lower levels of iPTH, FGF23, OC, P1NP and TRAP5b at the start of dialysis compared to those on 1.25 mmol/L. CTX-I, FGF23 and OC but not BALP, P1NP and TRAP5b decreased during dialysis independent of dialysate calcium.

CONCLUSIONS

In spite of immediate effects on iPTH, dialysate calcium does not acutely affect other parameters of bone and mineral metabolism.

OBJECTIVE

Dialysate calcium concentration is known to have both immediate and longer-term impact on parathyroid hormone levels in hemodialysis patients. Little is known about the acute impact of dialysate calcium on bone metabolism. In this cross-sectional study of prevalent hemodialysis patients, we found no evidence of immediate short-term dialysate calcium-induced changes of fibroblast growth factor 23 or anabolic and catabolic markers of bone turnover during hemodialysis. However, differences in CTX-I and to a lesser extent other parameters between groups of higher and lower dialysate calcium suggest a longer-term effect that remains to be validated.

BACKGROUND

The klotho (Klt)-fibroblast growth factor-23 (FGF-23)-vitamin D axis is the main component of calcium (Ca) and phosphorus (P) metabolisms; on the contrary, it is also secreted from the choroid plexus (CP).

OBJECTIVE

This study is aimed at evaluating serum soluble Klt (sKlt), FGF-23, and 25-(OH)-vitamin D levels in multiple sclerosis (MS) patients.

METHODS

Thirty-two relapsing-remitting MS patients (11 males and 21 females; mean age 38.3 years) and 31 age-sex matched healthy controls (12 males and 19 females; median age 38.5 years) were included in this study. All patients were diagnosed with MS according to the criteria of McDonald.

RESULTS

Serum sKlt, FGF-23, and P levels were significantly higher in MS patients compared to the control group (p < 0.01, p < 0.01, and p = 0.02, respectively). Serum 25-(OH)-vitamin D and Ca levels were significantly lower in MS patients (p < 0.01 and p = 0.04, respectively).

CONCLUSIONS

Klt, which is secreted from CP, could be a response to the inflammatory condition in MS. Elevated FGF-23 levels suppress 1α-hydroxylase and upregulates 24α-hydroxylase, which results in a decrease in 1,25-(OH)2D3 levels. Thus, the neuroprotective and immunomodulatory effects of vitamin D might not be seen in MS patients.

Background: Sorafenib and lenvatinib are first-line systemic therapies for unresectable hepatocellular carcinoma (HCC). However, the criteria for their selection remain unclear.

<strong class="sub-title"> Methods: </strong> We identified patients with unresectable HCC who were treated with sorafenib or lenvatinib between August 2009 and January 20<em>19</em> at the Hokkaido University Hospital. Patients who continued treatment for >2 months, underwent evaluation by computed tomography every 2-3 months, and had complete clinical data were included. Responders were patients with objective response (OR) for lenvatinib and patients with stable disease (SD) exceeding 6 months (long-SD) or OR for sorafenib. The predictive <em>factors</em> for treatment response, including <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF)<em>19</em> and 21, angiopoietin 2 (ANG2), hepatocyte <em>growth</em> <em>factor</em>, and vascular endothelial <em>growth</em> <em>factor</em>, were evaluated.

<strong class="sub-title"> Results: </strong> Overall, 27 and 29 patients treated with lenvatinib and sorafenib, respectively, were included. The responders for lenvatinib and sorafenib were 63% (17/27) and 38% (11/29), respectively. No significant predictive <em>factors</em> for treatment response were identified in patients treated with sorafenib. However, baseline serum FGF<em>19</em> and ANG2 levels were significantly associated with treatment response to lenvatinib. All (9/9) patients with low baseline ANG2 and FGF<em>19</em> levels who received lenvatinib achieved OR. Conversely, the OR was low (13%; 1/9) in patients with high baseline ANG2 and FGF<em>19</em> levels. Responder rate was 40% (2/5) in patients with high baseline ANG2 and FGF<em>19</em> levels who received sorafenib.

<strong class="sub-title"> Conclusion: </strong> This study is, to our knowledge, the first to demonstrate that baseline ANG2 and FGF<em>19</em> levels may aid in selecting optimal systemic therapy for patients with unresectable HCC.

<strong class="sub-title"> Keywords: </strong> angiopoietin‐2; <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em>; hepatocellular carcinoma; sorafenib; treatment outcome.

BACKGROUND

Our earlier studies demonstrated that topically applied substance P (SP) or curcumin on excision skin wound accelerated the wound healing in streptozotocin-induced diabetic rats. In the present study, we aimed to evaluate the wound healing potential of combination of SP and curcumin in diabetic rats.

METHODS

Open cutaneous excision wound was created on the back of each of the 60 diabetic rats. Wound-inflicted rats were equally divided into three groups namely, control, gel treated, and SP + curcumin treated. Normal saline, pluronic gel, and SP (0.5 × 10-6M) + curcumin (0.15%) were topically applied once daily for <em>19</em> d to these control, gel-treated, and SP + curcumin groups, respectively.

RESULTS

SP + curcumin combination significantly accelerated wound closure and decreased messenger RNA expressions of tumor necrosis factor-alpha, interleukin-1beta, and matrix metalloproteinase-9, whereas the combination markedly increased the expressions of interleukin-10, vascular endothelial growth factor, transforming growth factor-beta1, hypoxia-inducible factor 1-alpha, stromal cell-derived factors-1alpha, heme oxygenase-1 and endothelial nitric oxide synthase, and activities of superoxide dismutase, catalase, and glutathione peroxidase in granulation-healing tissue, compared with control and gel-treated groups. In combination group, granulation tissue was better, as was evidenced by improved fibroblast proliferation, collagen deposition, microvessel density, growth-associated protein 43-positive nerve fibers, and thick regenerated epithelial layer.

CONCLUSIONS

The combination of SP and curcumin accelerated wound healing in diabetic rats and both the drugs were compatible at the doses used in this study.

Hepatoblastoma is the most common liver cancer in children, accounting for over 65% of all childhood liver malignancies. Hepatoblastoma is distinct from adult liver cancer in that it is not associated with hepatitis virus infection, cirrhosis, or other underlying liver pathology. The paucity of appropriate cell and animal models has been hampering the mechanistic understanding of hepatoblastoma pathogenesis. Consequently, there is no molecularly targeted therapy for hepatoblastoma. To gain insight into cytokine signaling in hepatoblastoma, we employed mass spectrometry to analyze the proteins secreted from Hep293TT hepatoblastoma cell line we established and identified the specific secretion of <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>), a <em>growth</em> <em>factor</em> for liver cells. We determined that silencing FGF<em>19</em> by shRNAs or neutralizing secreted FGF<em>19</em> by anti-FGF<em>19</em> antibody inhibits the proliferation of hepatoblastoma cells. Furthermore, blocking FGF<em>19</em> signaling by an FGF receptor kinase inhibitor suppressed hepatoblastoma <em>growth</em>. RNA expression analysis in hepatoblastoma tumors revealed that the high expression of FGF<em>19</em> signaling pathway components as well as the low expression of FGF<em>19</em> signaling repression targets correlates with the aggressiveness of the tumors. These results suggest the role of FGF<em>19</em> as autocrine <em>growth</em> <em>factor</em> for hepatoblastoma.

Duodenal-jejunal bypass liner (DJBL) is an endoscopically implantable device designed to noninvasively mimic the effects of gastrointestinal bypass operations by excluding the duodenum and proximal jejunum from the contact with ingested food. The aim of our study was to assess the influence of DJBL on anthropometric parameters, glucose regulation, metabolic and hormonal profile in obese patients with type 2 diabetes mellitus (T2DM) and to characterize both the magnitude and the possible mechanisms of its effect. Thirty obese patients with poorly controlled T2DM underwent the implantation of DJBL and were assessed before and 1, 6 and 10months after the implantation, and 3months after the removal of DJBL. The implantation decreased body weight, and improved lipid levels and glucose regulation along with reduced glycemic variability. Serum concentrations of <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>19</em> (FGF<em>19</em>) and bile acids markedly increased together with a tendency to restoration of postprandial peak of GLP1. White blood cell count slightly increased and red blood cell count decreased throughout the DJBL implantation period along with decreased ferritin, iron and vitamin B12 concentrations. Blood count returned to baseline values 3months after DJBL removal. Decreased body weight and improved glucose control persisted with only slight deterioration 3months after DJBL removal while the effect on lipids was lost. We conclude that the implantation of DJBL induced a sustained reduction in body weight and improvement in regulation of lipid and glucose. The increase in FGF<em>19</em> and bile acids levels could be at least partially responsible for these effects.

OBJECTIVE

Recent studies suggested that circulating <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF) <em>19</em> levels might be associated with the fat content and distribution, and varied with different glucose tolerance status. This study aimed to investigate the association of serum FGF<em>19</em> levels with obesity and visceral fat accumulation in a Chinese population with differing glucose tolerance status.

RESULTS

The 2383 participants were divided into subgroups of glucose tolerance status: normal glucose tolerance (NGT, n = 1754), impaired glucose regulation (IGR, n = 499), and newly diagnosed diabetes mellitus (DM, n = 130). They were further stratified into quartiles of serum FGF<em>19</em> levels (Q1-Q4). Visceral fat area (VFA) and subcutaneous fat area were measured using magnetic resonance imaging. FGF<em>19</em> were detected via quantitative sandwich enzyme-linked immunosorbent assay. Serum FGF<em>19</em> levels showed a downtrend across the NGT, IGR, and DM groups (P for trend = 0.016). VFA was an independent and negative <em>factor</em> of serum FGF<em>19</em> levels (standardized β = -0.108, P = 0.001). After adjustment for glucose tolerance status, VFA differed significantly among FGF<em>19</em> quartiles (P < 0.001), showing a downtrend from Q1-Q4. The associations of serum FGF<em>19</em> levels and glucose tolerance status with VFA were independent of each other. After adjustment for insulin resistance and secretory function separately, VFA still decreased significantly from Q1-Q4 (all P < 0.001).

CONCLUSIONS

Serum FGF<em>19</em> levels were related to visceral fat accumulation. Independent of glucose tolerance status, serum FGF<em>19</em> levels were inversely associated with VFA.

BACKGROUND

In addition to their classical role as detergents, bile acids function as signaling molecules to regulate gastrointestinal physiology, carbohydrate and lipid metabolism, and energy expenditure. The pharmacodynamic potential of bile acids is dependent in part on the tight pharmacokinetic control of their concentration and metabolism, properties governed by their hepatic synthesis, enterohepatic cycling, and biotransformation via host and gut microbiota-catalyzed pathways. Key Messages: By altering the normal cycling and compartmentalization of bile acids, changes in hepatobiliary or intestinal transport can affect signaling and lead to the retention of cytotoxic hydrophobic bile acids and cell injury. This review discusses advances in our understanding of the intestinal transporters that maintain the enterohepatic cycling of bile acids, signaling via bile acid-activated nuclear and G protein receptors, and mechanisms of bile acid-induced cell injury.

CONCLUSIONS

Dysregulated expression of the Asbt and Ostα-Ostβ alters bile acid signaling via the gut-liver farnesoid X receptor-<em>fibroblast</em> <em>growth</em> <em>factor</em> 15/<em>19</em> axis and may contribute to other bile acid-regulated metabolic and cell injury pathways.

The bile acid (BA) nuclear receptor, farnesoid X receptor (FXR/NR1H4), maintains metabolic homeostasis by transcriptional control of numerous genes, including an intestinal hormone, <em>fibroblast</em> <em>growth</em> <em>factor</em>-<em>19</em> (FGF<em>19</em>; FGF15 in mice). Besides activation by BAs, the gene-regulatory function of FXR is also modulated by hormone or nutrient signaling-induced post-translational modifications. Recently, phosphorylation at Tyr-67 by the FGF15/<em>19</em> signaling-activated nonreceptor tyrosine kinase Src was shown to be important for FXR function in BA homeostasis. Here, we examined the role of this FXR phosphorylation in cholesterol regulation. In both hepatic FXR-knockout and FXR-knockdown mice, reconstitution of FXR expression up-regulated cholesterol transport genes for its biliary excretion, including scavenger receptor class B member 1 (<i>Scarb1</i>) and ABC subfamily G member 8 (<i>Abcg5/8</i>), decreased hepatic and plasma cholesterol levels, and increased biliary and fecal cholesterol levels. Of note, these sterol-lowering effects were blunted by substitution of Phe for Tyr-67 in FXR. Moreover, consistent with Src's role in phosphorylating FXR, Src knockdown impaired cholesterol regulation in mice. In hypercholesterolemic apolipoprotein E-deficient mice, expression of FXR, but not Y67F-FXR, ameliorated atherosclerosis, whereas Src down-regulation exacerbated it. Feeding or treatment with an FXR agonist induced <i>Abcg5/8</i> and <i>Scarb1</i> expression in WT, but not FGF15-knockout, mice. Furthermore, FGF<em>19</em> treatment increased occupancy of FXR at <i>Abcg5/8</i> and <i>Scarb1</i>, expression of these genes, and cholesterol efflux from hepatocytes. These FGF<em>19</em>-mediated effects were blunted by the Y67F-FXR substitution or Src down-regulation or inhibition. We conclude that phosphorylation of hepatic FXR by FGF15/<em>19</em>-induced Src maintains cholesterol homeostasis and protects against atherosclerosis.

A case of thanatophoric dysplasia (TD) type I associated with severely increased nuchal translucency at first trimester screening for Down syndrome is reported. A 38-year-old woman, G2P1, with previous uneventful pregnancy, was referred for amniocentesis at 16 weeks due to positive first trimester integrated test. Amniocentesis revealed a 46,XX fetus. At 16 weeks gestation, the ultrasound examination of the fetus revealed a narrow chest, short ribs, and a generalized severe shortening of the long bones. The patient underwent a follow-up scan at <em>19</em> weeks which demonstrated ultrasound findings consistent with severe rhizomelic micromelia. A wide prenatal panel of gene mutations related with skeletal dysplasia was performed. Nucleotidic sequence using QF-PCR on exons 7,10, 15, <em>19</em> of the <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor 3 (FGFR3) demonstrated a 742 C>T (R248C) mutation, which resulted in an Arg248Cys substitution in heterozygous state, leading to a prenatal diagnosis of thanatophoric dysplasia type I. The early diagnosis of this lethal form of skeletal dysplasia directed the prenatal counseling and allowed appropriate obstetric management. Necropsy, post-mortem x-ray, and histologic analysis of the <em>growth</em> plate might aid the diagnosis of TD type I.

The translocation t(4;14) is associated with a poor prognosis in myeloma, but its effect in the setting of new drugs such as thalidomide, bortezomib and lenalidomide continues to be investigated, and the role of candidate genes such as FGFR3 (<em>fibroblast</em> <em>growth</em> <em>factor</em> receptor 3) is not yet clarified. In the Australasian Leukaemia and Lymphoma Group (ALLG) MM6 randomized study comparing consolidation thalidomide and prednisolone with prednisolone alone following autologous stem cell transplant, patients on consolidation thalidomide and prednisolone had superior progression-free (PFS) and overall survival (OS). We now show that thalidomide consolidation benefited both t(4;14)-positive (PFS 29 vs. 17 months, p =0.03) and -negative (52 vs. 24 months, p =0.04) disease. PFS for patients with normal FGFR3 expression was significantly better than for those with up-regulated FGFR3 (31 vs. 21 months, p =0.02). Consolidation thalidomide conferred an improved PFS in patients with normal FGFR3 expression (41 vs. <em>19</em> months, p =0.02), but there was no improvement in patients with up-regulated FGFR3 (31 vs. 29 months, p =0.76). We conclude that consolidation thalidomide may mitigate the poor prognostic effect of t(4;14), and improves PFS in normal but not up-regulated FGFR3 expression. Thus the level of FGFR3 expression provides additional prognostic information to t(4;14) in myeloma induction and consolidation therapy.

The obesity epidemic and the urgent need for effective and safe drugs to treat obesity-related diseases have greatly increased research interest in the metabolic hormones, <em>fibroblast</em> <em>growth</em> <em>factor</em>-<em>19</em> (FGF<em>19</em>, FGF15 in mice), and FGF21. FGF<em>19</em> and FGF21 function as endocrine hormones that play key roles in energy metabolism and counteract obesity. Importantly, in obese humans and lab animals, circulating FGF<em>19</em> and FGF21 levels are elevated, and metabolic actions of these hormones are impaired but the underlying mechanisms remained unknown. Recent microRNA (miR) studies have revealed that aberrantly elevated miR-34a in obesity directly targets β-Klotho, the obligate coreceptor for both FGF<em>19</em> and FGF21, and attenuates metabolic signaling of these hormones. In this review, we will discuss recent findings in the miR and FGF<em>19</em>/21 fields, emphasizing the novel function of obesity-associated miR-34a in attenuation of FGF<em>19</em>/21 metabolic actions, and further discuss miRs, including miR-34a, as potential drug targets for obesity-related diseases.

There is evidence that regulation of follicle selection in cattle involves locally produced <em>growth</em> <em>factors</em>. In the present study, we investigated the expression of members of the <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF) 7 family during follicle deviation. The largest and second largest follicles were recovered during the second day of a synchronised follicle wave and the future dominant and future subordinate follicles were identified based on diameter and cytochrome P450, family <em>19</em>, subfamily A, polypeptide 1 (CYP<em>19</em>A1) mRNA levels in granulosa cells. Theca cells of the future dominant follicle contained less mRNA encoding FGF7 and FGF10 compared with those from the future subordinate follicle 2.5 days after ovulation, before a significant difference between the diameters of the future dominant and future subordinate follicles could be observed, but FGF22 mRNA levels did not change. Levels of mRNA encoding FGF receptors FGFR1B and FGFR2B in theca and granulosa cells, respectively, were lower in the future dominant follicle compared with the future subordinate follicle. Addition of FGF10 to granulosa cells in vitro significantly decreased oestradiol secretion, as well as CYP<em>19</em>A1, FSH receptor (FSHR) and insulin-like <em>growth</em> <em>factor</em> 1 receptor (IGF1R) mRNA abundance, whereas FGF22 had no effect. We conclude that FGF10 and FGFR2B expression is increased in the future subordinate follicle before morphological deviation, which may contribute to follicle selection.