Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation
Abstract
BACKGROUND & AIMS: Nonalcoholic steatohepatitis is morphologically identical to alcoholic hepatitis and has multiple etiologic associations and an unknown pathogenesis. The present study used a rat nutritional model of hepatic steatosis with inflammation to test the hypothesis that induction of the alcohol-inducible hepatic cytochrome P450 (CYP) 2E1 is associated with production of steatohepatitis. METHODS: Rats received a diet devoid of methionine-choline. CYP2E1 protein was detected in liver sections by immunohistochemistry and in hepatic microsomal fractions by immunoblotting; CYP2E1 activity was detected by N-demethylation of N,N-dimethylnltrosamine (NDMA). CYP2E1 messenger RNA was analyzed by Northern blotting and slot blot hybridization. RESULTS: After 4 weeks of methionine-choline devoid diet, macrovesicular steatosis and an inflammatory infiltrate were prominent in hepatic acinar zone 3. CYP2E1 immunostaining was increased and had a more extensive acinar distribution corresponding to that of the steatosis. Microsomal CYP2E1 protein, NDMA activity, and hepatic CYP2E1 messenger RNA levels were all correspondingly increased. CONCLUSIONS: CYP2E1 is induced, partly at a pretranslational level, in this experimental form of steatohepatitis. The finding of biochemical and histological similarities between this nutritional model of hepatic steatosis with inflammation and alcoholic hepatitis indicates possible clues to common pathogenetic mechanisms. The relevance of this finding to human nonalcoholic steatohepatitis remains uncertain and requires further investigation of human liver specimens. (Gastroenterology 1996 Dec;111(6):1645-53)
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The CYP2E1 inhibitor Q11 ameliorates LPS-induced sepsis in mice by suppressing oxidative stress and NLRP3 activation
2023, Biochemical PharmacologySepsis is an infection-induced, multi-organ system failure with a pathophysiology related to inflammation and oxidative stress. Increasing evidence indicates that cytochrome P450 2E1 (CYP2E1) is involved in the incidence and development of inflammatory diseases. However, a role for CYP2E1 in lipopolysaccharide (LPS)-induced sepsis has not been completely explored. Here we use Cyp2e1 knockout (cyp2e1-/-) mice to determine if CYP2E1 could be a therapeutic target for sepsis. We also evaluated the ability of Q11, a new specific CYP2E1 inhibitor, to prevent and ameliorate LPS-induced sepsis in mice and in LPS-treated J774A.1 and RAW264.7 cells. Cyp2e1 deletion significantly reduced hypothermia, multi-organ dysfunction and histological abnormalities in LPS-treated mice; consistent with this finding, the CYP2E1 inhibitor Q11 significantly prolonged the survival time of septic mice and ameliorated multi-organ injury induced by LPS. CYP2E1 activity in liver correlated with indicators of multi-organ injury, such as the level of lactate dehydrogenase (LDH) and blood urea nitrogen (BUN) (P < 0.05). Q11 significantly suppressed the expression of NLRP3 in tissues after LPS injection; in vitro studies revealed that activation of NLRP3 signaling and increase of ROS was attenuated by Q11 in LPS-stimulated macrophages, which was reflected by reduced expression of caspase-1 and formation of ASC specks. Overall, our results indicate that Q11 improves the survival of mice with LPS-induced sepsis and attenuates sepsis-induced multiple-organ injury, suggesting that CYP2E1 could be a therapeutic target for sepsis.
Wnt/beta‐catenin signaling and its modulators in nonalcoholic fatty liver diseases
2023, Hepatobiliary and Pancreatic Diseases InternationalNonalcoholic fatty liver disease (NAFLD) is a global health concern associated with significant morbidity and mortality. NAFLD is a spectrum of diseases originating from simple steatosis, progressing through nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis that may lead to hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is mediated by the triglyceride accumulation followed by proinflammatory cytokines expression leading to inflammation, oxidative stress, and mitochondrial dysfunction denoted as “two-hit hypothesis”, advancing with a “third hit” of insufficient hepatocyte proliferation, leading to the increase in hepatic progenitor cells contributing to fibrosis and HCC. Wnt/β-catenin signaling is responsible for normal liver development, regeneration, hepatic metabolic zonation, ammonia and drug detoxification, hepatobiliary development, etc., maintaining the overall liver homeostasis. The key regulators of canonical Wnt signaling such as LRP6, Wnt1, Wnt3a, β-catenin, GSK-3β, and APC are abnormally regulated in NAFLD. Many experimental studies have shown the aberrated Wnt/β-catenin signaling during the NAFLD progression and NASH to hepatic fibrosis and HCC. Therefore, in this review, we have emphasized the role of Wnt/β-catenin signaling and its modulators that can potentially aid in the inhibition of NAFLD.
Methionine cycle in nonalcoholic fatty liver disease and its potential applications
2022, Biochemical PharmacologyAs a chronic metabolic disease affecting epidemic proportions worldwide, the pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD) is not clear yet. There is also a lack of precise biomarkers and specific medicine for the diagnosis and treatment of NAFLD. Methionine metabolic cycle, which is critical for the maintaining of cellular methylation and redox state, is involved in the pathophysiology of NAFLD. However, the molecular basis and mechanism of methionine metabolism in NAFLD are not completely understood. Here, we mainly focus on specific enzymes that participates in methionine cycle, to reveal their interconnections with NAFLD, in order to recognize the pathogenesis of NAFLD from a new angle and at the same time, explore the clinical characteristics and therapeutic strategies.
Alleviation of non-alcoholic fatty liver disease by Huazhi Fugan Granules is associated with suppression of TLR4/NF-κB signaling pathway
2021, Clinica e Investigacion en ArteriosclerosisCitation Excerpt :It has been reported that TLR4 is also implicated in hepatic steatosis and NAFLD pathogenesis,19 MyD88 activates NF-kappa B (NF-kB) transcription factor, subsequently results in production of proinflammatory cytokines.19,20 In the present study, we investigated the effects and potential mechanisms of HZFGG on MCD diet-induced NAFLD mice, which is a classic model and has been used for over 40 years.21 C57BL/6 mice (male, 6-week-old, 18–22 g) were purchased from Shanghai SLAC Laboratory Animal Co., Ltd (Shanghai, China).
In parallel with the improvement of living standard, Non-alcoholic fatty liver disease (NAFLD) becomes the most common liver disease around the world. Huazhi Fugan Granules (HZFGG) is a formula which is used to treating of fatty liver, Based on the data we studied, HZFGG may have potential as a therapeutic formula for the alleviation of NAFLD.
The aim of our study was to identifying the improvement of HZFGG on NAFLD and exploring the potential mechanisms.
MCD diet fed C57BL/6 mice once a day for 4 weeks to induce NAFLD model, HZFGG (10, 15, 20 g/kg) orally administered simultaneously. The serum levels of TC, TG, ALT, AST were detected. H&E and Oil Red O staining were used to observed the liver sections. TNF-α, IL-1β and Gpx were also detected. The expression levels of TLR4, MyD88, p-NF-κB, NF-κB, p-IκBa were measured by western blotting assay. The apoptosis of the liver tissues were detected by TUNEL assay.
HZFGG decreased the serum levels of TC, TG, ALT, AST in MCD-diet mice. HZFGG alleviated inflammation by decreasing the levels of TNF-α and IL-1β and ameliorated oxidative stress through increased the level of Gpx. HZFGG Attenuates MCD-induced liver steatosis and injury in mice. Hepatocyte apoptosis was decreased after HZFGG treatment. Furthermore, HZFGG also suppressed the expression levels of TLR4 and MyD88, subsequently, inhibited the phosphorylation of NF-κB and IκBa.
HZFGG can improved MCD induced hepatic injury through inhibited TLR4/NF-κB signaling pathway in NAFLD model.
En paralelo con la mejora de la calidad de vida, la enfermedad de hígado graso no alcohólico (EHGNA) se ha convertido en la enfermedad hepática más común a nivel mundial. Los gránulos de Huazhi Fugan (HZFGG) son una fórmula utilizada para tratar el hígado graso. Basándonos en los datos que estudiamos, HZFGG puede tener potencial de fórmula terapéutica para el alivio de EHGNA.
El objetivo de este estudio fue identificar la mejora de EHGNA con el uso de HZFGG y explorar los mecanismos potenciales.
Se alimentó con dieta deficiente en metionina y colina (MCD) a ratones C57BL/6 una vez al día durante cuatro semanas, para inducir el modelo EHGNA, administrándose simultáneamente HZFGG oral (10, 15, 20 g/kg). Se detectaron los niveles séricos de TC, TG, ALT y AST. Se utilizaron tinciones de hematoxilina-eosina y rojo aceite para observar las secciones hepáticas. También se detectaron TNF-α, IL-1β y Gpx. Se midieron los niveles de expresión de TLR4, MyD88, p-NF-κB, NF-κB y p-IκBa, mediante la técnica de Western blot. Se detectó la apoptosis de los tejidos hepáticos utilizando la técnica TUNEL.
HZFGG redujo los niveles séricos de TC, TG, ALT, AST en los ratones con dieta MCD. HZFGG alivió la inflamación reduciendo los niveles de TNF-α e IL-1β, y mejoró el estrés oxidativo a través del incremento del nivel de Gpx. HZFGG atenúa la esteatosis y lesión hepáticas inducidas por MCD. La apoptosis hepatocítica se redujo tras el tratamiento con HZFGG. Además, HZFGG suprimió también los niveles de expresión de TLR4 y MyD88, y posteriormente inhibió la fosforilación de NF-κB e IκBa.
HZFGG puede mejorar la lesión hepática inducida por MCD, mediante la inhibición de la vía de señalización de TLR4/NF-κB en un modelo de EHGNA.
Quercetin and non-alcoholic fatty liver disease: A review based on experimental data and bioinformatic analysis
2021, Food and Chemical ToxicologyQuercetin, a polyphenol widely present in the plant kingdom, has received great interest due to pleiotropic effects. As evidenced by animal and cellular studies, quercetin exerts hepatoprotection against non-alcoholic fatty liver disease (NAFLD), particularly in hepatic steatosis and hepatitis. Mechanically, various hypotheses of such protective effects have been actively proposed, including improving fatty acid metabolism, anti-inflammation, anti-oxidant, modulating gut microbiota and bile acid, etc. Here, the role of quercetin in NAFLD was summarized. With a particular focus on molecular mechanism, we comprehensively discussed the pathways of quercetin on NAFLD based on the analysis from Gene Expression Omnibus (GEO) database and experimental evidence.
The GLP-1R agonist liraglutide limits hepatic lipotoxicity and inflammatory response in mice fed a methionine-choline deficient diet
2021, Translational ResearchNonalcoholic fatty liver disease (NAFLD) is the most common hepatic disorder related to type 2 diabetes (T2D). The disease can evolve toward nonalcoholic steatohepatitis (NASH), a state of hepatic inflammation and fibrosis. There is presently no drug that effectively improves and/or prevents NAFLD/NASH/fibrosis. GLP-1 receptor agonists (GLP-1Ra) are effective in treating T2D. As with the endogenous gut incretins, GLP-1Ra potentiate glucose-induced insulin secretion. In addition, GLP-1Ra limit food intake and weight gain, additional beneficial properties in the context of obesity/insulin-resistance. Nevertheless, these pleiotropic effects of GLP-1Ra complicate the elucidation of their direct action on the liver. In the present study, we used the classical methionine-choline deficient (MCD) dietary model to investigate the potential direct hepatic actions of the GLP-1Ra liraglutide. A 4-week infusion of liraglutide (570 µg/kg/day) did not impact body weight, fat accretion or glycemic control in MCD-diet fed mice, confirming the suitability of this model for avoiding confounding factors. Liraglutide treatment did not prevent lipid deposition in the liver of MCD-fed mice but limited the accumulation of C16 and C24-ceramide/sphingomyelin species. In addition, liraglutide treatment alleviated hepatic inflammation (in particular accumulation of M1 pro-inflammatory macrophages) and initiation of fibrosis. Liraglutide also influenced the composition of gut microbiota induced by the MCD-diet. This included recovery of a normal Bacteroides proportion and, among the Erysipelotrichaceae family, a shift between Allobaculum and Turicibacter genera. In conclusion, liraglutide prevents accumulation of C16 and C24-ceramides/sphingomyelins species, inflammation and initiation of fibrosis in MCD-diet-fed mice liver, suggesting beneficial hepatic actions independent of weight loss and global hepatic steatosis.