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Hepatology Communications Oct 2023Bile, which contains bile acids, the natural ligands for farnesoid x receptor (FXR), moves from the liver to the intestine through bile ducts. Ductular reaction often...
BACKGROUND
Bile, which contains bile acids, the natural ligands for farnesoid x receptor (FXR), moves from the liver to the intestine through bile ducts. Ductular reaction often occurs during biliary obstruction. A subset of patients with erythropoietic protoporphyria, an inherited genetic mutation in heme biosynthetic enzyme ferrochelatase, accumulate porphyrin-containing bile plugs, leading to cholestasis. Here, we examined the link between FXR, bile plug formation, and how heme biosynthesis relates to this connection.
METHODS
We treated female and male wild-type and global and tissue-specific Fxr knockout mice with a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine, an inhibitor of ferrochelatase, and examined the expression of heme biosynthetic genes. We mined FXR mouse ChIP-Seq data, performed biochemical and histological analysis, and tested HepG2 and primary human hepatocytes after treatment with obeticholic acid, an FXR agonist.
RESULTS
We observed that hepatic but not intestinal Fxr loss resulted in reduced bile plugs and ductular reaction in the liver. Then, we examined if FXR plays a regulatory role in heme biosynthesis and found significantly lower porphyrin accumulation in 3,5-diethoxycarbonyl-1, 4-dihydrocollidine-fed Fxr knockout mice. Gene expression and FXR mouse ChIP-Seq atlas analysis revealed that FXR orchestrates the expression of multiple heme biosynthetic enzymes. Finally, human HepG2 cells and primary human hepatocytes treated with obeticholic acid, showed increased expression of several heme biosynthetic genes.
CONCLUSIONS
Overall, our data show that hepatic Fxr is necessary to maintain ductular reaction and accumulation of bile plugs. FXR can direct the expression of multiple heme biosynthetic genes. Thus, modulating FXR activity in EPP patients may help alleviate its associated liver disease.
Topics: Animals; Female; Humans; Male; Mice; Cholestasis; Ferrochelatase; Heme; Liver; Porphyrins
PubMed: 37695073
DOI: 10.1097/HC9.0000000000000213 -
ACG Case Reports Journal Feb 2023Erythropoietic protoporphyria (EPP) presents with nonblistering photosensitivity. Hepatobiliary manifestations are seen in around 5% cases and include cholelithiasis,...
Erythropoietic protoporphyria (EPP) presents with nonblistering photosensitivity. Hepatobiliary manifestations are seen in around 5% cases and include cholelithiasis, elevations in liver enzymes, progressive jaundice, and end-stage liver disease. The diagnosis is suspected based on clinical features and elevated erythrocyte metal-free protoporphyrin and confirmed by genetic analysis showing loss-of-function mutations in the ferrochelatase (FECH) gene. We present an adolescent boy who presented with jaundice and photosensitivity with the liver biopsy showing deposition of brown pigments within the canaliculi and hepatocytes. This pigment showed Maltese cross birefringence on polarizing microscopy and Medusa-head appearance on electron microscopy. Genetic analysis revealed loss-of-function mutations in FECH. Introduction of EPP is an inborn error of heme biosynthesis caused by mutations in FECH with a prevalence of 1:75,000 to 1:200,000. We present a case of a 16-year-old adolescent boy with photosensitivity, abdominal pain, and jaundice with protoporphyrin deposition in the liver who was ultimately diagnosed with EPP based on genetic analysis.
PubMed: 36891180
DOI: 10.14309/crj.0000000000000996 -
Blood Apr 2007During erythroid differentiation and maturation, it is critical that the 3 components of hemoglobin, alpha-globin, beta-globin, and heme, are made in proper... (Review)
Review
During erythroid differentiation and maturation, it is critical that the 3 components of hemoglobin, alpha-globin, beta-globin, and heme, are made in proper stoichiometry to form stable hemoglobin. Heme-regulated translation mediated by the heme-regulated inhibitor kinase (HRI) provides one major mechanism that ensures balanced synthesis of globins and heme. HRI phosphorylates the alpha-subunit of eukaryotic translational initiation factor 2 (eLF2alpha) in heme deficiency, thereby inhibiting protein synthesis globally. In this manner, HRI serves as a feedback inhibitor of globin synthesis by sensing the intracellular concentration of heme through its heme-binding domains. HRI is essential not only for the translational regulation of globins, but also for the survival of erythroid precursors in iron deficiency. Recently, the protective function of HRI has also been demonstrated in murine models of erythropoietic protoporphyria and beta-thalassemia. In these 3 anemias, HRI is essential in determining red blood cell size, number, and hemoglobin content per cell. Translational regulation by HRI is critical to reduce excess synthesis of globin proteins or heme under nonoptimal disease states, and thus reduces the severity of these diseases. The protective role of HRI may be more common among red cell disorders.
Topics: Anemia; Anemia, Hypochromic; Anemia, Iron-Deficiency; Animals; Blood Proteins; Enzyme Activation; Erythropoiesis; Heme; Humans; Mice; Models, Biological; Protoporphyria, Erythropoietic; Signal Transduction; beta-Thalassemia; eIF-2 Kinase
PubMed: 17110456
DOI: 10.1182/blood-2006-08-041830 -
Clinical Liver Disease 2024
Review
Diagnosis and management of protoporphyria-related liver dysfunction in erythropoietic protoporphyria and x-linked protoporphyria: A patient-friendly summary of the 2023 evidence-based consensus guidelines.
PubMed: 38487349
DOI: 10.1097/CLD.0000000000000133 -
Frontiers in Molecular Biosciences 20225-Aminolevulinate synthase (ALAS; E.C. 2.3.1.37) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the key regulatory step of porphyrin biosynthesis in... (Review)
Review
5-Aminolevulinate synthase (ALAS; E.C. 2.3.1.37) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the key regulatory step of porphyrin biosynthesis in metazoa, fungi, and α-proteobacteria. ALAS is evolutionarily related to transaminases and is therefore classified as a fold type I PLP-dependent enzyme. As an enzyme controlling the key committed and rate-determining step of a crucial biochemical pathway ALAS is ideally positioned to be subject to allosteric feedback inhibition. Extensive kinetic and mutational studies demonstrated that the overall enzyme reaction is limited by subtle conformational changes of a hairpin loop gating the active site. These findings, coupled with structural information, facilitated early prediction of allosteric regulation of activity via an extended C-terminal tail unique to eukaryotic forms of the enzyme. This prediction was subsequently supported by the discoveries that mutations in the extended C-terminus of the erythroid ALAS isoform (ALAS2) cause a metabolic disorder known as X-linked protoporphyria not by diminishing activity, but by enhancing it. Furthermore, kinetic, structural, and molecular modeling studies demonstrated that the extended C-terminal tail controls the catalytic rate by modulating conformational flexibility of the active site loop. However, the precise identity of any such molecule remains to be defined. Here we discuss the most plausible allosteric regulators of ALAS activity based on divergences in AlphaFold-predicted ALAS structures and suggest how the mystery of the mechanism whereby the extended C-terminus of mammalian ALASs allosterically controls the rate of porphyrin biosynthesis might be unraveled.
PubMed: 35911972
DOI: 10.3389/fmolb.2022.920668 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Nov 2023Erythropoietic protoporphyria (EPP) is an inherited metabolic disease caused by the deficiency in ferrochelatase (FECH) encoded by the gene, and it is inherited in an...
Erythropoietic protoporphyria (EPP) is an inherited metabolic disease caused by the deficiency in ferrochelatase (FECH) encoded by the gene, and it is inherited in an autosomal recessive manner. EPP usually produces acute pain photosensitivity after exposure to sunlight in infancy or early childhood, and liver failure is the most serious associated complication. This article reported an adult female case of EPP complicated with thyrotoxicosis and liver dysfunction which is a rare condition. The patient's liver function improved after liver protection treatment, her thyroid function returned to normal, and her EPP symptoms improved significantly. Moreover, the c.286C>T gene mutation may be the pathogenic locus of EPP. For patients with abnormal liver function, the possibility of EPP should be considered after the common causes are excluded, and gene detection should be done to confirm the diagnosis in time. When EPP is associated with thyrotoxicosis and liver dysfunction, priority may be given to hepatoprotective therapy.
Topics: Humans; Child, Preschool; Female; Adult; Protoporphyria, Erythropoietic; Thyrotoxicosis; Liver Failure; Mutation
PubMed: 38432869
DOI: 10.11817/j.issn.1672-7347.2023.230242 -
Actas Dermo-sifiliograficas Apr 2013In recent years, important advances have been made in our understanding of the genetics of porphyrias, particularly with respect to erythropoietic protoporphyria (EPP)...
In recent years, important advances have been made in our understanding of the genetics of porphyrias, particularly with respect to erythropoietic protoporphyria (EPP) and congenital erythropoietic porphyria (CEP), 2 forms of erythropoietic porphyria no longer considered to be monogenic. The identification of mutations in genes not previously associated with these disorders as causative factors or modulators of severity has helped to explain the presence of genotypic and phenotypic differences between patients carrying the same mutations. These advances have also led to the identification of causative genetic defects in patients who, based on molecular studies, had no mutations in the uroporphyrinogen III synthase gene UROS (in CEP) or in the ferrochelatase gene FECH (in EPP). Better understanding and characterization of the genetics of porphyrias will allow us to determine genotypic and phenotypic correlations and improve the molecular classification of these diseases, which will have both practical and prognostic implications.
Topics: Humans; Phenotype; Porphyria, Erythropoietic
PubMed: 22766189
DOI: 10.1016/j.ad.2011.12.021 -
Postgraduate Medical Journal Dec 2007
Review
Topics: Animals; Disease Models, Animal; Humans; Liver Diseases; Liver Transplantation; Pedigree; Protoporphyria, Erythropoietic; Protoporphyrins
PubMed: 18057171
DOI: 10.1136/gut.2006.097576 -
Gut Jul 2007
Review
Topics: Animals; Disease Models, Animal; Disease Progression; Humans; Liver Diseases; Liver Failure; Liver Transplantation; Mice; Protoporphyria, Erythropoietic; Rats
PubMed: 17360790
DOI: 10.1136/gut.2006.097576 -
Patient Related Outcome Measures 2024Erythropoietic protoporphyria (EPP), a rare inherited disorder, presents in early childhood with severe, painful phototoxicity, with significant impacts on...
Development and Content Validation of Novel Patient-Reported Outcome Measures to Assess Disease Severity and Change in Patients with Erythropoietic Protoporphyria: The EPP Impact Questionnaire (EPIQ).
PURPOSE
Erythropoietic protoporphyria (EPP), a rare inherited disorder, presents in early childhood with severe, painful phototoxicity, with significant impacts on health-related quality of life (HRQoL). Previous studies have not captured all concepts important to patients. Therefore, this study sought to develop a novel, comprehensive, and content valid patient-reported outcome (PRO) measure to assess the efficacy of new therapies.
PATIENTS AND METHODS
Qualitative interviews were conducted with EPP participants and clinical experts to obtain views on concepts relevant to patients. Results informed the development of novel PROs, which were debriefed during subsequent combined concept elicitation and cognitive debriefing interviews.
RESULTS
Twenty-three interviews were conducted with 17 adults and 6 adolescents with EPP. Concept elicitation revealed that participants experienced many symptoms with significant variability. The most common were burning, pain, swelling, and tingling. Tingling was the most common prodromal symptom, while burning was the most bothersome, and pain was the worst full reaction symptom. Participants reported being negatively impacted in their ability to do daily activities, and social and emotional functioning. Many reported impacted ability to work and be productive at their job. Participants reviewed and completed the newly developed PRO measures assessing full reactions and ability to do activities, as well as items to assess severity and change in severity of prodromal symptoms, full reactions, and EPP overall. All measures were found to be comprehensive, clear, and relevant.
CONCLUSION
PRO measures are needed to assess important aspects of HRQoL and evaluate therapeutic response. These PRO measures are unique in assessing overall severity and change in EPP.
PubMed: 38375415
DOI: 10.2147/PROM.S438892