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Hepatology (Baltimore, Md.) Jan 2022Peroxisome proliferator-activated receptor α (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy...
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 Ppara mice, while these effects were abolished in hepatocyte-specific Ppara-deficient (Ppara ) 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.
Topics: Animals; Cell Proliferation; Disease Models, Animal; Gene Expression Regulation; Gene Knockdown Techniques; Hepatectomy; Hepatocytes; Hepatomegaly; Humans; Liver; Liver Regeneration; Male; Mice; Mice, Transgenic; PPAR alpha; Pyrimidines; Signal Transduction; TEA Domain Transcription Factors; YAP-Signaling Proteins
PubMed: 34387904
DOI: 10.1002/hep.32105 -
Cell Metabolism Jun 2023Insulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen and lipids. How these activities are coordinated to prevent hypoglycemia and...
Insulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen and lipids. How these activities are coordinated to prevent hypoglycemia and hepatosteatosis is unclear. Fructose-1,6-bisphosphatase (FBP1) is rate controlling for gluconeogenesis. However, inborn human FBP1 deficiency does not cause hypoglycemia unless accompanied by fasting or starvation, which also trigger paradoxical hepatomegaly, hepatosteatosis, and hyperlipidemia. Hepatocyte FBP1-ablated mice exhibit identical fasting-conditional pathologies along with AKT hyperactivation, whose inhibition reversed hepatomegaly, hepatosteatosis, and hyperlipidemia but not hypoglycemia. Surprisingly, fasting-mediated AKT hyperactivation is insulin dependent. Independently of its catalytic activity, FBP1 prevents insulin hyperresponsiveness by forming a stable complex with AKT, PP2A-C, and aldolase B (ALDOB), which specifically accelerates AKT dephosphorylation. Enhanced by fasting and weakened by elevated insulin, FBP1:PP2A-C:ALDOB:AKT complex formation, which is disrupted by human FBP1 deficiency mutations or a C-terminal FBP1 truncation, prevents insulin-triggered liver pathologies and maintains lipid and glucose homeostasis. Conversely, an FBP1-derived complex disrupting peptide reverses diet-induced insulin resistance.
Topics: Humans; Mice; Animals; Fructose; Fructose-Bisphosphatase; Proto-Oncogene Proteins c-akt; Insulin; Hepatomegaly; Hypoglycemia; Glucose
PubMed: 37084733
DOI: 10.1016/j.cmet.2023.03.021 -
Archives of Disease in Childhood Oct 2016Leukaemia is the most common cancer of childhood, accounting for a third of cases. In order to assist clinicians in its early detection, we systematically reviewed all... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Leukaemia is the most common cancer of childhood, accounting for a third of cases. In order to assist clinicians in its early detection, we systematically reviewed all existing data on its clinical presentation and estimated the frequency of signs and symptoms presenting at or prior to diagnosis.
DESIGN
We searched MEDLINE and EMBASE for all studies describing presenting features of leukaemia in children (0-18 years) without date or language restriction, and, when appropriate, meta-analysed data from the included studies.
RESULTS
We screened 12 303 abstracts for eligibility and included 33 studies (n=3084) in the analysis. All were cohort studies without control groups. 95 presenting signs and symptoms were identified and ranked according to frequency. Five features were present in >50% of children: hepatomegaly (64%), splenomegaly (61%), pallor (54%), fever (53%) and bruising (52%). An additional eight features were present in a third to a half of children: recurrent infections (49%), fatigue (46%), limb pain (43%), hepatosplenomegaly (42%), bruising/petechiae (42%), lymphadenopathy (41%), bleeding tendency (38%) and rash (35%). 6% of children were asymptomatic on diagnosis.
CONCLUSIONS
Over 50% of children with leukaemia have palpable livers, palpable spleens, pallor, fever or bruising on diagnosis. Abdominal symptoms such as anorexia, weight loss, abdominal pain and abdominal distension are common. Musculoskeletal symptoms such as limp and joint pain also feature prominently. Children with unexplained illness require a thorough history and focused clinical examination, which should include abdominal palpation, palpation for lymphadenopathy and careful scrutiny of the skin. Occurrence of multiple symptoms and signs should alert clinicians to possible leukaemia.
Topics: Abdominal Pain; Adolescent; Child; Child, Preschool; Contusions; Early Detection of Cancer; Exanthema; Fever; Gastrointestinal Diseases; Hemorrhage; Hepatomegaly; Humans; Infant; Infant, Newborn; Infections; Leukemia; Musculoskeletal Diseases; Recurrence; Skin Diseases; Splenomegaly
PubMed: 27647842
DOI: 10.1136/archdischild-2016-311251 -
Nature May 2017Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing β-catenin-dependent signalling through the Wnt receptor...
Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing β-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors. As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD-LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic β-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine.
Topics: Animals; Cell Differentiation; Cell Lineage; Cell Proliferation; Frizzled Receptors; HEK293 Cells; Hepatocytes; Hepatomegaly; Humans; Hydrophobic and Hydrophilic Interactions; Intestines; Ligands; Liver; Low Density Lipoprotein Receptor-Related Protein-5; Low Density Lipoprotein Receptor-Related Protein-6; Mesenchymal Stem Cells; Mice; Models, Molecular; Organoids; Protein Multimerization; Signal Transduction; Solubility; Tissue Culture Techniques; Wnt Proteins; Wnt Signaling Pathway; beta Catenin
PubMed: 28467818
DOI: 10.1038/nature22306 -
Pharmacological Research Feb 2023Pregnane X receptor (PXR) plays an important role in the regulation of metabolic homeostasis. Yes-associated protein (YAP) is a critical regulator of liver size and...
Pregnane X receptor (PXR) plays an important role in the regulation of metabolic homeostasis. Yes-associated protein (YAP) is a critical regulator of liver size and liver regeneration. Recently, we reported that PXR-induced liver enlargement and regeneration depend on YAP signalling, but the underlying mechanisms remain unclear. This study aimed to reveal how PXR regulates or interacts with YAP signalling during PXR-induced hepatomegaly and liver regeneration. Immunoprecipitation (IP), Co-IP and GST pull-down assays were performed in vitro to reveal the regulatory mechanisms involved in the PXR-YAP interaction. The roles of YAP-TEAD binding and Sirt2-driven deacetylation and polyubiquitination of YAP were further investigated in vitro and in vivo. The results showed that the ligand-binding domain (LBD) of PXR and the WW domain of YAP were critical for the PXR-YAP interaction. Furthermore, disruption of the YAP-TEAD interaction using the binding inhibitor verteporfin significantly decreased PXR-induced liver enlargement and regeneration after 70 % partial hepatectomy (PHx). Mechanistically, PXR activation significantly decreased YAP acetylation, which was interrupted by the sirtuin inhibitor nicotinamide (NAM). In addition, p300-induced YAP acetylation contributed to K48-linked YAP ubiquitination. Interestingly, PXR activation remarkably inhibited K48-linked YAP ubiquitination while inducing K63-linked YAP polyubiquitination. Sirt2 interference abolished the deacetylation and K63-linked polyubiquitination of YAP, suggesting that the PXR-induced deacetylation and polyubiquitination of YAP are Sirt2 dependent. Taken together, this study demonstrates that PXR induce liver enlargement and regeneration via the regulation of YAP acetylation and ubiquitination and YAP-TEAD binding, providing evidences for using PXR as potential target to promote hepatic development and liver repair.
Topics: Animals; Mice; Hepatomegaly; Pregnane X Receptor; Sirtuin 2; Ubiquitination; YAP-Signaling Proteins; Liver
PubMed: 36657504
DOI: 10.1016/j.phrs.2023.106666 -
Genes & Development Jun 2012The Drosophila TEAD ortholog Scalloped is required for Yki-mediated overgrowth but is largely dispensable for normal tissue growth, suggesting that its mammalian...
The Drosophila TEAD ortholog Scalloped is required for Yki-mediated overgrowth but is largely dispensable for normal tissue growth, suggesting that its mammalian counterpart may be exploited for selective inhibition of oncogenic growth driven by YAP hyperactivation. Here we test this hypothesis genetically and pharmacologically. We show that a dominant-negative TEAD molecule does not perturb normal liver growth but potently suppresses hepatomegaly/tumorigenesis resulting from YAP overexpression or Neurofibromin 2 (NF2)/Merlin inactivation. We further identify verteporfin as a small molecule that inhibits TEAD-YAP association and YAP-induced liver overgrowth. These findings provide proof of principle that inhibiting TEAD-YAP interactions is a pharmacologically viable strategy against the YAP oncoprotein.
Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Cycle Proteins; Cell Transformation, Neoplastic; DNA-Binding Proteins; Genes, Dominant; HEK293 Cells; Hepatomegaly; Humans; Liver; Mice; Mice, Transgenic; Multiprotein Complexes; Neurofibromin 2; Phenotype; Phosphoproteins; Porphyrins; Protein Binding; TEA Domain Transcription Factors; Transcription Factors; Verteporfin; YAP-Signaling Proteins
PubMed: 22677547
DOI: 10.1101/gad.192856.112 -
Biochimica Et Biophysica Acta.... Oct 2018Glycogen disease type III (GSDIII), a rare incurable autosomal recessive disorder due to glycogen debranching enzyme deficiency, presents with liver, heart and skeletal...
Glycogen disease type III (GSDIII), a rare incurable autosomal recessive disorder due to glycogen debranching enzyme deficiency, presents with liver, heart and skeletal muscle impairment, hepatomegaly and ketotic hypoglycemia. Muscle weakness usually worsens to fixed myopathy and cardiac involvement may present in about half of the patients during disease. Management relies on careful follow-up of symptoms and diet. No common agreement was reached on sugar restriction and treatment in adulthood. We administered two dietary regimens differing in their protein and carbohydrate content, high-protein (HPD) and high-protein/glucose-free (GFD), to our mouse model of GSDIII, starting at one month of age. Mice were monitored, either by histological, biochemical and molecular analysis and motor functional tests, until 10 months of age. GFD ameliorated muscle performance up to 10 months of age, while HPD showed little improvement only in young mice. In GFD mice, a decreased muscle glycogen content and fiber vacuolization was observed, even in aged animals indicating a protective role of proteins against skeletal muscle degeneration, at least in some districts. Hepatomegaly was reduced by about 20%. Moreover, the long-term administration of GFD did not worsen serum parameters even after eight months of high-protein diet. A decreased phosphofructokinase and pyruvate kinase activities and an increased expression of Krebs cycle and gluconeogenesis genes were seen in the liver of GFD fed mice. Our data show that the concurrent use of proteins and a strictly controlled glucose supply could reduce muscle wasting, and indicate a better metabolic control in mice with a glucose-free/high-protein diet.
Topics: Animals; Citric Acid Cycle; Diet, High-Protein; Diet, High-Protein Low-Carbohydrate; Disease Models, Animal; Female; Glycogen Storage Disease Type III; Hepatomegaly; Male; Mice; Mice, Knockout; Muscle, Skeletal; Phosphofructokinases; Physical Conditioning, Animal; Pyruvate Kinase; Treatment Outcome
PubMed: 30076962
DOI: 10.1016/j.bbadis.2018.07.031 -
Journal of Hepatology Jun 2020Hepatomegaly can be triggered by insulin and insulin-unrelated etiologies. Insulin acts via AKT, but how other challenges cause hepatomegaly is unknown.
BACKGROUND & AIMS
Hepatomegaly can be triggered by insulin and insulin-unrelated etiologies. Insulin acts via AKT, but how other challenges cause hepatomegaly is unknown.
METHODS
Since many hepatomegaly-inducing toxicants and stressors activate NRF2, we examined the effect of NRF2 activation on liver size and metabolism using a conditional allele encoding a constitutively active NRF2 variant to generate Nrf2 mice in which NRF2 is selectively activated in hepatocytes. We also used adenoviruses encoding variants of the autophagy adaptor p62/SQSTM1, which activates liver NRF2, as well as liver-specific ATG7-deficient mice (Atg7) and liver specimens from patients with hepatic sinusoidal obstruction syndrome (HSOS) and autoimmune hepatitis (AIH). RNA sequencing and cell signaling analyses were used to determine cellular consequences of NRF2 activation and diverse histological analyses were used to study effects of the different manipulations on liver and systemic pathophysiology.
RESULTS
Hepatocyte-specific NRF2 activation, due to p62 accumulation or inhibition of KEAP1 binding, led to hepatomegaly associated with enhanced glycogenosis, steatosis and G2/M cell cycle arrest, fostering hyperplasia without cell division. Surprisingly, all manipulations that led to NRF2 activation also activated AKT, whose inhibition blocked NRF2-induced hepatomegaly and glycogenosis, but not NRF2-dependent antioxidant gene induction. AKT activation was linked to NRF2-mediated transcriptional induction of PDGF and EGF receptor ligands that signaled through their cognate receptors in an autocrine manner. Insulin and insulin-like growth factors were not involved. The NRF2-AKT signaling axis was also activated in human HSOS- and AIH-related hepatomegaly.
CONCLUSIONS
NRF2, a transcription factor readily activated by xenobiotics, oxidative stress and autophagy disruptors, may be a common mediator of hepatomegaly; its effects on hepatic metabolism can be reversed by AKT/tyrosine kinase inhibitors.
LAY SUMMARY
Hepatomegaly can be triggered by numerous etiological factors, including infections, liver cancer, metabolic disturbances, toxicant exposure, as well as alcohol abuse or drug-induced hepatitis. This study identified the oxidative stress response transcription factor NRF2 as a common mediator of hepatomegaly. NRF2 activation results in elevated expression of several growth factors. These growth factors are made by hepatocytes and activate their receptors in an autocrine fashion to stimulate the accumulation of glycogen and lipids that lead to hepatocyte and liver enlargement. The protein kinase AKT plays a key role in this process and its inhibition leads to reversal of hepatomegaly.
Topics: Adult; Animals; Autophagy; Disease Models, Animal; ErbB Receptors; Female; Genes, erbB-1; Hemangioma; Hepatic Veno-Occlusive Disease; Hepatitis, Autoimmune; Hepatomegaly; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; NF-E2-Related Factor 2; Oxidative Stress; Proto-Oncogene Proteins c-akt; Receptor, Platelet-Derived Growth Factor alpha; Signal Transduction
PubMed: 32105670
DOI: 10.1016/j.jhep.2020.01.023 -
Internal Medicine (Tokyo, Japan) Feb 2024
Topics: Humans; Liver Diseases; Amyloidosis; Multiple Myeloma; Hepatomegaly
PubMed: 37344422
DOI: 10.2169/internalmedicine.2186-23 -
Romanian Journal of Morphology and... 2012We present the case of a female patient, aged 12 years, with fatigability and exertional myalgias, progressively developed within the last two years. Negative family...
We present the case of a female patient, aged 12 years, with fatigability and exertional myalgias, progressively developed within the last two years. Negative family history, as well as negative personal medical history, were found. At physical examination, short stature, proximal muscle weakness and mild hepatomegaly were noted. Urine ketones level was slightly decreased, serum transaminases, creatine kinase and lactate dehydrogenase levels were increased. Electromyographical examination showed a myopathic non-specific pattern. Deltoid muscle biopsy revealed: small, clear vesicles are present on Hematoxylin-Eosin and modified Gömöri trichrome stains; modified Gömöri trichrome stain also revealed muscle fibers (especially type I of muscle fibers) having mild to moderate mitochondrial proliferation (red rim and speckled sarcoplasm). The lipid storage has been well demonstrated by Sudan Black stain, which revealed small lipid droplets in type I muscle fibers. Abnormal internal architecture with a punctate pattern was showed by adenine dinucleotide tetrazolium reductase and succinate dehydrogenase stains. Electron microscopy showed small inter-myofibrillar accumulations of round, amorphous, homogeneous acellular substances that are not membrane bounded. These features indicate that these are neutral fat (lipid) droplets. Subsarcolemmal accumulations of mitochondria were also revealed. The differential diagnosis of this case is discussed, and the up to date general data concerning carnitine deficiency are presented. The aim of our case-report is to emphasize the role of muscle biopsy in carnitine deficiency, as well as to remind the necessity of keeping in mind such metabolic disorders when doing the differential diagnostic of a muscular weakness.
Topics: Biopsy; Carnitine; Child; Diagnosis, Differential; Disease Progression; Electromyography; Female; Hepatomegaly; Humans; Lipids; Microscopy, Electron; Mitochondria; Muscle Weakness; Muscles; Muscular Diseases
PubMed: 22395524
DOI: No ID Found