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简介：AbstractObjective:Rubicon is an inhibitory interacting protein of the autophagy-related protein Uvrag. We previously showed that Rubicon deficiency promotes autophagic flux in vivo and that autophagy can degrade lipid droplets. This study aimed to investigate the effects of Rubicon deficiency on fasting-induced hepatic steatosis.Methods:Two-month-old wild-type (WT) and Rubicon-deficient mice were subjected to feeding or fasting for 24 hours to induce hepatic steatosis. The distribution of liver lipid droplets was revealed by oil red O staining. Hepatic and plasma triglyceride, non-esterified fatty acid (NEFA), and cholesterol levels were detected using commercially available kits. Real-time reverse transcriptasepolymerase chain reaction was performed to analyze the mRNA expression of genes related to lipid metabolism in the liver. Western blot was conducted to assess autophagy-related protein levels in the liver. The animal experiments were approved by the Institutional Animal Care and Use Committee at Shanghai Jiao Tong University, China.Results:We showed that under fasting conditions, Rubicon-deficient mice had more lipid droplets in the liver than WT controls. Consistent with these results, the hepatic triglyceride, NEFA, and cholesterol levels in fasted Rubicon-deficient mice were significantly higher than those of fasted WT controls. The levels of SREBP-1, a key regulator of lipid synthesis, were significantly lower in livers from fasted WT mice than those of fed WT mice. However, the decrease in SREBP-1 in fasted mice was attenuated by Rubicon deficiency. Western blot analysis demonstrated that the fasting-induced increase in autophagic flux was amplified by Rubicon deficiency. Finally, we showed that Rubicon deficiency in mice led to elevated plasma triglyceride and NEFA acid levels under fasting conditions.Conclusion:Rubicon deficiency exacerbates fasting-induced hepatic steatosis in mice.

简介：AbstractFibroblast growth factor 21 (FGF21) is a fasting or stress inducible metabolic hormone produced mainly in the liver. It plays important roles in regulating both glucose and lipid homeostasis via interacting with a heterodimeric receptor complex comprising FGF receptor 1 (FGFR1) and β-klotho (KLB). For the past decade, great effort has been made on developing FGF21 derivatives or specific FGF21 receptor agonists into therapeutic agents for various metabolic disorders including type 2 diabetes (T2D), obesity, and more importantly, nonalcoholic fatty liver disease (NAFLD). Here we have reviewed FGF21 gene and protein structures, its expression pattern, cellular signaling cascades that mediate FGF21 production and function. We have then summarized the six clinical trials utilizing four FGF21 analogues. Finally, two recent literatures on the development of GLP-1 and FGF21 dual agonists were presented briefly.

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简介：AbstractPurpose:Liver is the most frequently injured organ in abdominal trauma. Today non-operative management (NOM) is considered as the standard of care in hemodynamically stable patients, with or without the adjunct of angioembolisation (AE). This systematic review assesses the incidence of complications in patients who sustained liver injuries and were treated with simple clinical observation. Given the differences in indications of treatment and severity of liver trauma and acknowledging the limitations of this study, an analysis of the results has been done in reference to the complications in patients who were treated with AE.Methods:A systematic literature review searched "liver trauma" , "hepatic trauma" , "conservative management" , "non operative management" on MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials databases, EMBASE, and Google Scholar, to identify studies published on the conservative management of traumatic liver injuries between January 1990 and June 2020. Patients with traumatic liver injuries (blunt and penetrating) treated by NOM, described at least one outcome of interests and provided morbidity outcomes from NOM were included in this study. Studies reported the outcome of NOM without separating liver from other solid organs; studies reported NOM complications together with those post-intervention; case reports; studies including less than 5 cases; studies not written in English; and studies including patients who had NOM with AE as primary management were excluded. Efficacy of NOM and overall morbidity and mortality were assessed, the specific causes of morbidity were investigated, and the American Association for the Surgery of Trauma classification was used in all the studies analysed. Statistical significance has been calculated using the Chi-square test.Results:A total of 19 studies qualified for inclusion criteria were in this review. The NOM success rate ranged from 85% to 99%. The most commonly reported complications were hepatic collection (3.1%), followed by bile leak (1.5%), with variability between the studies. Other complications included hepatic haematoma, bleeding, fistula, pseudoaneurysm, compartment syndrome, peritonitis, and gallbladder ischemia, all with an incidence below 1%.Conclusion:NOM with simple clinical observation showed an overall low incidence of complications, but higher for bile leak and collections. In patients with grade III and above injuries, the incidence of bile leak, collections and compartment syndrome did not show a statistically significant difference with the AE group. However, the latter result is limited by the small number of studies available and it requires further investigations.

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简介：AbstractBackground:We previously found that the intestinal epithelial chemokine (C-C motif) ligand 7 (CCL7) plays an important role in the development of toxin-induced acute liver damage. The detailed effects of intestinal epithelial CCL7 on chronic diseases; however, are still unclear. Here, we aimed to investigate the impact of intestinal epithelial CCL7 overexpression on high-fat diet (HFD)-induced obesity and steatohepatitis in mice.Methods:Intestinal epithelial CCL7 overexpression (CCL7tgIEC) mice and their wild-type (WT) littermates were fed with normal chow or HFD for 16 weeks to induce obesity and non-alcoholic fatty liver disease. Body weight gain, as well as adipose tissue index were assessed. Liver injury was monitored by histological analysis and real time polymerase chain reaction. Gut microbial composition was analyzed by 16S rRNA gene sequencing.Results:We found that the CCL7tgIEC mice on a HFD had markedly decreased weight gain (8.9 vs. 17.0 g, P < 0.05) and a lower adipose tissue index that include mesenteric fat (1.0% vs. 1.76%, P < 0.05), gonadal fat (2.1% vs. 6.1%, P < 0.05), subcutaneous fat (1.0% vs. 2.8%, P < 0.05) compared to WT animals. HFD-induced glucose intolerance and insulin resistance were also significantly improved in CCL7tgIEC mice compared to WT. Furthermore, HFD-fed CCL7tgIEC mice displayed less hepatic lipid accumulation and lower expression of inflammatory factors than WT mice. 16S rRNA gene sequencing demonstrated that CCL7 overexpression in intestinal epithelial cells improved HFD-induced gut microbial dysbiosis.Conclusions:Our study revealed that CCL7 overexpression in the intestinal epithelium protects mice against the progression of diet-induced obesity, hepatic steatosis, and enteric dysbiosis.

简介：AbstractBackground:The efficacy of entecavir (ETV) add-on peg-interferon therapy compared with ETV monotherapy in treatment-naïve hepatitis B virus (HBV) patients remains controversial. We investigated whether adding peg-interferon to ongoing ETV treatment leads to a better curative effect or not.Methods:All patients have been recruited between August 2013 and January 2015 from the Shanghai Public Health Clinical Center and Zhongshan Hospital (China). Eligible HBV patients (n = 144) were randomly divided (1:1) to receive either ETV monotherapy (n = 70) or peg-interferon add-on therapy from week 26 to 52 (n = 74). Patients were followed-up for at least 2 years. Indexes including hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) seroconversion rate, sustained virologic response, transient elastography value, and histological scores were evaluated every 3 months until the end of the study. The rate of patients with HBsAg loss was defined as the primary endpoint criteria.Results:At week 26, no patient achieved HBsAg seroconversion in either group. At week 52, one patient in the monotherapy group was HBsAg-negative but there was none in the combination therapy group. The monotherapy group showed significantly better liver function recovery results than the combination therapy group. At week 78, one patient in the combination group had HBsAg seroconverted. At week 104, only three patients in the combination therapy group were HBsAg-negative compared with one patient in monotherapy. The mean alanine aminotransferase and aspartate aminotransferase levels and transient elastography values decreased significantly compared with baseline. Both groups showed a favorable decrease in alpha-fetoprotein (monotherapy: 4.5 [2.8, 7.1] vs. 2.2 [1.8, 3.1] ng/mL, P < 0.001; combination therapy: 5.7 [3.0, 18.8] vs. 3.2 [2.0, 4.3] ng/mL, P < 0.001) and an improved result of liver biopsy examination scores. The combination group showed a better improvement in histology compared with the monotherapy group (mean transient elastography value 6.6 [4.9, 9.8] vs. 7.8 [5.4, 11.1] kPa, P = 0.028). But there was no significant difference in HBsAg conversion rate (1.8% [1/56] vs. 4.1% [3/73], P = 0.809) and HBeAg conversion rate (12.5% [7/56] vs. 11.0% [8/73], P = 0.787), as well as HBV-DNA, sustained virologic response (93.2% vs. 98.5%, P = 0.150) between the two groups.Conclusions:Both therapies supported liver function recovery and histology improvement. Combination therapy did not show better anti-viral efficacy in HBsAg or HBeAg seroconversion compared with monotherapy. However, combination therapy played a more positive role in reversing hepatic fibrosis compared with monotherapy.Trial registration:ClinicalTrials.gov: NCT02849132; https://clinicaltrials.gov/ct2/show/NCT02849132

简介：AbstractObjective:This study aimed at investigating the expression of nuclear factor kappa B (NF-κB) and mammalian target of rapamycin (mTOR) related signal pathways in liver tissues of intrahepatic cholestasis of pregnancy animal models.Methods:Estrogen (EE)-induced cholestasis and a placental ischemia-reperfusion (IR) model were established in pregnant rats. All pregnant rats were divided into four groups by random number table: EE-IR group (n= 6), EE-sham group (n = 6), control-IR group (n= 6) and control-sham group (n= 6). Liver expression of mTOR, its upstream regulator DNA damage response-1 (REDD1), and downstream factor glucose transporter type-1 (GLUT1), accompanied by NF-κB (p65 is the most important component), its activator toll-like receptor 4 (TLR4), and inhibitor IκBα, were detected by western blot analysis and real-time polymerase chain reaction. The intergroup comparisons were performed with a one-way analysis of variance, the comparisons among groups were analyzed with the nonparametric Kruskal-Wallis test.Results:Giving pregnant rats EE alone reduced the hepatic expression of IκBα (0.72 ± 0.20 vs. 1.01 ± 0.07, P= 0.008). Meanwhile, giving pregnant rats placental IR alone increased liver levels of REDD1 (3.24 ± 0.98 vs. 1.06 ± 0.24, P= 0.025), GLUT1 (2.37 ± 0.82 vs. 1.09 ± 0.10, P= 0.039), TLR4 (2.12 ± 0.29 vs. 1.20 ± 0.28, P= 0.010), and p65 (2.09 ± 0.85 vs. 1.04 ± 0.06, P= 0.023), and decreased hepatic mTOR (0.50 ± 0.07 vs. 1.01 ± 0.03, P= 0.001) and IκBα (0.61 ± 0.08 vs. 1.01 ± 0.07, P= 0.014) expression. Subjecting EE-treated rats to placental IR did not further alter liver levels of GLUT1 (2.02 ± 0.45 vs. 1.79 ± 0.39, P= 0.240), TLR4 (2.10 ± 0.74 vs. 1.60 ± 0.36, P= 0.129), or p65 (2.41 ± 0.83 vs. 1.65 ± 0.46, P= 0.145), whereas it did decrease hepatic mTOR (0.42 ± 0.09 vs. 0.90 ± 0.14, P= 0.008) and IκBα (0.43 ± 0.09 vs. 0.72 ± 0.20, P= 0.004) expression and enhance REDD1 expression (4.46 ± 0.65 vs. 2.05 ± 0.47, P= 0.009). Placental IR stress did impact the hepatic expression of REDD1-mTOR-GLUT1 and TLR4/NF-κB/IκBα in pregnant rats.Conclusion:Placental IR-induced hepatic GLUT1, TLR4, and p65 alternation, which responded efficiently in control rats, were impaired in EE-induced ICP rats.