M Olleros Santos-Ruiz1, M C Sádaba2, I Martín-Estal3, U Muñoz2, C Sebal Neira2, I Castilla-Cortázar4. 1. Fundacion de Investigacion HM Hospitales, Madrid, Spain. 2. Department of Medical Physiology, School of Medicine, Universidad San Pablo-CEU, Madrid, Spain. 3. Escuela de Medicina, CITES, Tecnologico de Monterrey, Monterrey, Mexico. 4. Fundacion de Investigacion HM Hospitales, Madrid, Spain; Escuela de Medicina, CITES, Tecnologico de Monterrey, Monterrey, Mexico. Electronic address: iccortazar@itesm.mx.
Abstract
BACKGROUND & AIMS: We previously described in cirrhosis and aging, both conditions of IGF-1 deficiency, a clear hepatic mitochondrial dysfunction with increased oxidative damage. In both conditions, the hepatic mitochondrial function was improved with low doses of IGF-1. The aim of this work was to explore if the only mere IGF-1 partial deficiency, without any exogenous insult, is responsible for hepatic mitochondrial dysfunction. METHODS: Heterozygous (igf1+/-) mice were divided into two groups: untreated and treated mice with low doses of IGF-1. WT group was used as controls. Parameters of hepatic mitochondrial function were determined by flow cytometry, antioxidant enzyme activities were determined by spectrophotometry, and electron chain transport enzyme levels were determined by immunohistochemistry and immunofluorescence analyses. Liver expression of genes coding for proteins involved in mitochondrial protection and apoptosis was studied by microarray analysis and RT-qPCR. RESULTS: Hz mice showed a significant reduction in hepatic mitochondrial membrane potential (MMP) and ATPase activity, and an increase in intramitochondrial free radical production and proton leak rates, compared to controls. These parameters were normalized by IGF-1 replacement therapy. No significant differences were found between groups in oxygen consumption and antioxidant enzyme activities, except for catalase, whose activity was increased in both Hz groups. Relevant genes coding for proteins involved in mitochondrial protection and survival were altered in Hz group and were reverted to normal in Hz+IGF-1 group. CONCLUSIONS: The mere IGF-1 partial deficiency is per se associated with hepatic mitochondrial dysfunction sensitive to IGF-1 replacement therapy. Results in this work prove that IGF-1 is involved in hepatic mitochondrial protection, because it is able to reduce free radical production, oxidative damage and apoptosis. All these IGF-1 actions are mediated by the modulation of the expression of genes encoding citoprotective and antiapoptotic proteins.
BACKGROUND & AIMS: We previously described in cirrhosis and aging, both conditions of IGF-1 deficiency, a clear hepatic mitochondrial dysfunction with increased oxidative damage. In both conditions, the hepatic mitochondrial function was improved with low doses of IGF-1. The aim of this work was to explore if the only mere IGF-1 partial deficiency, without any exogenous insult, is responsible for hepatic mitochondrial dysfunction. METHODS: Heterozygous (igf1+/-) mice were divided into two groups: untreated and treated mice with low doses of IGF-1. WT group was used as controls. Parameters of hepatic mitochondrial function were determined by flow cytometry, antioxidant enzyme activities were determined by spectrophotometry, and electron chain transport enzyme levels were determined by immunohistochemistry and immunofluorescence analyses. Liver expression of genes coding for proteins involved in mitochondrial protection and apoptosis was studied by microarray analysis and RT-qPCR. RESULTS: Hz mice showed a significant reduction in hepatic mitochondrial membrane potential (MMP) and ATPase activity, and an increase in intramitochondrial free radical production and proton leak rates, compared to controls. These parameters were normalized by IGF-1 replacement therapy. No significant differences were found between groups in oxygen consumption and antioxidant enzyme activities, except for catalase, whose activity was increased in both Hz groups. Relevant genes coding for proteins involved in mitochondrial protection and survival were altered in Hz group and were reverted to normal in Hz+IGF-1 group. CONCLUSIONS: The mere IGF-1 partial deficiency is per se associated with hepatic mitochondrial dysfunction sensitive to IGF-1 replacement therapy. Results in this work prove that IGF-1 is involved in hepatic mitochondrial protection, because it is able to reduce free radical production, oxidative damage and apoptosis. All these IGF-1 actions are mediated by the modulation of the expression of genes encoding citoprotective and antiapoptotic proteins.
Authors: Alan Robson Trigueiro de Sousa; Wilson Rodrigues Freitas Junior; Eduardo Araujo Perez; Elias Jirjoss Ilias; Anderson Soares Silva; Vera Lucia Santos Alves; João Pedro Ribeiro Afonso; Miriã Cândida Oliveira; Adriano Luís Fonseca; Marcos Mota da Silva; Maria Eduarda Moreira Lino; Manoel Carneiro Oliveira Junior; Rodolfo Paula Vieira; Wilson José Sena Pedro; André Luis Lacerda Bachi; Giuseppe Insalaco; Carlos Alberto Malheiros; Luis Vicente Franco Oliveira Journal: Obes Surg Date: 2021-09-23 Impact factor: 4.129