Changes in PGC-1α-Dependent Mitochondrial Biogenesis Are Associated with Inflexible Hepatic Energy Metabolism in the Offspring Born to Dexamethasone-Treated Mothers

• DOI: 10.3390/livers1040016
• Publication Date: 2021-10-12T12:09:32Z
• Authors: Carolina Vieira C...; Caio Jordão Teixeira; Tanyara Baliani P...; Amanda Rabello Cr...; Gilson Masahiro M...; Andressa Godoy Am...; Lucas Carminatti ...; Frhancielly Shirl...; Mariana Mayumi Onari; Lorena de Souza A...; Gizela A. Pereira; Dimitrius Santiag...; Leonardo Reis Sil...; Gabriel Forato Anhê; Silvana Bordin
• Keywords: 0301 basic medicine; Pediatric; Medicine (General); 0303 health sciences; mitochondrial biogenesis; glucocorticoids; hepatic steatosis; Liver Disease; miR-29a-c; PGC-1α; 32 Biomedical and Clinical Sciences; Perinatal Period - Conditions Originating in Perinatal Period; liver; 3101 Biochemistry and Cell Biology; 03 medical and health sciences; gluconeogenesis; R5-920; metabolic programming; FOS: Biological sciences; Genetics; Digestive Diseases; 31 Biological Sciences

In the present study we investigated the participation of hepatic peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) in the metabolic programming of newborn rats exposed in utero to dexamethasone (DEX). On the 21st day of life, fasted offspring born to DEX-treated mothers displayed increased conversion of pyruvate into glucose with simultaneous upregulation of PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase). Increased oxidative phosphorylation, higher ATP/ADP ratio and mitochondrial biogenesis and lower pyruvate levels were also found in the progeny of DEX-treated mothers. On the other hand, the 21-day-old progeny of DEX-treated mothers had increased hepatic triglycerides (TAG) and lower CPT-1 activity when subjected to short-term fasting. At the mechanistic level, rats exposed in utero to DEX exhibited increased hepatic PGC-1α protein content with lower miR-29a-c expression. Increased PGC-1α content was concurrent with increased association to HNF-4α and NRF1 and reduced PPARα expression. The data presented herein reveal that changes in the transcription machinery in neonatal liver of rats born to DEX-treated mothers leads to an inflexible metabolic response to fasting. Such programming is hallmarked by increased oxidative phosphorylation of pyruvate with impaired FFA oxidation and hepatic TAG accumulation.