Hepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12.
肝星状细胞活化通过 Igfbp3 和 serpina12 促进酒精诱导的脂肪性肝炎。
- 作者列表："Arab JP","Cabrera D","Sehrawat TS","Jalan-Sakrikar N","Verma VK","Simonetto D","Cao S","Yaqoob U","Leon J","Freire M","Vargas JI","De Assuncao TM","Kwon JH","Guo Y","Kostallari E","Cai Q","Kisseleva T","Oh Y","Arrese M","Huebert RC","Shah VH
BACKGROUND:/Aim: Steatohepatitis drives fibrogenesis in alcoholic liver disease. However, recent studies have suggested that hepatic stellate cells (HSC) may regulate the parenchymal cell injury and inflammation that precedes liver fibrosis, although the mechanism remains incompletely defined. Neuropilin-1 (NRP-1) and synectin are membrane proteins implicated in HSC activation. In this study, we disrupted NRP-1 and synectin as models to evaluate the role of HSC activation on the development of steatohepatitis in response to alcohol feeding in mice METHODS: Mice with HSC-selective deletion of NRP (ColCre/NRP-1loxP) or synectin (ColCre/synectinloxP) vs. paired NRP-1loxP or synectinloxP mice were fed a control diet or the chronic/binge alcohol feeding model. Several markers of steatosis and inflammation were evaluated RESULTS: ColCre/NRP-1loxP mice showed less fibrosis, as expected, but also less inflammation and steatosis as assessed by Oil-Red O and Bodipy staining and hepatic triglyceride content. Similar results were observed in the synectin model. Hepatocytes treated with supernatant of HSC from ColCre/NRP-1loxP mice compared to supernatant from NRP-1loxP mice were protected against ethanol-induced lipid droplet formation. An adipokine and inflammatory protein array from the supernatant of HSC with NRP-1-knockdown showed a significant reduction in Igfbp3 (a major insulin-like growth factor binding protein with multiple metabolic functions) and an increase in SerpinA12 (a serine-protease inhibitor) secretion compared to wildtype HSC. Recombinant Igfbp3 induced lipid droplets, triglyceride accumulation, and lipogenic genes in hepatocytes in vitro, while SerpinA12 was protective against ethanol-induced steatosis. Finally, Igfbp3 was increased, and SerpinA12 was decreased in serum and liver tissue from patients with alcoholic hepatitis CONCLUSION: Selective deletion of NRP-1 from HSC attenuates alcohol-induced steatohepatitis through regulation of Igfbp3 and SerpinA12 signaling.
背景:/目的: 脂肪性肝炎驱动酒精性肝病的纤维化形成。然而，最近的研究表明，肝星状细胞 (HSC) 可能调节肝纤维化前的实质细胞损伤和炎症，尽管其机制尚未完全确定。Neuropilin-1 (NRP-1) 和 synectin 是参与 HSC 活化的膜蛋白。在这项研究中，我们破坏了 NRP-1 和 synectin 作为模型，以评估 HSC 激活在小鼠酒精喂养后脂肪性肝炎发展中的作用。方法: HSC 选择性缺失 NRP (ColCre/NRP-1loxP) 或 synectin (ColCre/synectinloxP) 的小鼠对配对 NRP-1loxP 或 synectinloxP 小鼠进行对照饮食或慢性/暴饮酒精喂养模型。评估了脂肪变性和炎症的几个标志物结果: ColCre/NRP-1loxP 小鼠表现出较少的纤维化，正如预期的那样, 而且通过油红 O 和 Bodipy 染色和肝甘油三酯含量评估的炎症和脂肪变性也较少。在 synectin 模型中观察到类似的结果。用 ColCre/NRP-1loxP 小鼠的 HSC 上清液处理的肝细胞与 NRP-1loxP 小鼠的上清液处理的肝细胞相比，保护免受乙醇诱导的脂滴形成。NRP-1-knockdown 的 HSC 上清液中的脂肪因子和炎症蛋白阵列显示 Igfbp3 (一种具有多种代谢功能的主要胰岛素样生长因子结合蛋白) 显著降低与野生型 HSC 相比，SerpinA12 (一种丝氨酸蛋白酶抑制剂) 分泌增加。重组 Igfbp3 在体外诱导肝细胞脂滴、甘油三酯积累和成脂基因，而 SerpinA12 对乙醇诱导的脂肪变性具有保护作用。最终，酒精性肝炎患者血清和肝组织中 Igfbp3 升高，SerpinA12 降低。结论: HSC 选择性缺失 NRP-1 通过调节 Igfbp3 和 SerpinA12 信号减弱酒精诱导的脂肪性肝炎。
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.
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.
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.