Foxj3 Regulates Thermogenesis of Brown and Beige Fat Via Induction of PGC-1α.

Enhancing the development of and thermogenesis in brown and beige fat represents a potential treatment for obesity. In this study, we show that Foxj3 expression in fat is stimulated by cold exposure and a ß-adrenergic agonist. Adipose-specific Foxj3 knockout impaired the thermogenic function of brown fat, leading to morphological whitening of brown fat and obesity. Adipose Foxj3-deficient mice displayed increased fasting blood glucose levels and hepatic steatosis while on a chow diet. Foxj3 deficiency inhibited the browning of inguinal white adipose tissue (iWAT) following ß3-agonist treatment of mice. Furthermore, depletion of Foxj3 in primary brown adipocytes reduced the expression of thermogenic genes and cellular respiration, indicating that the Foxj3 effects on the thermogenic program are cell autonomous. In contrast, Foxj3 overexpression in primary brown adipocytes enhanced the thermogenic program. Moreover, AAV-mediated Foxj3 overexpression in brown fat and iWAT increased energy expenditure and improved systemic metabolism on either a chow or high-fat diet. Finally, Foxj3 deletion in fat inhibited the ß3-agonist-mediated induction of WAT browning and brown adipose tissue thermogenesis. Mechanistically, cold-inducible Foxj3 stimulated the expression of PGC-1α and UCP1, subsequently promoting energy expenditure. This study identifies Foxj3 as a critical regulator of fat thermogenesis, and targeting Foxj3 in fat might be a therapeutic strategy for treating obesity and metabolic diseases.

Development and validation of a nomogram predictive model for colorectal adenoma with low-grade intraepithelial neoplasia using routine laboratory tests: A single-center case-control study in China.

Background: Colorectal cancer (CRC) is the third most common cancer in the world and has a high mortality rate. Colorectal adenoma (CRA) is precancerous lesions of CRC. The purpose of the present study was to construct a nomogram predictive model for CRA with low-grade intraepithelial neoplasia (LGIN) in order to identify high-risk individuals, facilitating early diagnosis and treatment, and ultimately reducing the incidence of CRC. Methods: We conducted a single-center case-control study. Based on the results of colonoscopy and pathology, 320 participants were divided into the CRA group and the control group, the demographic and laboratory test data were collected. A development cohort (n = 223) was used for identifying the risk factors for CRA with LGIN and to develop a predictive model, followed by an internal validation. An independent validation cohort (n = 97) was used for external validation. Receiver operating characteristic curve, calibration plot and decision curve analysis were used to evaluate discrimination ability, accuracy and clinical practicability of the model. Results: Four predictors, namely sex, age, albumin and monocyte count, were included in the predictive model. In the development cohort, internal validation and external validation cohort, the area under the curve (AUC) of this risk predictive model were 0.946 (95%CI: 0.919-0.973), 0.909 (95 % CI: 0.869-0.940) and 0.928 (95%CI: 0.876-0.980), respectively, which demonstrated the model had a good discrimination ability. The calibration plots showed a good agreement and the decision curve analysis (DCA) suggested the predictive model had a high clinical net benefit. Conclusion: The nomogram model exhibited good performance in predicting CRA with LGIN, which can aid in the early detection of high-risk patients, improve early treatment, and ultimately reduce the incidence of CRC.

Allogeneic Vessels in Pancreaticoduodenectomy with Portal Vein Resection: Risk of Portal Vein Thrombosis and Prognosis.

BACKGROUND: Allogeneic vessels (AV) are commonly used in pancreaticoduodenectomy (PD) with portal vein resection (PVR), but the epidemiological characteristics of portal vein thrombosis (PVT) are still unclear. METHODS: The clinicopathological data of patients who underwent PD combined with PVR in our hospital from January 2011 to October 2022 were retrospectively collected. All patients underwent regular contrast-enhanced CT of the abdomen after surgery to identify PVT or recurrence and metastasis of the tumor. RESULTS: A total of 878 patients received PD, of which 213 patients who also underwent PVR were included in the study. Among them are 16 (7.5%) tangential/patch reconstructions, 51 (23.9%) end-to-end anastomosis, and 146 (68.5%) AV reconstructions. The cumulative incidence of PVT in 1 month, 3 months, 6 months, 1 year, 2 years, and 3 years after surgery was 0.9%, 7.3%, 7.3%, 15.9%, 23.4%, and 27.6%, respectively. The results of logistic regression analysis showed that diabetes, operation procedure, and AV reconstruction were independent risk factors for PVT (P < 0.05). In the Cox analysis, PVT was clearly correlated with tumor recurrence (P = 0.038, hazard ratio (HR) = 1.553) and overall survival (P = 0.044, HR = 1.592) of pancreatic cancer patients. CONCLUSION: The prevalence of PVT is high in PD with PVR, particularly in patients undergoing AV reconstructions. The occurrence of PVT has a clear correlation with the patient's long-term prognosis.

Clinical Value of Mean Platelet Volume to Platelet Ratio (MPR) in Distinguishing Mass-Forming Chronic Pancreatitis and Pancreatic Cancer.

BACKGROUND: Correctly distinguishing mass-forming chronic pancreatitis (MFCP) from pancreatic cancer (PC) is of clinical significance to determine optimal therapy and improve the prognosis of patients. According to research, inflammation status in PC is different from that in MFCP. Mean platelet volume/platelet ratio (MPR) is a platelet-related inflammation index which has been proven to be valuable in the diagnosis and prognosis of various malignant cancers due to the change in mean platelet volume and platelet count under abnormal inflammatory conditions caused by tumors. Thus, we conducted this study to investigate the clinical value of MPR in distinguishing MFCP from PC. METHODS: We retrospectively analyzed the data of 422 patients who were suspected to have PC during imaging examination at our department from January 2012 to December 2021. Included patients were divided into the PC (n = 383) and MFCP groups (n = 39), according to their pathological diagnosis. Clinical data including MPR were compared within these two groups and the diagnostic value was explored using logistic regression. The ROC curve between MPR and PC occurrence was drawn and an optimal cut-off value was obtained. Propensity score matching was applied to match MFCP patients with PC patients according to their age and carbohydrate antigen 19-9 (CA19-9). Differences in MPR between groups were compared to verify our findings. RESULTS: The area under the ROC curve between MPR and PC occurrence was 0.728 (95%CI: 0.652-0.805) and the optimal cut-off value was 0.045 with a 69.2% sensitivity and 68.0% accuracy. For all the included patients, MPRs in the MFCP and PC groups were 0.04 (0.04, 0.06) and 0.06 (0.04, 0.07), respectively (p = 0.005). In patients with matching propensity scores, MPRs in the MFCP and PC groups were 0.04 (0.03, 0.06) and 0.06 (0.05, 0.08), respectively (p = 0.005). Multiple logistic regression in all included patients and matched patients confirmed MPR and CA19-9 as independent risk markers in distinguishing PC. Combining CA19-9 with MPR can increase the sensitivity and accuracy in diagnosing PC to 93.2% and 89.5%, respectively. CONCLUSION: MPR in PC patients is significantly higher than that in MFCP patients and may be adopted as a potential indicator to distinguish MFCP and PC. Its differential diagnosis capacity can be improved if combined with CA19-9.

Corrigendum: Application of cholecystic duct plasty in the prevention of biliary complications following orthotopic liver transplantation.

[This corrects the article DOI: 10.3389/fsurg.2023.1087327.].

Prognostic and recurrent significance of SII in patients with pancreatic head cancer undergoing pancreaticoduodenectomy.

Background: To investigate the clinical significance of preoperative inflammatory status in patients with pancreatic head carcinoma (PHC), we performed a single-center study to assess it. Method: We studied a total of 164 patients with PHC undergoing PD surgery (with or without allogeneic venous replacement) from January 2018 to April 2022. Systemic immune-inflammation index (SII) was the most important peripheral immune index in predicting the prognosis according to XGBoost analysis. The optimal cutoff value of SII for OS was calculated according to Youden index based on the receiver operating characteristic (ROC) curve and the cohort was divided into Low SII group and High SII group. Demographic, clinical data, laboratory data, follow-up data variables were obtained and compared between the two groups. Kaplan-Meier curves, univariable and multivariable Cox regression models were used to determine the association between preoperative inflammation index, nutritional index and TNM staging system with OS and DFS respectively. Results: The median follow-up time was 16 months (IQR 23), and 41.4% of recurrences occurred within 1 year. The cutoff value of SII was 563, with a sensitivity of 70.3%, and a specificity of 60.7%. Peripheral immune status was different between the two groups. Patients in High SII group had higher PAR, NLR than those in Low SII group (P <0.01, <0.01, respectively), and lower PNI (P <0.01). Kaplan-Meier analysis showed significantly poorer OS and DFS (P < 0.001, <0.001, respectively) in patients with high SII. By using the multivariable Cox regression model, high SII (HR, 2.056; 95% CI, 1.082-3.905, P=0.028) was significant predictor of OS. Of these 68 high-risk patients who recurrence within one year, patients with widespread metastasis had lower SII and worse prognosis (P <0.01). Conclusion: High SII was significantly associated with poor prognosis in patients with PHC. However, in patients who recurrence within one year, SII was lower in patients at TNM stage III. Thus, care needs to be taken to differentiate those high-risk patients.

Prognostic value of perioperative serum low-density lipoprotein cholesterol level for postoperative prognosis of pancreatic cancer: a retrospective study.

BACKGROUND: As a common malignant tumour, pancreatic cancer (PC) has the worst clinical outcome. Early evaluation of the postoperative prognosis has certain clinical value. Low-density lipoprotein cholesterol (LDL-c), which is mainly composed of cholesteryl esters, phospholipids, and proteins, plays an important role in transporting cholesterol into peripheral tissues. LDL-c has also been reported to be correlated with the occurrence and progression of malignant tumours and can predict postoperative prognosis in various tumours. AIMS: To determine correlation between serum LDL-c level and clinical outcome in PC patients after surgery. METHODS: Data of PC patients that received surgery at our department from January 2015 to December 2021 were retrospectively analysed. Receiver operating characteristic (ROC) curves between perioperative serum LDL-c at different timepoints and survival rate at postoperative 1-year were drawn, and the optimal cut-off value was calculated. Patients were categorized into low and high LDL-c groups, and their clinical data and outcome were compared. Univariate and multivariate analyses were applied to screen out risk markers for poor prognosis of PC patients after surgery. RESULTS: The area under the ROC curve of serum LDL-c at 4 weeks after surgery and prognosis was 0.669 (95% CI: 0.581-0.757), and the optimal cut-off value was 1.515 mmol/L. The median disease-free survival (DFS) rates of low and high LDL-c groups were 9 months and 16 months, respectively, and the 1-, 2- and 3-year DFS rates were 42.6%, 21.1% and 11.7% in low LDL-c group, respectively, and, 60.2%, 35.3% and 26.2% in high LDL-c group, respectively (P = 0.005). The median overall survival (OS) rates of low and high LDL-c groups were 12 months and 22 months, respectively, and the 1-, 2- and 3-year OS rates were 46.8%, 22.6% and 15.8% in low LDL-c group, respectively, and 77.9%, 46.8% and 30.4% in high LDL-c group, respectively (P = 0.004). Multivariate analysis confirmed low postoperative 4-week serum LDL-c as independent risk marker for early tumour recrudesce and poor clinical outcome in PC patients. CONCLUSION: High postoperative 4-week serum LDL-c is a prognostic marker for prolonged DFS and OS time in PC patients.

Prognostic Value for Perioperative Serum Total Cholesterol Level on Postoperative Long-Term Prognosis of Pancreatic Cancer: A Retrospective Clinical Study.

Cholesterol correlates with occurrence and progression of pancreatic cancer and has predictive value for postoperative prognosis in various cancers. Our study intended to reveal the relationship between perioperative serum total cholesterol (TC) level and postoperative prognosis of pancreatic cancer. We retrospectively analyzed the data of pancreatic cancer patients who underwent surgical treatment at our hospital from January 2015 to December 2021. ROC curves between serum TC level at each time point and 1-year survival rate were drawn, from which study object and optimal cutoff value was determined. Patients were divided into low and high-TC groups, and perioperative data and prognosis were compared. Risk factors for poor postoperative prognosis were identified by univariate and multivariate analysis. Overall survival rates at postoperative 1, 2 and 3 years in the low and high-TC groups were 52.9%, 29.4%, and 15.6% and 80.4%, 47.2%, and 33.8% (p = 0.005), respectively. Multivariate analysis confirmed tumor differentiation degree (RR = 2.054, 95% CI: 1.396-3.025), pTNM stage (RR = 1.595, 95% CI: 1.020-2.494), lymph node metastasis (RR = 1.693, 95% CI: 1.127-2.544), and postoperative 4-week serum TC level (RR = 0.663, 95% CI: 0.466-0.944) as independent risk factors for prognosis of pancreatic cancer. We conclude that postoperative 4-week serum TC level has certain predictive value for long-term postoperative prognosis of pancreatic cancer.

Effect of the preoperative prognostic nutritional index on the long-term prognosis in patients with borderline resectable pancreatic cancer after pancreaticoduodenectomy.

Background: The preoperative prognostic nutritional index (PNI) is an indicator of systemic immune-nutritional condition and is a well-known prognostic biomarker in cancer patients. This study aims to reflect the correlation between the preoperative PNI and prognosis in patients with borderline resectable pancreatic cancer (BRPC) after pancreaticoduodenectomy (PD). Methods: Medical records of patients with BRPC after PD between Jan 2011 and Dec 2021 in our hospital were retrospectively analyzed. The preoperative PNI was calculated, and the receiver operating characteristic curve was obtained based on the preoperative PNI and the 1-year survival rate. Patients were divided into two groups (High-PNI and Low-PNI) following the best cut-off value of the preoperative PNI, and demographic and pathologic findings were compared between the two groups. Univariate and multivariate analysis were performed to identify risk factors in recurrence and long-term survival. Results: The best cut-off value for the preoperative PNI was 44.6 (sensitivity: 62.46%; specificity: 83.33%; area under the curve: 0.724). Patients in the low-PNI group had significantly shorter recurrence-free survival (P=0.008) and overall survival (P=0.009). The preoperative PNI (P=0.009) and lymph node metastasis (P=0.04) were independent risk factors for tumor recurrence. The preoperative PNI (P=0.001), lymph node metastasis (P=0.04), neoadjuvant chemotherapy (P=0.04) were independent risk factors for long-term survival in patients. Conclusion: The preoperative PNI, lymph node metastasis, neoadjuvant chemotherapy were independent risk factors for recurrence and long-term survival in patients with BRPC. The preoperative PNI might be an indicator that can predict BRPC patients' recurrence and survival. Patients with high-PNI would benefit from neoadjuvant chemotherapy.

Application of cholecystic duct plasty in the prevention of biliary complications following orthotopic liver transplantation.

Background: The purpose was aimed to evaluate the safety and effectiveness of cholecystic duct plasty (CDP) and biliary reconstruction techniques preventing biliary complications following orthotopic liver transplantation (OLT) first proposed by our center. Methods: 127 enrolled patients who underwent LT in our center from January 2015 to December 2019 were analyzed retrospectively. According to the mode of biliary tract reconstruction, patients were divided into CDP group (Group 1, n = 53) and control group (Group 2, n = 74). The differences of perioperative general data, biliary complications and long-term prognosis between two groups were compared and analyzed. Results: All patients completed the operation successfully, the incidence of perioperative complications was 22.8%. There was no significant difference in perioperative general data and complications between the two groups. Follow-up ended in June 2020, with a median follow-up period of 31 months. During the follow-up period, biliary complications occurred in 26 patients, with an overall incidence of 20.5%. The overall incidence of biliary complications and anastomotic stenosis in Group 1 was lower than that in Group 2 (P < 0.05). There was no significant difference in overall prognosis between the two groups (P = 0.274), however, the cumulative incidence of biliary complications in Group 1 was lower than that in Group 2 (P = 0.035). Conclusion: Reconstruction of common bile duct by CDP represents considerable safety and practicability, particularly for patients with small diameter of common bile duct or wide discrepancy of bile duct size between donor and recipient.

Development and validation of machine learning models for predicting prognosis and guiding individualized postoperative chemotherapy: A real-world study of distal cholangiocarcinoma.

Background: Distal cholangiocarcinoma (dCCA), originating from the common bile duct, is greatly associated with a dismal prognosis. A series of different studies based on cancer classification have been developed, aimed to optimize therapy and predict and improve prognosis. In this study, we explored and compared several novel machine learning models that might lead to an improvement in prediction accuracy and treatment options for patients with dCCA. Methods: In this study, 169 patients with dCCA were recruited and randomly divided into the training cohort (n = 118) and the validation cohort (n = 51), and their medical records were reviewed, including survival outcomes, laboratory values, treatment strategies, pathological results, and demographic information. Variables identified as independently associated with the primary outcome by least absolute shrinkage and selection operator (LASSO) regression, the random survival forest (RSF) algorithm, and univariate and multivariate Cox regression analyses were introduced to establish the following different machine learning models and canonical regression model: support vector machine (SVM), SurvivalTree, Coxboost, RSF, DeepSurv, and Cox proportional hazards (CoxPH). We measured and compared the performance of models using the receiver operating characteristic (ROC) curve, integrated Brier score (IBS), and concordance index (C-index) following cross-validation. The machine learning model with the best performance was screened out and compared with the TNM Classification using ROC, IBS, and C-index. Finally, patients were stratified based on the model with the best performance to assess whether they benefited from postoperative chemotherapy through the log-rank test. Results: Among medical features, five variables, including tumor differentiation, T-stage, lymph node metastasis (LNM), albumin-to-fibrinogen ratio (AFR), and carbohydrate antigen 19-9 (CA19-9), were used to develop machine learning models. In the training cohort and the validation cohort, C-index achieved 0.763 vs. 0.686 (SVM), 0.749 vs. 0.692 (SurvivalTree), 0.747 vs. 0.690 (Coxboost), 0.745 vs. 0.690 (RSF), 0.746 vs. 0.711 (DeepSurv), and 0.724 vs. 0.701 (CoxPH), respectively. The DeepSurv model (0.823 vs. 0.754) had the highest mean area under the ROC curve (AUC) than other models, including SVM (0.819 vs. 0.736), SurvivalTree (0.814 vs. 0.737), Coxboost (0.816 vs. 0.734), RSF (0.813 vs. 0.730), and CoxPH (0.788 vs. 0.753). The IBS of the DeepSurv model (0.132 vs. 0.147) was lower than that of SurvivalTree (0.135 vs. 0.236), Coxboost (0.141 vs. 0.207), RSF (0.140 vs. 0.225), and CoxPH (0.145 vs. 0.196). Results of the calibration chart and decision curve analysis (DCA) also demonstrated that DeepSurv had a satisfactory predictive performance. In addition, the performance of the DeepSurv model was better than that of the TNM Classification in C-index, mean AUC, and IBS (0.746 vs. 0.598, 0.823 vs. 0.613, and 0.132 vs. 0.186, respectively) in the training cohort. Patients were stratified and divided into high- and low-risk groups based on the DeepSurv model. In the training cohort, patients in the high-risk group would not benefit from postoperative chemotherapy (p = 0.519). In the low-risk group, patients receiving postoperative chemotherapy might have a better prognosis (p = 0.035). Conclusions: In this study, the DeepSurv model was good at predicting prognosis and risk stratification to guide treatment options. AFR level might be a potential prognostic factor for dCCA. For the low-risk group in the DeepSurv model, patients might benefit from postoperative chemotherapy.

Venous thromboembolism in patients undergoing distal cholangiocarcinoma surgery: Prevalence, risk factors, and outcomes.

BACKGROUND: To investigate venous thromboembolism (VTE) in patients undergoing distal cholangiocarcinoma (dCCA) surgery, we performed a single-center study to assess its prevalence, risk factors, prognosis. METHOD: We studied a total of 177 patients undergoing dCCA surgery from January 2017 to April 2022. Demographic, clinical data, laboratory data (including lower extremity ultrasound findings), and outcome variables were obtained, and compared between VTE and non-VTE groups. RESULTS: Of the 177 patients undergoing dCCA surgery (aged 65.2 ± 9.6 years; 108 (61.0%) male), 64 patients developed VTE after surgery. Logistic multivariate analysis showed that, age, operation procedure, TNM stage, ventilator duration and preoperative D-dimer were independent risk factors. Based on these factors, we constructed the nomogram to predict VTE after dCCA for the first time. The areas under the receiver operating curve (ROC) of the nomogram were 0.80 (95% CI: 0.72-0.88) and 0.79 (95% CI: 0.73-0.89) in the training and validation groups, respectively. Patients developed VTE had a worse prognosis by Kaplan-Meier curve analysis (p = 0.001). CONCLUSION: The prevalence of VTE is high and is associated with adverse outcomes in patients undergoing dCCA surgery. We developed a nomogram assessing VTE risk, which may help clinicians to screen out people at high risk for VTE and to undertake rational preventive measures.

Prognostic Value of Neoadjuvant Chemotherapy in Patients with Borderline Resectable Pancreatic Carcinoma Followed by Pancreatectomy with Portal Vein Resection and Reconstruction with Venous Allograft.

BACKGROUND: Neo-adjuvant chemotherapy (NAC) represents one of the current research hotspots in the field of pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to evaluate the prognostic value of NAC in patients with borderline resectable pancreatic cancer (BRPC) followed by pancreatectomy with portal vein (PV) resection and reconstruction with venous allograft (VAG). METHODS: Medical records of patients with BPRC who underwent pancreatectomy with concomitant PV resection and reconstruction with VAG between April 2013 and March 2021 were analyzed retrospectively. Outcomes of patients with and without NAC (NAC, Group 1 vs. non-NAC, Group 2) were compared with focus on R0 resection rates, morbidity, and survival. RESULTS: Of the 77 patients with pancreatectomy, PV resection and reconstruction with VAG were identified. Overall survival (OS) rates of 0.5-, 1-, and 2-year were 80.5%, 59.7%, and 31.2%, respectively (median survival time, MST, 14 months). Of these, 24 patients (Group 1) underwent operation following received NAC, and the remaining 53 patients did not (Group 2). The R0 resection rate of vascular margin was 100% vs. 84.9% (p = 0.04), respectively. Morbidity of post-operative pancreatic fistula (POPF) was 0% vs. 17.8% (p = 0.07), respectively. The OS of 0.5-, 1- and 2-year and MST of 2 groups were 83.3%, 66.7%, 41.7%, 16 months, and 79.2%, 55.6%, 26.4%, 13 months, respectively. Multivariate analysis revealed that carbohydrate antigen 19-9 (CA19-9) serum level and postoperative chemotherapy were independent prognostic factors in patients with BRPC after surgery. CONCLUSION: NAC might improve the R0 resection rate and POPF in patients with BRPC who underwent pancreatectomy with concomitant PV resection and reconstruction with VAG. Survival benefit exists in patients with BRPC who received NAC before pancreatectomy. Postoperative chemotherapy also had a favorable effect on OS of BRPC patients. Elevated CA 19-9 serum level is associated with poor prognosis, even after NAC-combining operation.

Clinical value of extended lymphadenectomy in radical surgery for pancreatic head carcinoma at different T stages.

BACKGROUND: As the lymph-node metastasis rate and sites vary among pancreatic head carcinomas (PHCs) of different T stages, selective extended lymphadenectomy (ELD) performance may improve the prognosis of patients with PHC. AIM: To investigate the effect of ELD on the long-term prognosis of patients with PHC of different T stages. METHODS: We analyzed data from 216 patients with PHC who underwent surgery at our hospital between January 2011 and December 2021. The patients were divided into extended and standard lymphadenectomy (SLD) groups according to extent of lymphadenectomy and into T1, T2, and T3 groups according to the 8th edition of the American Joint Committee on Cancer's staging system. Perioperative data and prognoses were compared among groups. Risk factors associated with prognoses were identified through univariate and multivariate analyses. RESULTS: The 1-, 2- and 3-year overall survival (OS) rates in the extended and SLD groups were 69.0%, 39.5%, and 26.8% and 55.1%, 32.6%, and 22.1%, respectively (P = 0.073). The 1-, 2- and 3-year disease-free survival rates in the extended and SLD groups of patients with stage-T3 PHC were 50.3%, 25.1%, and 15.1% and 22.1%, 1.7%, and 0%, respectively (P = 0.025); the corresponding OS rates were 65.3%, 38.1%, and 21.8% and 36.1%, 7.5%, and 0%, respectively (P = 0.073). Multivariate analysis indicated that portal vein invasion and lymphadenectomy extent were risk factors for prognosis in patients with stage-T3 PHC. CONCLUSION: ELD may improve the prognosis of patients with stage-T3 PHC and may be of benefit if performed selectively.

FGF9 Alleviates the Fatty Liver Phenotype by Regulating Hepatic Lipid Metabolism.

Although the fatty liver has been linked to numerous impairments of energy homeostasis, the molecular mechanism responsible for fatty liver development remains largely unknown. In the present study, we show that fibroblast growth factors 9 (FGF9) expression is increased in the liver of diet-induced obese (DIO), db/db, and ob/ob mice relative to their respective controls. The long-term knockdown of hepatic FGF9 expression mediated by adeno-associated virus expressing FGF9-specific short hairpin RNA (AAV-shFGF9) aggravated the fatty liver phenotype of DIO mice. Consistently, downregulation of FGF9 expression mediated by adenovirus expressing FGF9-specific shRNA (Ad-shFGF9) in the primary hepatocyte promoted the cellular lipid accumulation, suggesting that FGF9 exerts its effects in an autocrine manner. In contrast, adenoviruses expressing FGF9 (Ad-FGF9) mediated FGF9 overexpression in the liver of DIO mice alleviated hepatic steatosis and improved the insulin sensitivity and glucose intolerance. Moreover, the liver-specific FGF9 transgenic mice phenocopied the Ad-FGF9-infected mice. Mechanistically, FGF9 inhibited the expression of genes involved in lipogenesis and increased the expression of genes involved in fatty acid oxidation, thereby reducing cellular lipid accumulation. Thus, targeting FGF9 might be exploited to treat nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome.

Transcription factor Klf9 controls bile acid reabsorption and enterohepatic circulation in mice via promoting intestinal Asbt expression.

Bile acid (BA) homeostasis is regulated by the extensive cross-talk between liver and intestine. Many bile-acid-activated signaling pathways have become attractive therapeutic targets for the treatment of metabolic disorders. In this study we investigated the regulatory mechanisms of BA in the intestine. We showed that the BA levels in the gallbladder and faeces were significantly increased, whereas serum BA levels decreased in systemic Krüppel-like factor 9 (Klf9) deficiency (Klf9-/-) mice. These phenotypes were also observed in the intestine-specific Klf9-deleted (Klf9vil-/-) mice. In contrast, BA levels in the gallbladder and faeces were reduced, whereas BA levels in the serum were increased in intestinal Klf9 transgenic (Klf9Rosa26+/+) mice. By using a combination of biochemical, molecular and functional assays, we revealed that Klf9 promoted the expression of apical sodium-dependent bile acid transporter (Asbt) in the terminal ileum to enhance BA absorption in the intestine. Reabsorbed BA affected liver BA synthetic enzymes by regulating Fgf15 expression. This study has identified a previously neglected transcriptional pathway that regulates BA homeostasis.