Liver macrophages mediate effects of downhill running and caloric restriction on nonalcoholic fatty liver disease of high fat diet-fed mice.


  • 影响因子:3.40
  • DOI:10.1016/j.lfs.2020.117978
  • 作者列表:"Ai L","Luo W","Yuan P","Liu L","Zhou Y
  • 发表时间:2020-06-15

AIMS:The mechanism of physical activity and calorie restriction remedying non-alcoholic fatty liver disease (NAFLD) remains elusive. The purpose of this study is to explore the effects of eccentric exercise and dietary regulation allied or alone on high-fat diet (HFD) induced NAFLD and its potential mechanism. MATERIALS AND METHODS:Mice were fed with HFD for 12 weeks and subsequently treated with chronic downhill running and caloric restriction for 8 weeks. Related biochemical index were examined both before and during intervention to evaluate the liver injury and dyslipidemia. Levels of MCP1, TNFα, IL-1β, IL-6 and IL-10 were detected by ELISA. Liver morphology was observed by H&E and oil red O staining. Protein contents of iNOS, Arg-1, IL-1β and IL-10 were determined by Western blot. CD86 and CD206 fluorescence were determined by Immunofluorescence. KEY FINDING: (1) 12 weeks' HFD induced hyperlipemia and hepatic steatosis by activating M1 macrophages phenotype and inhibiting M2 macrophages. (2) Chronic downhill running and caloric restriction promoted liver M2 macrophages phenotype, and inhibited M1 macrophages, to attenuate chronic inflammation and ameliorate hepatic steatosis. (3) The effects of downhill running and dietary regulation allied were more effective on improving NAFLD compared with downhill running or caloric restriction alone. SIGNIFICANCE:Eccentric exercise accompanied by caloric restriction attenuates HFD-related NAFLD by promoting M2 macrophages phenotype and inhibiting M1 macrophages in liver. These findings may be help to designing better non-pharmacological intervention programs for NAFLD patients.


目的: 体力活动和热量限制治疗非酒精性脂肪性肝病 (NAFLD) 的机制仍不清楚。本研究旨在探讨离心运动和饮食调节联合或单独对高脂饮食 (HFD) 诱导的 NAFLD 的影响及其潜在机制。 材料和方法: 用 HFD 喂养小鼠 12 周,随后用慢性下坡跑和热量限制治疗 8 周。干预前及干预过程中检测相关生化指标,评价肝损伤及血脂异常。ELISA 法检测 MCP1 、 tnf α 、 il-1 β 、 IL-6 、 IL-10 水平。通过 H & E 和油红 O 染色观察肝脏形态。Western blot 法测定 iNOS 、 Arg-1 、 il-1 β 和 IL-10 的蛋白含量。免疫荧光法测定 CD86 和 CD206 荧光。关键发现 :( 1) 12 周的 HFD 通过激活 M1 巨噬细胞表型和抑制 M2 巨噬细胞诱导高脂血症和肝脏脂肪变性。(2) 慢性下坡跑和热量限制可促进肝 M2 巨噬细胞表型,抑制 M1 巨噬细胞,减轻慢性炎症,改善肝脏脂肪变性。(3) 与单纯下坡跑或热量限制相比,下坡跑和饮食调节联合作用对改善 NAFLD 更有效。 意义: 伴有热量限制的离心运动通过促进肝脏 M2 巨噬细胞表型和抑制 M1 巨噬细胞来减弱 HFD 相关的 NAFLD。这些发现可能有助于为 NAFLD 患者设计更好的非药物干预方案。



作者列表:["Moon AM","Jiang Y","Rogal SS","Tapper EB","Lieber SR","Barritt AS 4th"]

METHODS:BACKGROUND:Opioids are often prescribed for pain in cirrhosis and may increase the risk of hepatic encephalopathy (HE). AIMS:To assess the association between opioids and HE in patients with well-compensated cirrhosis. METHODS:We used the IQVIA PharMetrics (Durham, NC) database to identify patients aged 18-64 years with cirrhosis. We excluded patients with any decompensation event from 1 year before cirrhosis diagnosis to 6 months after cirrhosis diagnosis. Over the 6 months after cirrhosis diagnosis, we determined the duration of continuous opioid use and classified use into short term (1-89 days) and chronic (90-180 days). We assessed whether patients developed HE over the subsequent year (ie 6-18 months after cirrhosis diagnosis). We used a landmark analysis and performed multivariable Cox proportional hazards regression to assess associations between opioid use and HE, adjusting for relevant confounders. RESULTS:The cohort included 6451 patients with compensated cirrhosis, of whom 23.3% and 4.7% had short-term and chronic opioid prescriptions respectively. Over the subsequent year, HE occurred in 6.3% patients with chronic opioid prescriptions, 5.0% with short-term opioid prescriptions and 3.3% with no opioid prescriptions. In the multivariable model, an increased risk of HE was observed with short-term (adjusted hazard ratio, HR 1.44, 95% CI 1.07-1.94) and chronic opioid prescriptions (adjusted HR 1.83, 95% CI 1.07-3.12) compared to no opioid prescriptions. CONCLUSION:In this national cohort of privately insured patients with cirrhosis, opioid prescriptions were associated with the risk of incident HE. Opioid use should be minimised in those with cirrhosis and, when required, limited to short duration.

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作者列表:["Chen VL","Chen Y","Du X","Handelman SK","Speliotes EK"]

METHODS:BACKGROUND AND AIMS:Cirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver-related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits. METHODS:We carried out a genome-wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top-associating loci for replication with cirrhosis in a hospital-based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites. RESULTS:Unbiased genome-wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase-to-platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits. CONCLUSIONS:We identified eight loci that reproducibly associate with population-based cirrhosis and define their diverse effects on human diseases and traits.

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作者列表:["Li H","Wieser A","Zhang J","Liss I","Markwardt D","Hornung R","Neumann-Cip AC","Mayerle J","Gerbes A","Steib CJ"]

METHODS:BACKGROUND:Spontaneous bacterial peritonitis (SBP) is a serious complication in patients with liver cirrhosis. In recent years, it has been postulated that the rate of multidrug-resistant organisms (MDROs) is increasing, especially in nosocomial SBP patients. Aim of the present work was to investigate this hypothesis and its possible clinical consequences. MATERIALS AND METHODS:One hundred and three culture-positive patients between 2007 and 2014 were compared with 81 patients between 2015 and 2017, to study the change of microbiological profiles and their clinical consequences. The cirrhosis patients with bacterascites requiring treatment were included as well. RESULTS:The most prevalent Gram-negative bacteria isolated from ascites were Enterobacterales (31.6%) and in Gram-positive pathogens Staphylococci (22.8%). There was a significant increase in MDROs (22.3% ICU 40.7%, P = .048), accompanied by an increased incidence of sepsis (from 21.4% to 37.0%, P = .021), hepatorenal syndrome (from 40.8% to 58.0%, P = .007) and the need of catecholamine therapy (from 21.4% to 38.8%, P = .036). Nosocomial origin correlated with higher MDRO proportion, more complications and lower antimicrobial susceptibility rates in 12 commonly used antibiotics. MDROs were confirmed as an isolated predictor for inpatient mortality and complications in multivariable logistic regression. CONCLUSIONS:The feeling in clinical practice that MDROs have increased in the last 11 years could be confirmed in our study in Munich, Germany. Nosocomial SBP correlated with significantly higher MDRO rates (nearly 50%) and complication rates. In our opinion, an antibiotic combination with comprehensive effect should be taken into account in nosocomial SBP patients in this region.