RÉSUMÉ
Human pregnane X receptor (PXR) is critical for regulating the expression of key drug-metabolizing enzymes such as CYP3A and CYP2C. Our recent study revealed that treatment with rodent-specific PXR agonist pregnenolone-16α-carbonitrile (PCN) significantly induced hepatomegaly and promoted liver regeneration after two-thirds partial hepatectomy (PHx) in mice. However, it remains unclear whether PXR activation induces hepatomegaly and liver regeneration and simultaneously promotes metabolic function of the liver. Here, we investigated the metabolism activity of CYP1A2, CYP3A1/2 and CYP2C6/11 during PXR activation-induced liver enlargement and regeneration in rats after cocktail dosing of CYP probe drugs. For PCN-induced hepatomegaly, a notable increase in the metabolic activity of CYP3A1/2 and CYP2C6/11, as evidenced by the plasma exposure of probe substrates and the AUC ratios of the characteristic metabolites to its corresponding probe substrates. The metabolic activity of CYP1A2, CYP3A1/2 and CYP2C6/11 decreased significantly after PHx. However, PCN treatment obviously enhanced the metabolic activity of CYP2C6/11 and CYP3A1/2 in PHx rats. Furthermore, the protein expression levels of CYP3A1/2 and CYP2C6/11 in liver were up-regulated. Taken together, this study demonstrates that PXR activation not only induces hepatomegaly and liver regeneration in rats, but also promotes the protein expression and metabolic activity of the PXR downstream metabolizing enzymes such as CYP3A1/2 and CYP2C6/11 in the body.
Sujet(s)
Cytochrome P-450 CYP3A , Hépatomégalie , Régénération hépatique , Foie , Récepteur du prégnane X , Prégnénolone carbonitrile , Animaux , Récepteur du prégnane X/métabolisme , Récepteur du prégnane X/génétique , Régénération hépatique/effets des médicaments et des substances chimiques , Mâle , Cytochrome P-450 CYP3A/métabolisme , Prégnénolone carbonitrile/pharmacologie , Foie/métabolisme , Foie/enzymologie , Foie/effets des médicaments et des substances chimiques , Rats , Hépatomégalie/métabolisme , Hépatomégalie/anatomopathologie , Aryl hydrocarbon hydroxylases/métabolisme , Aryl hydrocarbon hydroxylases/génétique , Famille-2 de cytochromes P450/métabolisme , Famille-2 de cytochromes P450/génétique , Rat Sprague-Dawley , Cytochrome P-450 CYP1A2/métabolisme , Cytochrome P-450 CYP1A2/génétique , Steroid 16-alpha-hydroxylase/métabolisme , Steroid 16-alpha-hydroxylase/génétique , Steroid 12-alpha-hydroxylase/métabolisme , Steroid 12-alpha-hydroxylase/génétique , HépatectomieRÉSUMÉ
The activation of pregnane X receptor (PXR) or peroxisome proliferator-activated receptor α (PPARα) can induce liver enlargement. Recently, we reported that PXR or PPARα activation-induced hepatomegaly depends on yes-associated protein (YAP) signaling and is characterized by hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. However, it remains unclear whether PXR or PPARα activation-induced hepatomegaly can be reversed after the withdrawal of their agonists. In this study, we investigated the regression of enlarged liver to normal size following the withdrawal of PCN or WY-14643 (typical agonists of mouse PXR or PPARα) in C57BL/6 mice. The immunohistochemistry analysis of CTNNB1 and KI67 showed a reversal of hepatocyte size and a decrease in hepatocyte proliferation after the withdrawal of agonists. In details, the expression of PXR or PPARα downstream proteins (CYP3A11, CYP2B10, ACOX1, and CYP4A) and the expression of proliferation-related proteins (CCNA1, CCND1, and PCNA) returned to the normal levels. Furthermore, YAP and its downstream proteins (CTGF, CYR61, and ANKRD1) also restored to the normal states, which was consistent with the change in liver size. These findings demonstrate the reversibility of PXR or PPARα activation-induced hepatomegaly and provide new data for the safety of PXR and PPARα as drug targets.
Sujet(s)
Prolifération cellulaire , Hépatocytes , Hépatomégalie , Foie , Récepteur PPAR alpha , Récepteur du prégnane X , Pyrimidines , Protéines de signalisation YAP , Animaux , Mâle , Souris , Protéines adaptatrices de la transduction du signal/métabolisme , Aryl hydrocarbon hydroxylases , bêta-Caténine/métabolisme , Protéines du cycle cellulaire/métabolisme , Protéines du cycle cellulaire/génétique , Prolifération cellulaire/effets des médicaments et des substances chimiques , Cytochrome P-450 CYP3A , Cytochrome P-450 CYP4A/métabolisme , Cytochrome P-450 CYP4A/génétique , Famille-2 de cytochromes P450 , Famille-4 de cytochromes P450/génétique , Famille-4 de cytochromes P450/métabolisme , Hépatocytes/effets des médicaments et des substances chimiques , Hépatocytes/métabolisme , Hépatocytes/anatomopathologie , Hépatomégalie/induit chimiquement , Hépatomégalie/métabolisme , Hépatomégalie/anatomopathologie , Antigène KI-67/métabolisme , Foie/effets des médicaments et des substances chimiques , Foie/métabolisme , Foie/anatomopathologie , Protéines membranaires , Souris de lignée C57BL , Phosphoprotéines/métabolisme , Phosphoprotéines/génétique , Récepteur PPAR alpha/agonistes , Récepteur PPAR alpha/métabolisme , Récepteur du prégnane X/métabolisme , Récepteur du prégnane X/génétique , Pyrimidines/pharmacologie , Transduction du signal/effets des médicaments et des substances chimiques , Steroid hydroxylases , Protéines de signalisation YAP/métabolismeRÉSUMÉ
The hepatic deletion of Rbpjκ (RbpjF/F::AlbCre) in the mouse leads to exhibition of the Alagille syndrome phenotype during early postnatal liver development with hyperlipidemia and cholestasis due to attenuated disruption of NOTCH signaling. Given the roles of NRF2 signaling in the regulation of lipid metabolism and bile ductal formation, it was anticipated that these symptoms could be alleviated by enhancing NRF2 signaling in the RbpjF/F::AlbCre mouse by hepatic deletion of Keap1 in compound Keap1F/F::RbpjF/F::AlbCre mice. Unexpectedly, these mice developed higher hepatic and plasma cholesterol levels with more severe cholestatic liver damage during the pre-weaning period than in the RbpjF/F::AlbCre mice. In addition, hypercholesterolemia and hepatic damage were sustained throughout the growth period unlike in the RbpjF/F::AlbCre mouse. These enhanced abnormalities in lipid metabolism appear to be due to NRF2-dependent changes in gene expression related to cholesterol synthetic and subsequent bile acid production pathways. Notably, the hepatic expression of Cyp1A7 and Abcb11 genes involved in bile acid homeostasis was significantly reduced in Keap1F/F::RbpjF/F::AlbCre compared to RbpjF/F::AlbCre mice. The accumulation of liver cholesterol and the weakened capacity for bile excretion during the 3 pre-weaning weeks in the Keap1F/F::RbpjF/F::AlbCre mice may aggravate hepatocellular damage level caused by both excessive cholesterol and residual bile acid toxicity in hepatocytes. These results indicate that a tuned balance of NOTCH and NRF2 signaling is of biological importance for early liver development after birth.
Sujet(s)
Hépatomégalie , Hypercholestérolémie , Facteur de transcription CBF-1 , Protéine-1 de type kelch associée à ECH , Foie , Animaux , Protéine-1 de type kelch associée à ECH/métabolisme , Protéine-1 de type kelch associée à ECH/génétique , Souris , Hypercholestérolémie/génétique , Hypercholestérolémie/métabolisme , Hypercholestérolémie/anatomopathologie , Foie/métabolisme , Foie/anatomopathologie , Hépatomégalie/génétique , Hépatomégalie/métabolisme , Hépatomégalie/anatomopathologie , Facteur de transcription CBF-1/génétique , Facteur de transcription CBF-1/métabolisme , Facteur-2 apparenté à NF-E2/métabolisme , Facteur-2 apparenté à NF-E2/génétique , Métabolisme lipidique/génétique , Délétion de gène , Transduction du signal , Cholestérol/métabolisme , Souris knockout , Mâle , Acides et sels biliaires/métabolismeRÉSUMÉ
BACKGROUND AND AIMS: Systemic mastocytosis (SM) is characterized by the accumulation of atypical mast cells (MCs) in organs. Liver histology of SM has been marginally described and accurate histological classification is critical, given the consequences of aggressive SM diagnosis. We aimed to describe the histological features associated with liver SM using updated tools. METHODS: Using the database of the French Reference Centre for Mastocytosis, we retrospectively identified patients with a liver biopsy (LB) and a diagnosis of SM. All LB procedures were performed according to the local physician in charge and centrally reviewed by an expert pathologist. RESULTS: A total of 28 patients were included: 6 had indolent SM, 9 had aggressive SM, and 13 had SM with an associated hematologic neoplasm. Twenty-five (89%) patients presented hepatomegaly, and 19 (68%) had portal hypertension. The LB frequently showed slight sinusoid dilatation (82%). Fibrosis was observed in 3/6 indolent SM and in almost all advanced SM cases (21/22), but none of them showed cirrhosis. A high MC burden (>50 MCs/high-power field) was correlated with elevated blood alkaline phosphatase levels (p = .030). The presence of portal hypertension was associated with a higher mean fibrosis grade (1.6 vs. 0.8 in its absence; p = .026). In advanced SM, the presence of nodular regenerative hyperplasia (NRH) was associated with decreased overall survival (9.5 vs. 46.3 months, p = .002). CONCLUSIONS: MC infiltration induced polymorphic hepatic lesions and the degree of fibrosis is associated with portal hypertension. NRH identifies a poor prognosis subgroup of patients with advanced SM. Assessing liver histology can aid in SM prognostic evaluation.
Sujet(s)
Hépatomégalie , Foie , Mastocytose généralisée , Humains , Mastocytose généralisée/anatomopathologie , Mastocytose généralisée/complications , Études rétrospectives , Femelle , Foie/anatomopathologie , Mâle , Adulte d'âge moyen , Adulte , Biopsie , Hépatomégalie/anatomopathologie , Hépatomégalie/étiologie , Sujet âgé , Hypertension portale/anatomopathologie , Hypertension portale/étiologie , France , Cirrhose du foie/anatomopathologie , Mastocytes/anatomopathologie , Phosphatase alcaline/sang , PronosticRÉSUMÉ
BACKGROUND: Glycogen storage disease type IX is a rare disorder that can cause a wide variety of symptoms depending on the specific deficiency of the phosphorylase kinase enzyme and the organs it affects. CASE PRESENTATION: A 4-and-a-half-year-old Caucasian girl was referred to our clinic with a liver biopsy report indicating a diagnosis of glycogen storage disease. Prior to being referred to our clinic, the patient had been under the care of pediatric gastroenterologists. The patient's initial symptoms included chronic abdominal pain, constipation, and elevated liver transaminase. With the help of the pediatric gastroenterologists, cholestasis, Wilson disease, and autoimmune hepatitis were ruled out. Given that glycogen storage diseases type I and type III are the most common, we initially managed the patient with frequent feedings and a diet that included complex carbohydrates such as a corn starch supplement and a lactose restriction. Following an unfavorable growth velocity and hepatomegaly during the follow-up period, genetic analysis was conducted, which revealed a novel mutation of the phosphorylase kinase regulatory subunit beta gene- a c.C412T (P.Q138x) mutation. As the diagnosis of glycogen storage disease type IX was confirmed, the treatment regimen was altered to a high protein diet (more than 2 g/kg/day) and a low fat diet. CONCLUSION: Given the mild and varied clinical manifestations of glycogen storage disease type IX, it is possible for the diagnosis to be overlooked. It is important to consider glycogen storage disease type IX in children who present with unexplained hepatomegaly and elevated transaminase levels. Furthermore, due to the distinct management of glycogen storage disease type IX compared with glycogen storage disease type I and glycogen storage disease type III, genetic analysis is essential for an accurate diagnosis.
Sujet(s)
Glycogénose de type I , Glycogénose , Enfant d'âge préscolaire , Femelle , Humains , Douleur abdominale/étiologie , Constipation , Glycogénose/diagnostic , Glycogénose/génétique , Glycogénose/anatomopathologie , Glycogénose de type I/complications , Glycogénose de type I/diagnostic , Glycogénose de type I/génétique , Hépatomégalie/anatomopathologie , Iran , Foie/anatomopathologie , Mutation , Phosphorylase kinase/génétique , Phosphorylase kinase/métabolisme , TransaminasesRÉSUMÉ
Liver venous deprivation (LVD) is an emerging, minimally invasive strategy to induce rapid liver hypertrophy of the future liver remnant (FLR) before a major hepatectomy. LVD (aka "double vein embolization") entails same-session percutaneous embolization of the portal and hepatic veins of the planned liver resection. This report discusses LVD's utilization and technical challenges in managing a 49-year-old male with recurrent multifocal colorectal liver metastases (CRLM). The patient initially underwent neoadjuvant FOLFOX chemotherapy followed by a simultaneous laparoscopic sigmoid colectomy and liver surgery (microwave ablation of segment V and wedge resections of segment one and IVb), followed by completion of chemotherapy. The patient had an R0 resection with clear colon and liver surgical margins. Nine months after the initial surgery, the patient had a rise in tumor markers, and surveillance imaging demonstrated recurrence of liver metastases in segments I and V. LVD was performed by interventional radiology, which led to a 28% increase in FLR (segments II, III, and IV); initially measuring 464 cm3 before LVD and measuring 594 cm3 on post-procedure day 21. The patient underwent right hemi-hepatectomy and caudate resection on post-procedure day 29. The patient did not have any complications and was discharged on postoperative day 6. The patient remains disease-free with no evidence of recurrence at 12 months follow-up.
Sujet(s)
Embolisation thérapeutique , Tumeurs du foie , Mâle , Humains , Adulte d'âge moyen , Hépatectomie/méthodes , Veines hépatiques , Veine porte/chirurgie , Veine porte/anatomopathologie , Résultat thérapeutique , Foie/anatomopathologie , Tumeurs du foie/anatomopathologie , Embolisation thérapeutique/méthodes , Hépatomégalie/anatomopathologie , Hépatomégalie/chirurgie , LigatureRÉSUMÉ
The patient is a female infant, 4 months and 9 days old, who was admitted to the hospital due to recurrent fever, cough, and hepatomegaly for over a month. The patient was a healthy full-term infant with a normal birth history. At 2 months and 22 days after birth, she developed recurrent fever, cough, and respiratory distress. Chest imaging revealed diffuse bilateral lung lesions, and fiberoptic bronchoscopy showed interstitial changes in both lungs. These suggested the presence of interstitial lung disease. The patient also presented with hepatomegaly, anemia, hyperlipidemia, hypothyroidism, and malnutrition. Genetic testing indicated compound heterozygous variations in the MARS1 gene. This mutation can cause interstitial lung and liver disease, which is a severe rare disorder that typically manifests in infancy or early childhood. It is inherited in an autosomal recessive manner and characterized by early-onset respiratory insufficiency and liver disease in infants or young children. Since its first reported case in 2013, as of June 2023, only 38 related cases have been reported worldwide. This article reports the multidisciplinary diagnosis and treatment of interstitial lung and liver disease in an infant caused by MARS1 gene mutation.
Sujet(s)
Maladies du foie , Pneumopathies interstitielles , Femelle , Humains , Nourrisson , Toux , Hépatomégalie/anatomopathologie , Poumon/anatomopathologie , Pneumopathies interstitielles/diagnostic , Pneumopathies interstitielles/génétique , Pneumopathies interstitielles/anatomopathologie , MutationRÉSUMÉ
Research on Alzheimer's disease (AD) has classically focused on alterations that occur in the brain and their intra- and extracellular neuropathological hallmarks. However, the oxi-inflammation hypothesis of aging may also play a role in neuroimmunoendocrine dysregulation and the disease's pathophysiology, where the liver emerges as a target organ due to its implication in regulating metabolism and supporting the immune system. In the present work, we demonstrate organ (hepatomegaly), tissue (histopathological amyloidosis), and cellular oxidative stress (decreased glutathione peroxidase and increased glutathione reductase enzymatic activities) and inflammation (increased IL-6 and TNFð¼) as hallmarks of hepatic dysfunction in 16-month-old male and female 3xTg-AD mice at advanced stages of the disease, and as compared to age- and sex-matched non-transgenic (NTg) counterparts. Moreover, liver-brain axis alterations were found through behavioral (increased neophobia) and HPA axis correlations that were enhanced under forced isolation. In all cases, sex (male) and isolation (naturalistic and forced) were determinants of worse hepatomegaly, oxidative stress, and inflammation progression. In addition, obesity in old male NTg mice was translated into a worse steatosis grade. Further research is underway determine whether these alterations could correlate with a worse disease prognosis and to establish potential integrative system targets for AD research.
Sujet(s)
Maladie d'Alzheimer , Souris , Mâle , Femelle , Animaux , Maladie d'Alzheimer/métabolisme , Axe hypothalamohypophysaire/métabolisme , Hépatomégalie/métabolisme , Hépatomégalie/anatomopathologie , Axe hypophyso-surrénalien/métabolisme , Encéphale/métabolisme , Vieillissement/métabolisme , Souris transgéniques , Inflammation/anatomopathologie , Obésité/métabolismeRÉSUMÉ
BACKGROUND AND AIM: Amyloidosis is a systemic disease characterized by extracellular deposition of amyloid protein, most commonly in the heart and kidney. Hepatic amyloidosis is a rare form of presentation that ranges from mild hepatomegaly and altered liver biochemical tests to acute liver failure. The aims of this study were to evaluate the prevalence of amyloidosis in patients undergoing liver biopsy and describe its main clinical characteristics and prognostic impact. METHODS: A retrospective analysis of all patients with a histological diagnosis of hepatic amyloidosis between January 2010 and December 2019 was performed. MAJOR RESULTS: A total of 7 patients were identified from a total of 1773 liver biopsy procedures (0.4%), with a female predominance (6/7) and median age of diagnosis of 62 years. The most common clinical manifestations included hepatomegaly (4/7), jaundice (2/7) and peripheral edema (2/7), whereas 3/7 patients were asymptomatic. Every patient presented abnormalities in liver biochemical tests, more commonly cholestasis (6/7), but also cytolysis (4/7) or hyperbilirubinemia (2/7). Abnormal imaging findings included hepatomegaly, steatosis or parenchymal heterogeneity. In most patients (5/7), other organs were involved, most commonly with nephrotic syndrome (3/7) and infiltrative cardiomyopathy (3/7). The most common type was AA amyloidosis (3/7) followed by AL amyloidosis (2/7). The 1-year mortality rate was 43% and the median survival was 24 months. CONCLUSIONS: We report a low prevalence (0.4%) of amyloidosis among patients undergoing liver biopsy. Although rare, hepatic amyloidosis is associated with a dismal prognosis and a high index of suspicion is crucial to achieve an early diagnosis. .
Sujet(s)
Amyloïdose , Défaillance hépatique aigüe , Humains , Femelle , Adulte d'âge moyen , Mâle , Hépatomégalie/complications , Hépatomégalie/diagnostic , Hépatomégalie/anatomopathologie , Études transversales , Études rétrospectives , Amyloïdose/complicationsRÉSUMÉ
The patient is a female infant, 4 months and 9 days old, who was admitted to the hospital due to recurrent fever, cough, and hepatomegaly for over a month. The patient was a healthy full-term infant with a normal birth history. At 2 months and 22 days after birth, she developed recurrent fever, cough, and respiratory distress. Chest imaging revealed diffuse bilateral lung lesions, and fiberoptic bronchoscopy showed interstitial changes in both lungs. These suggested the presence of interstitial lung disease. The patient also presented with hepatomegaly, anemia, hyperlipidemia, hypothyroidism, and malnutrition. Genetic testing indicated compound heterozygous variations in the MARS1 gene. This mutation can cause interstitial lung and liver disease, which is a severe rare disorder that typically manifests in infancy or early childhood. It is inherited in an autosomal recessive manner and characterized by early-onset respiratory insufficiency and liver disease in infants or young children. Since its first reported case in 2013, as of June 2023, only 38 related cases have been reported worldwide. This article reports the multidisciplinary diagnosis and treatment of interstitial lung and liver disease in an infant caused by MARS1 gene mutation.
Sujet(s)
Femelle , Humains , Nourrisson , Toux , Hépatomégalie/anatomopathologie , Maladies du foie , Poumon/anatomopathologie , Pneumopathies interstitielles/anatomopathologie , MutationRÉSUMÉ
Peroxisome proliferator-activated receptor α (PPARα) is closely related to lipid metabolism and various liver diseases. Previous study has shown that chronic treatment with PPARα agonist WY-14643 can induce liver tumors in rodents, but the implications of this process on lipid metabolism in the liver remain unclear. Thus, this study aimed to explore the influences of chronic treatment with WY-14643 on the liver and hepatic lipid metabolism. Wild-type C57BL/6 mice were treated with WY-14643 (100 mg/kg/week, i.p.) or corn oil, and liver and serum samples were collected for testing after 42 weeks of WY-14643 treatment. The results showed that hepatomegaly, liver tumors with mild liver injury, and hepatocyte proliferation were induced in mice treated with WY-14643. The mRNA and protein expression levels of PPARα downstream targets acyl-CoA oxidase 1 and cytochrome P450 4A were significantly upregulated in the WY-14643-treated group. Lipidomic analysis revealed that chronic treatment with WY-14643 disturbed lipid homeostasis, especially triglycerides (TGs), which were significantly elevated after WY-14643 treatment. Moreover, TG homeostasis-related genes were significantly increased in the WY-14643-treated group. In conclusion, these findings demonstrated that hepatomegaly and liver tumors induced by chronic treatment with WY-14643 in mice are accompanied by hepatocyte proliferation and TG accumulation. SIGNIFICANCE STATEMENT: The present study clearly demonstrated that sustained peroxisome proliferator-activated receptor α (PPARα) activation by chronic treatment with WY-14643 induces hepatomegaly and liver tumors with triglyceride accumulation by regulating lipid homeostasis-related genes in mice. These findings may help to clarify the influences of sustained PPARα activation on liver lipid homeostasis and provide data for the clinically rational use of drugs that can activate PPARα.
Sujet(s)
Tumeurs du foie , Récepteur PPAR alpha , Souris , Animaux , Récepteur PPAR alpha/génétique , Récepteur PPAR alpha/métabolisme , Triglycéride/métabolisme , Hépatomégalie/induit chimiquement , Hépatomégalie/anatomopathologie , Souris knockout , Souris de lignée C57BL , Foie/métabolisme , Tumeurs du foie/métabolisme , Carcinogenèse/métabolisme , Carcinogenèse/anatomopathologieRÉSUMÉ
We report a case of a young girl of South Asian descent presented with faltering growth, hepatomegaly, hypertriglyceridaemia and raised transaminases. Subsequent ultrasound scans identified fatty infiltration in her liver, and a liver biopsy showed fibrosis and steatosis. The patient's serum triglycerides normalised without intervention by the age of 28 months. At age 6, whole-exome sequencing of the patient's genome identified novel homozygous variants in the glycerol-3-phosphate dehydrogenase 1 (GPD1) gene, GPD1 c.500G>A (p.Gly167Asp), leading to a diagnosis of GPD1 deficiency.
Sujet(s)
Hypertriglycéridémie , Stéatose hépatique non alcoolique , Enfant , Enfant d'âge préscolaire , Femelle , Hépatomégalie/étiologie , Hépatomégalie/anatomopathologie , Homozygote , Humains , Hypertriglycéridémie/complications , Hypertriglycéridémie/génétique , Foie/imagerie diagnostique , Foie/anatomopathologie , Cirrhose du foie/anatomopathologie , Stéatose hépatique non alcoolique/complications , Stéatose hépatique non alcoolique/génétiqueSujet(s)
Hémochromatose , Maladies des chevaux , Animaux , Biopsie/médecine vétérinaire , Hémochromatose/diagnostic , Hémochromatose/anatomopathologie , Hémochromatose/médecine vétérinaire , Hépatomégalie/anatomopathologie , Hépatomégalie/médecine vétérinaire , Maladies des chevaux/diagnostic , Maladies des chevaux/anatomopathologie , Equus caballus , Foie/anatomopathologieRÉSUMÉ
Elemicin (Ele) is a constituent of natural alkenylbenzene present in many foods and herbs. Ele exposure could induce hepatomegaly and hepatosteatosis. However, the role of gut microbiota in Ele-induced hepatotoxicity remains unclear. Here, the mice were treated with 200 mg/kg/day of Ele for 4 weeks with or without depletion of gut microbiota by antibiotics cocktail treatment. The mice treated with Ele showed enlargement of liver and slight hepatosteatosis, accompanied by higher levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG). Ele could also shift the structure of fecal microbiota and increase the richness. Functional prediction of the microbiota revealed the enrichment of non-alcoholic fatty liver disease pathway upon Ele exposure. Compared with control group, Patescibacteria and Epsilonbacteraeota were significantly enriched at the phylum level upon Ele treatment. A total of 20 genera were significant with respect specifically to Ele exposure, including decreased Alistipes and elevated Ruminiclostridium_9 and Gordonibacter. Among them, 13 retained significant associations with ALT and TG by Spearman correlation test, 4 were correlated with AST. Further MaAsLin analysis revealed that ALT was associated with 4 differentially abundant genera, such as Alistipes and Ruminiclostridium_9 and Gordonibacter. In addition, only Alistipes was significantly correlated with serum TG. Intriguingly, depletion of the microbiota significantly attenuated hepatosteatosis, restore increased ALT, AST and TG and inhibit the expression of genes involved in de novo lipogenesis and adipocyte differentiation, such as Fasn, ADIPOQ and leptin. Collectively, depletion of gut microbiota protected against Ele induced aberrant lipid metabolism in mice.
Sujet(s)
Bactéries/effets des médicaments et des substances chimiques , Lésions hépatiques dues aux substances/étiologie , Stéatose hépatique/induit chimiquement , Microbiome gastro-intestinal/effets des médicaments et des substances chimiques , Hépatomégalie/induit chimiquement , Métabolisme lipidique/effets des médicaments et des substances chimiques , Foie/effets des médicaments et des substances chimiques , Pyrogallol/analogues et dérivés , Alanine transaminase/sang , Animaux , Aspartate aminotransferases/sang , Bactéries/croissance et développement , Bactéries/métabolisme , Marqueurs biologiques/sang , Lésions hépatiques dues aux substances/métabolisme , Lésions hépatiques dues aux substances/microbiologie , Lésions hépatiques dues aux substances/anatomopathologie , Dysbiose , Stéatose hépatique/métabolisme , Stéatose hépatique/microbiologie , Stéatose hépatique/anatomopathologie , Hépatomégalie/métabolisme , Hépatomégalie/microbiologie , Hépatomégalie/anatomopathologie , Foie/métabolisme , Foie/anatomopathologie , Souris de lignée C57BL , Pyrogallol/toxicité , Triglycéride/sangRÉSUMÉ
RNF43/ZNRF3 negatively regulate WNT signalling. Both genes are mutated in several types of cancers, however, their contribution to liver disease is unknown. Here we describe that hepatocyte-specific loss of Rnf43/Znrf3 results in steatohepatitis and in increase in unsaturated lipids, in the absence of dietary fat supplementation. Upon injury, Rnf43/Znrf3 deletion results in defective hepatocyte regeneration and liver cancer, caused by an imbalance between differentiation/proliferation. Using hepatocyte-, hepatoblast- and ductal cell-derived organoids we demonstrate that the differentiation defects and lipid alterations are, in part, cell-autonomous. Interestingly, ZNRF3 mutant liver cancer patients present poorer prognosis, altered hepatic lipid metabolism and steatohepatitis/NASH signatures. Our results imply that RNF43/ZNRF3 predispose to liver cancer by controlling the proliferative/differentiation and lipid metabolic state of hepatocytes. Both mechanisms combined facilitate the progression towards malignancy. Our findings might aid on the management of those RNF43/ZNRF3 mutated individuals at risk of developing fatty liver and/or liver cancer.
Sujet(s)
Carcinome hépatocellulaire/métabolisme , Tumeurs du foie/métabolisme , Régénération hépatique , Foie/métabolisme , Ubiquitin-protein ligases/métabolisme , Adulte , Animaux , Carcinome hépatocellulaire/anatomopathologie , Différenciation cellulaire , Prolifération cellulaire , Stéatose hépatique/anatomopathologie , Délétion de gène , Régulation de l'expression des gènes , Hépatocytes/métabolisme , Hépatocytes/anatomopathologie , Hépatomégalie/anatomopathologie , Humains , Hyperplasie , Gouttelettes lipidiques/métabolisme , Métabolisme lipidique/génétique , Lipidomique , Foie/anatomopathologie , Tumeurs du foie/anatomopathologie , Souris , PronosticRÉSUMÉ
CASE PRESENTATION: We report a case of severe glycogenic hepatopathy in a 17-year-old boy with poorly controlled type 1 diabetes. On presentation, major findings included unexplained pronounced hepatomegaly and increased liver enzymes, ferritin, and triglycerides. Histology and electron microscopy evaluation showed severe glycogen storage, steatosis, and signs of fibrosis, resembling the histomorphological findings of Mauriac syndrome. After information about the nature of the disease and intensification of insulin therapy with insulin pump, liver enzymes, ferritin, and triglycerides normalized within 1 month. CONCLUSION: Glycogenic hepatopathy is a rare but important potential complication in poorly controlled juvenile diabetic patients. With improved metabolic control, it is fully reversible.
Sujet(s)
Diabète de type 1 , Maladies du foie , Adolescent , Diabète de type 1/complications , Diabète de type 1/diagnostic , Diabète de type 1/traitement médicamenteux , Glycogène/métabolisme , Hépatomégalie/complications , Hépatomégalie/anatomopathologie , Humains , Maladies du foie/complications , Maladies du foie/diagnostic , Maladies du foie/anatomopathologie , MâleRÉSUMÉ
OBJECTIVES: Glycogen storage diseases (GSDs) are heterogeneous disorders caused by various enzyme deficiencies. GSD type IX α2, the most common subtype of GSD IX, is due to a deficiency of hepatic phosphorylase kinase. Herein we will report a novel mutation in this disease with an unusual presentation. CASE PRESENTATION: we describe a 3-year-old boy who suffered from hepatomegaly, fatty liver disease, and liver cirrhosis. The cause of cirrhosis at a young age was unknown based on the laboratory data and liver biopsy, so we performed a targeted-gene sequencing (TGS) covering 450 genes involved in inborn metabolic diseases consisting of glycogen storage disorders genes with hepatic involvement. He was found out to have a rare novel pathogenic variant in the PHKA2 gene. CONCLUSIONS: This novel variant c.2226+2T > C expands the mutational spectrum of the PHKA2 gene. Also, severe liver damage (cirrhosis) in patients with GSD- IX α2 has rarely been reported, which needs further discussion. We hypothesize that unidentified PHKA2 variants may be a rare cause of childhood liver cirrhosis.
Sujet(s)
Glycogénose , Phosphorylase kinase , Enfant d'âge préscolaire , Glycogénose/complications , Glycogénose/génétique , Hépatomégalie/anatomopathologie , Humains , Foie , Cirrhose du foie/complications , Cirrhose du foie/génétique , Cirrhose du foie/métabolisme , Mâle , Mutation , Phosphorylase kinase/génétiqueRÉSUMÉ
BACKGROUND AND AIMS: Peroxisome proliferator-activated receptor α (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy homeostasis. PPARα activation induces hepatomegaly and plays an important role in liver regeneration, but the underlying mechanisms remain unclear. APPROACH AND RESULTS: In this study, the effect of PPARα activation on liver enlargement and regeneration was investigated in several strains of genetically modified mice. PPARα activation by the specific agonist WY-14643 significantly induced hepatomegaly and accelerated liver regeneration after 70% partial hepatectomy (PHx) in wild-type mice and Pparafl/fl mice, while these effects were abolished in hepatocyte-specific Ppara-deficient (PparaΔHep ) mice. Moreover, PPARα activation promoted hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Mechanistically, PPARα activation regulated expression of yes-associated protein (YAP) and its downstream targets (connective tissue growth factor, cysteine-rich angiogenic inducer 61, and ankyrin repeat domain 1) as well as proliferation-related proteins (cyclins A1, D1, and E1). Binding of YAP with the PPARα E domain was critical for the interaction between YAP and PPARα. PPARα activation further induced nuclear translocation of YAP. Disruption of the YAP-transcriptional enhancer factor domain family member (TEAD) association significantly suppressed PPARα-induced hepatomegaly and hepatocyte enlargement and proliferation. In addition, PPARα failed to induce hepatomegaly in adeno-associated virus-Yap short hairpin RNA-treated mice and liver-specific Yap-deficient mice. Blockade of YAP signaling abolished PPARα-induced hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. CONCLUSIONS: This study revealed a function of PPARα in regulating liver size and liver regeneration through activation of the YAP-TEAD signaling pathway. These findings have implications for understanding the physiological functions of PPARα and suggest its potential for manipulation of liver size and liver regeneration.
Sujet(s)
Hépatomégalie/génétique , Régénération hépatique/génétique , Récepteur PPAR alpha/métabolisme , Facteurs de transcription à domaine TEA/métabolisme , Protéines de signalisation YAP/métabolisme , Animaux , Prolifération cellulaire/effets des médicaments et des substances chimiques , Prolifération cellulaire/génétique , Modèles animaux de maladie humaine , Régulation de l'expression des gènes/effets des médicaments et des substances chimiques , Techniques de knock-down de gènes , Hépatectomie/effets indésirables , Hépatocytes/anatomopathologie , Hépatomégalie/anatomopathologie , Humains , Foie/anatomopathologie , Foie/chirurgie , Régénération hépatique/effets des médicaments et des substances chimiques , Mâle , Souris , Souris transgéniques , Récepteur PPAR alpha/agonistes , Pyrimidines/administration et posologie , Transduction du signal/effets des médicaments et des substances chimiques , Transduction du signal/génétique , Protéines de signalisation YAP/génétiqueRÉSUMÉ
Perfluorooctanoic acid (PFOA) can accumulate in the livers of humans and animals via the food chain, resulting into liver injury, which is closely related to intestinal flora dysbiosis. Gastrodin has been reported to have hepatoprotective effect. However, whether gastrodin can alleviate PFOA-induced liver injury via modulating gut microbiota remains unclear. Herein, a PFOA-induced liver injury model was established by gavage of PFOA (5 mg/kg body weight) in 2% Tween 80 solution once daily for 6 weeks in mice, and then gastrodin in saline (20 mg/kg body weight) was used once daily for 8 weeks to treat liver damage. The biochemical indexes associated with liver function, oxidative stress, and inflammatory factors were examined. Hematoxylin-eosin staining was used to determine the liver histopathological changes. Besides, 16S rRNA sequencing was used to analyze the difference of gut microbiota between the model and treatment groups. The results showed that gastrodin significantly improved the oxidative stress caused by PFOA. Intestinal flora analysis showed that gastrodin treatment significantly increased the relative abundance of probiotics, such as Lactobacillus, Bifidobacterium, and Bacteroides, while the harmful bacteria, including Desulfovibrio were decreased. Gastrodin treatment also significantly increased the level of short-chain fatty acids (SCFAs), such as butyric acid and isobutyric acid. Spearman correlation analysis showed that the composition changes of gut microbiota and SCFAs increase were both beneficial to alleviate the liver injury caused by PFOA. To sum up, gastrodin can effectively alleviate PFOA-induced liver injury through regulating gut microbiota composition.
Sujet(s)
Alcools benzyliques/pharmacologie , Alcools benzyliques/toxicité , Microbiome gastro-intestinal , Glucosides/pharmacologie , Glucosides/toxicité , Foie/traumatismes , Foie/microbiologie , Animaux , Caprylates , Caecum/métabolisme , Cytokines/sang , Modèles animaux de maladie humaine , Acides gras volatils/métabolisme , Fluorocarbones , Microbiome gastro-intestinal/effets des médicaments et des substances chimiques , Hépatomégalie/sang , Hépatomégalie/anatomopathologie , Médiateurs de l'inflammation/sang , Foie/effets des médicaments et des substances chimiques , Foie/anatomopathologie , Mâle , Souris de lignée C57BL , Stress oxydatif/effets des médicaments et des substances chimiques , Phylogenèse , Agents protecteurs/pharmacologieRÉSUMÉ
The liver is a crucial center in the regulation of energy homeostasis under starvation. Although downregulation of mammalian target of rapamycin complex 1 (mTORC1) has been reported to play pivotal roles in the starvation responses, the underpinning mechanisms in particular upstream factors that downregulate mTORC1 remain largely unknown. To identify genetic variants that cause liver energy disorders during starvation, we conduct a zebrafish forward genetic screen. We identify a liver hulk (lvh) mutant with normal liver under feeding, but exhibiting liver hypertrophy under fasting. The hepatomegaly in lvh is caused by enlarged hepatocyte size and leads to liver dysfunction as well as limited tolerance to starvation. Positional cloning reveals that lvh phenotypes are caused by mutation in the ftcd gene, which encodes the formimidoyltransferase cyclodeaminase (FTCD). Further studies show that in response to starvation, the phosphorylated ribosomal S6 protein (p-RS6), a downstream effector of mTORC1, becomes downregulated in the wild-type liver, but remains at high level in lvh. Inhibition of mTORC1 by rapamycin rescues the hepatomegaly and liver dysfunction of lvh. Thus, we characterize the roles of FTCD in starvation response, which acts as an important upstream factor to downregulate mTORC1, thus preventing liver hypertrophy and dysfunction.