Sandra Torres1, Anna Baulies1, Naroa Insausti-Urkia1, Cristina Alarcón-Vila1, Raquel Fucho1, Estel Solsona-Vilarrasa1, Susana Núñez1, David Robles1, Vicent Ribas1, Leslie Wakefield2, Markus Grompe2, M Isabel Lucena3, Raul J Andrade3, Sanda Win4, Tin A Aung4, Neil Kaplowitz4, Carmen García-Ruiz5, Jose C Fernández-Checa6. 1. Cell Death and Proliferation, IIBB-CSIC, Barcelona, Spain; Liver Unit, Hospital Cínic, IDIBAPS and CIBEREHD, Barcelona, Spain. 2. Oregon Health and Science University, Portland, Oregon. 3. Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, CIBEREHD, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain. 4. USC Research Center for Liver Disease, USC Keck School of Medicine, Los Angeles, California. 5. Cell Death and Proliferation, IIBB-CSIC, Barcelona, Spain; Liver Unit, Hospital Cínic, IDIBAPS and CIBEREHD, Barcelona, Spain; USC Research Center for ALPD, Keck School of Medicine, Los Angeles, California. 6. Cell Death and Proliferation, IIBB-CSIC, Barcelona, Spain; Liver Unit, Hospital Cínic, IDIBAPS and CIBEREHD, Barcelona, Spain; USC Research Center for ALPD, Keck School of Medicine, Los Angeles, California. Electronic address: checa229@yahoo.com.
Abstract
BACKGROUND & AIMS: Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Mitochondrial SH3BP5 (also called SAB) and phosphorylation of c-Jun N-terminal kinase (JNK) mediate the hepatotoxic effects of APAP. We investigated the involvement of steroidogenic acute regulatory protein (STARD1), a mitochondrial cholesterol transporter, in this process and sensitization by valproic acid (VPA), which depletes glutathione and stimulates steroidogenesis. METHODS: Nonfasted C57BL/6J mice (control) and mice with liver-specific deletion of STARD1 (Stard1ΔHep), SAB (SabΔHep), or JNK1 and JNK2 (Jnk1+2ΔHep) were given VPA with or without APAP. Liver tissues were collected and analyzed by histology and immunohistochemistry and for APAP metabolism, endoplasmic reticulum (ER) stress, and mitochondrial function. Adult human hepatocytes were transplanted into Fah-/-/Rag2-/-/Il2rg-/-/NOD (FRGN) mice to create mice with humanized livers. RESULTS: Administration of VPA before administration of APAP increased the severity of liver damage in control mice. The combination of VPA and APAP increased expression of CYP2E1, formation of NAPQI-protein adducts, and depletion of glutathione from liver tissues of control mice, resulting in ER stress and the upregulation of STARD1. Livers from control mice given VPA and APAP accumulated cholesterol in the mitochondria and had sustained mitochondrial depletion of glutathione and mitochondrial dysfunction. Inhibition of ER stress, by administration of tauroursodeoxycholic acid to control mice, prevented upregulation of STARD1 in liver and protected the mice from hepatoxicity following administration of VPA and APAP. Administration of N-acetylcysteine to control mice prevented VPA- and APAP-induced ER stress and liver injury. Stard1ΔHep mice were resistant to induction of ALF by VPA and APAP, despite increased mitochondrial levels of glutathione and phosphorylated JNK; we made similar observations in fasted Stard1ΔHep mice given APAP alone. SabΔHep mice or Jnk1+2ΔHep mice did not develop ALF following administration of VPA and APAP. The ability of VPA to increase the severity of APAP-induced liver damage was observed in FRGN mice with humanized liver. CONCLUSIONS: In studies of mice, we found that upregulation of STARD1 following ER stress mediates APAP hepatoxicity via SH3BP5 and phosphorylation of JNK1 and JNK2.
BACKGROUND & AIMS:Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Mitochondrial SH3BP5 (also called SAB) and phosphorylation of c-Jun N-terminal kinase (JNK) mediate the hepatotoxic effects of APAP. We investigated the involvement of steroidogenic acute regulatory protein (STARD1), a mitochondrial cholesterol transporter, in this process and sensitization by valproic acid (VPA), which depletes glutathione and stimulates steroidogenesis. METHODS: Nonfasted C57BL/6J mice (control) and mice with liver-specific deletion of STARD1 (Stard1ΔHep), SAB (SabΔHep), or JNK1 and JNK2 (Jnk1+2ΔHep) were given VPA with or without APAP. Liver tissues were collected and analyzed by histology and immunohistochemistry and for APAP metabolism, endoplasmic reticulum (ER) stress, and mitochondrial function. Adult human hepatocytes were transplanted into Fah-/-/Rag2-/-/Il2rg-/-/NOD (FRGN) mice to create mice with humanized livers. RESULTS: Administration of VPA before administration of APAP increased the severity of liver damage in control mice. The combination of VPA and APAP increased expression of CYP2E1, formation of NAPQI-protein adducts, and depletion of glutathione from liver tissues of control mice, resulting in ER stress and the upregulation of STARD1. Livers from control mice given VPA and APAP accumulated cholesterol in the mitochondria and had sustained mitochondrial depletion of glutathione and mitochondrial dysfunction. Inhibition of ER stress, by administration of tauroursodeoxycholic acid to control mice, prevented upregulation of STARD1 in liver and protected the mice from hepatoxicity following administration of VPA and APAP. Administration of N-acetylcysteine to control mice prevented VPA- and APAP-induced ER stress and liver injury. Stard1ΔHep mice were resistant to induction of ALF by VPA and APAP, despite increased mitochondrial levels of glutathione and phosphorylated JNK; we made similar observations in fasted Stard1ΔHep mice given APAP alone. SabΔHep mice or Jnk1+2ΔHep mice did not develop ALF following administration of VPA and APAP. The ability of VPA to increase the severity of APAP-induced liver damage was observed in FRGN mice with humanized liver. CONCLUSIONS: In studies of mice, we found that upregulation of STARD1 following ER stress mediates APAP hepatoxicity via SH3BP5 and phosphorylation of JNK1 and JNK2.
Authors: Antonio Segovia-Zafra; Daniel E Di Zeo-Sánchez; Carlos López-Gómez; Zeus Pérez-Valdés; Eduardo García-Fuentes; Raúl J Andrade; M Isabel Lucena; Marina Villanueva-Paz Journal: Acta Pharm Sin B Date: 2021-11-18 Impact factor: 11.413
Authors: Laura Conde de la Rosa; Carmen Garcia-Ruiz; Carmen Vallejo; Anna Baulies; Susana Nuñez; Maria J Monte; Jose J G Marin; Lucia Baila-Rueda; Ana Cenarro; Fernando Civeira; Josep Fuster; Juan C Garcia-Valdecasas; Joana Ferrer; Michael Karin; Vicent Ribas; Jose C Fernandez-Checa Journal: J Hepatol Date: 2021-01-27 Impact factor: 30.083
Authors: Carmen Garcia-Ruiz; Laura Conde de la Rosa; Vicent Ribas; Jose C Fernandez-Checa Journal: Semin Cancer Biol Date: 2020-08-14 Impact factor: 17.012