Hepatic ChREBP activation limits NAFLD development in a mouse model for Glycogen Storage Disease type Ia.
肝 ChREBP 激活限制了糖原累积症 Ia 型小鼠模型的 NAFLD 发展。
- 作者列表："Lei Y","Hoogerland JA","Bloks VW","Bos T","Bleeker A","Wolters H","Wolters JC","Hijmans BS","van Dijk TH","Thomas R","van Weeghel M","Mithieux G","Houtkooper RH","de Bruin A","Rajas F","Kuipers F","Oosterveer MH
:Glycogen storage disease type Ia (GSD Ia) is an inborn error of metabolism caused by defective glucose-6-phosphatase (G6PC) activity. GSD Ia patients exhibit severe hepatomegaly due to glycogen and triglyceride (TG) accumulation in the liver. We have previously shown that the activity of Carbohydrate Response Element Binding Protein (ChREBP), a key regulator of glycolysis and de novo lipogenesis, is increased in GSD Ia. In the current study we assessed the contribution of ChREBP to non-alcoholic fatty liver disease (NAFLD) development in a mouse model for hepatic GSD Ia. Liver-specific G6pc knockout (L-G6pc-/- ) mice were treated with AAV2/8-shChREBP to normalize hepatic ChREBP activity to levels observed in wildtype (L-G6pc+/+ ) mice receiving AAV8-shScramble. Hepatic ChREBP knockdown markedly increased liver weight and hepatocyte size in L-G6pc-/- mice. This was associated with hepatic accumulation of G6P, glycogen and lipids, while the expression of glycolytic and lipogenic genes was reduced. Enzyme activities, flux measurements, hepatic metabolite analysis and VLDL-TG secretion assays revealed that hepatic ChREBP knockdown reduced downstream glycolysis and de novo lipogenesis, but also strongly suppressed hepatic VLDL lipidation hence promoting the storage of 'old fat'. Interestingly, enhanced VLDL-TG secretion in shScramble-treated L-G6pc-/- mice associated with a ChREBP-dependent induction of the VLDL lipidation proteins MTTP and TM6SF2, the latter being confirmed by ChIP-PCR. CONCLUSION: Attenuation of hepatic ChREBP induction in GSD Ia liver aggravates hepatomegaly due to further accumulation of glycogen and lipids as a result of reduced glycolysis and suppressed VLDL-TG secretion. TM6SF2, critical for VLDL formation, was identified as a novel ChREBP target in mouse liver. Altogether, our data show that enhanced ChREBP activity limits NAFLD development in GSD Ia by balancing hepatic TG production and -secretion.
: 糖原累积病 Ia 型 (GSD Ia) 是由葡萄糖-6-磷酸酶 (G6PC) 活性缺陷引起的先天性代谢错误。GSD Ia 患者由于肝内糖原和甘油三酯 (TG) 蓄积而表现出严重的肝肿大。我们之前已经表明，糖酵解和新生脂肪生成的关键调节因子碳水化合物反应元件结合蛋白 (ChREBP) 的活性在 GSD Ia 中增加。在目前的研究中，我们在肝脏 GSD Ia 的小鼠模型中评估了 ChREBP 对非酒精性脂肪性肝病 (NAFLD) 发展的贡献。用 AAV2/8-shChREBP 处理肝脏特异性 G6pc 基因敲除 (L-G6pc-/-) 小鼠，使肝脏 ChREBP 活性正常化至接受 L-G6pc 的野生型 (AAV8-shScramble +/+) 小鼠中观察到的水平。肝 ChREBP 敲除显著增加 L-G6pc-/-小鼠的肝脏重量和肝细胞大小。这与肝脏 G6P 、糖原和脂质的积累有关，而糖酵解和脂肪生成基因的表达减少。酶活性、通量测量、肝代谢物分析和 VLDL-TG 分泌测定揭示了肝 ChREBP 敲除降低了下游糖酵解和新生脂肪生成, 而且强烈抑制肝脏 VLDL 脂化，从而促进 '老脂肪' 的储存。有趣的是，shScramble 处理的 L-G6pc-/-小鼠 VLDL-TG 分泌增加与 VLDL 脂质化蛋白 MTTP 和 TM6SF2 的 ChREBP 依赖性诱导相关, 后者经 ChIP-PCR 证实。结论: GSD Ia 肝脏 ChREBP 诱导减弱，由于糖酵解减少和 VLDL-TG 分泌抑制，糖原和脂质进一步积累，加重肝肿大。TM6SF2，对 VLDL 形成至关重要，被确定为小鼠肝脏中一个新的 ChREBP 靶点。总之，我们的数据显示，增强的 ChREBP 活性通过平衡肝脏 TG 产生和-分泌限制了 GSD Ia 中 NAFLD 的发展。
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.