Mathilde Di Filippo1, Philippe Moulin2, Pascal Roy3, Marie Elisabeth Samson-Bouma4, Sophie Collardeau-Frachon5, Sabrina Chebel-Dumont6, Noël Peretti7, Jérôme Dumortier8, Fabien Zoulim9, Thierry Fontanges10, Rossella Parini11, Miriam Rigoldi11, Francesca Furlan11, Grazia Mancini12, Dominique Bonnefont-Rousselot13, Eric Bruckert14, Jacques Schmitz15, Jean Yves Scoazec16, Sybil Charrière2, Sylvie Villar-Fimbel17, Frederic Gottrand18, Béatrice Dubern19, Diane Doummar20, Francesca Joly21, Marie Elisabeth Liard-Meillon22, Alain Lachaux23, Agnès Sassolas24. 1. UF Dyslipidémies Cardiobiologie, Département de Biochimie et de Biologie Moléculaire du GHE, Laboratoire de Biologie Médicale Multi Sites, Hospices Civils de Lyon, Lyon, France; INSERM U1060, INSA de Lyon, INRA U1235, Univ Lyon-1, Université de Lyon, Villeurbanne, Oullins, France. Electronic address: mathilde.di-filippo@chu-lyon.fr. 2. INSERM U1060, INSA de Lyon, INRA U1235, Univ Lyon-1, Université de Lyon, Villeurbanne, Oullins, France; Fédération d'Endocrinologie, Maladies métaboliques, Diabète et Nutrition, Hôpital Louis Pradel, Hospices Civils de Lyon, Bron, France. 3. Service de Biostatistique, Hospices Civils de Lyon, Lyon, France; Centre National de la Recherche Scientifique UMR5558, Univ Lyon-1, Villeurbanne, France. 4. INSERM UMR698, Paris 7-Université Paris Diderot, CHU X. Bichat Secteur C Bernard, Paris, France. 5. Service de pathologie, Hospices Civils de Lyon et Université Claude Bernard, CHU de Lyon, France. 6. UF Dyslipidémies Cardiobiologie, Département de Biochimie et de Biologie Moléculaire du GHE, Laboratoire de Biologie Médicale Multi Sites, Hospices Civils de Lyon, Lyon, France. 7. Service de Gastroentérologie Hépatologie et Nutrition Pédiatrique, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France. 8. Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils, Lyon, France. 9. Service d'Hépato-Gastro-Entérologie, Hôpital de la Croix Rousse, Hospices Civils, Lyon, France. 10. Service d'Hépato-Gastro-Entérologie, Centre Hospitalier Pierre Oudot, Bourgoin Jallieu, France. 11. Rare Metabolic Disease Unit, Department of Pediatrics, Fondazione MBBM, San Gerardo Hospital, Monza, Italy. 12. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. 13. Unité pédagogique de Biochimie, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France; UPMC University Paris 6, UMR_S1166 Inserm ICAN, Paris, France; Service de Biochimie métabolique, Groupe hospitalier Pitié-Salpêtrière-Charles Foix, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. 14. Service d'Endocrinologie, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France. 15. Service de Gastroentérologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France. 16. Service d'anatomie pathologique, Hôpital Edouard Herriot, Hospices Civils, Lyon, France. 17. Fédération d'Endocrinologie, Maladies métaboliques, Diabète et Nutrition, Hôpital Louis Pradel, Hospices Civils de Lyon, Bron, France. 18. Department of Pediatric Gastroenterology Hepatology and Nutrition, Jeanne de Flandre university hospital, Lille, France. 19. Nutrition et Gastroentérologie Pédiatriques, Hôpital Trousseau, AP-HP, Paris, France; Institut de Cardiométabolisme et Nutrition (ICAN), INSERM UMRS U872 (Eq7) Nutriomique, Université Pierre et Marie Curie-Paris 6, Paris, France. 20. Service de Neuropédiatrie, Hôpital Trousseau, Paris, France. 21. Service de Gastroentérologie et d'Assistance Nutritive, Hôpital Beaujon, Clichy, France. 22. Anatomie et Cytologie Pathologiques, Brive, France. 23. Service de Gastroentérologie Hépatologie et Nutrition Pédiatrique, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France; INSERM U 1111, Faculté de médecine Lyon Est, Université Lyon 1, Lyon, France. 24. UF Dyslipidémies Cardiobiologie, Département de Biochimie et de Biologie Moléculaire du GHE, Laboratoire de Biologie Médicale Multi Sites, Hospices Civils de Lyon, Lyon, France; INSERM U1060, INSA de Lyon, INRA U1235, Univ Lyon-1, Université de Lyon, Villeurbanne, Oullins, France.
Abstract
BACKGROUND & AIMS: Non-alcoholic steatohepatitis leading to fibrosis occurs in patients with abetalipoproteinemia (ABL) and homozygous or compound heterozygous familial hypobetalipoproteinemia (Ho-FHBL). We wanted to establish if liver alterations were more frequent in one of both diseases and were influenced by comorbidities. METHODS: We report genetic, clinical, histological and biological characteristics of new cases of ABL (n =7) and Ho-FHBL (n = 7), and compare them with all published ABL (51) and Ho-FHBL (22) probands. RESULTS: ABL patients, diagnosed during infancy, presented mainly with diarrhea, neurological and ophthalmological impairments and remained lean, whereas Ho-FHBL were diagnosed later, with milder symptoms often becoming overweight in adulthood. Despite subtle differences in lipid phenotype, liver steatosis was observed in both groups with a high prevalence of severe fibrosis (5/27 for Ho-FHBL vs. 4/58 for ABL (n.s.)). Serum triglycerides concentration was higher in Ho-FHBL whereas total and HDL-cholesterol were similar in both groups. In Ho-FHBL liver alterations were found to be independent from the apoB truncation size and apoB concentrations. CONCLUSIONS: Our findings provide evidence for major liver abnormalities in both diseases. While ABL and Ho-FHBL patients have subtle differences in lipid phenotype, carriers of APOB mutations are more frequently obese. These results raise the question of a complex causal link between apoB metabolism and obesity. They suggest that the genetic defect in VLDL assembly is critical for the occurrence of liver steatosis leading to fibrosis and shows that obesity and insulin resistance might contribute by increasing lipogenesis.
BACKGROUND & AIMS:Non-alcoholic steatohepatitis leading to fibrosis occurs in patients with abetalipoproteinemia (ABL) and homozygous or compound heterozygous familial hypobetalipoproteinemia (Ho-FHBL). We wanted to establish if liver alterations were more frequent in one of both diseases and were influenced by comorbidities. METHODS: We report genetic, clinical, histological and biological characteristics of new cases of ABL (n =7) and Ho-FHBL (n = 7), and compare them with all published ABL (51) and Ho-FHBL (22) probands. RESULTS:ABLpatients, diagnosed during infancy, presented mainly with diarrhea, neurological and ophthalmological impairments and remained lean, whereas Ho-FHBL were diagnosed later, with milder symptoms often becoming overweight in adulthood. Despite subtle differences in lipid phenotype, liver steatosis was observed in both groups with a high prevalence of severe fibrosis (5/27 for Ho-FHBL vs. 4/58 for ABL (n.s.)). Serum triglycerides concentration was higher in Ho-FHBL whereas total and HDL-cholesterol were similar in both groups. In Ho-FHBL liver alterations were found to be independent from the apoB truncation size and apoB concentrations. CONCLUSIONS: Our findings provide evidence for major liver abnormalities in both diseases. While ABL and Ho-FHBLpatients have subtle differences in lipid phenotype, carriers of APOB mutations are more frequently obese. These results raise the question of a complex causal link between apoB metabolism and obesity. They suggest that the genetic defect in VLDL assembly is critical for the occurrence of liver steatosis leading to fibrosis and shows that obesity and insulin resistance might contribute by increasing lipogenesis.
Authors: Elizabeth P Newberry; Yan Xie; Susan M Kennedy; Mark J Graham; Rosanne M Crooke; Hui Jiang; Anping Chen; Daniel S Ory; Nicholas O Davidson Journal: Hepatology Date: 2017-01-19 Impact factor: 17.425
Authors: Jorge Simon; Maitane Nuñez-García; Pablo Fernández-Tussy; Lucía Barbier-Torres; David Fernández-Ramos; Beatriz Gómez-Santos; Xabier Buqué; Fernando Lopitz-Otsoa; Naroa Goikoetxea-Usandizaga; Marina Serrano-Macia; Rubén Rodriguez-Agudo; Maider Bizkarguenaga; Imanol Zubiete-Franco; Virginia Gutiérrez-de Juan; Diana Cabrera; Cristina Alonso; Paula Iruzubieta; Manuel Romero-Gomez; Sebastiaan van Liempd; Azucena Castro; Ruben Nogueiras; Marta Varela-Rey; Juan Manuel Falcón-Pérez; Erica Villa; Javier Crespo; Shelly C Lu; Jose M Mato; Patricia Aspichueta; Teresa C Delgado; María Luz Martínez-Chantar Journal: Cell Metab Date: 2020-02-21 Impact factor: 27.287
Authors: Ji-Yeon Shin; Antonio Hernandez-Ono; Tatyana Fedotova; Cecilia Östlund; Michael J Lee; Sarah B Gibeley; Chun-Chi Liang; William T Dauer; Henry N Ginsberg; Howard J Worman Journal: J Clin Invest Date: 2019-08-13 Impact factor: 14.808