Glucagon Regulates Hepatic Mitochondrial Biogenesis and Function through Foxo1

The liver is an important organ regulating the energy metabolism, which is tightly governed by multiple hormones. Glucagon secreted from the alpha-cell of the pancreatic islets is a counterregulatory hormone contrary to the action of insulin. In addition to promoting hepatic glucose production, glucagon also plays multiple roles in the liver via its G protein-coupled glucagon receptor. In this study, we found that glucagon attenuated the mitochondrial oxygen consumption and ATP production in primary mouse hepatocytes and decreased hepatic mitochondrial copy numbers. To investigate the molecular mechanisms, we found that glucagon increased the expression of Foxo1 in protein level, which controls the expression of genes responsible for heme biosynthesis, frataxin (FXN) and uroporphyrinogen decarboxylase (UROD). The lower production of heme by glucagon impaired the integrity of electron transport chain (ETC), reducing the heme-dependent complex III (Uqcrc1) and complex IV (mt-Co1). Furthermore, glucagon downregulated mitochondrial transcription factor A (TFAM) and nuclear transcription factors 1 (NRF-1), impairing the mitochondrial biogenesis, which was abolished in Foxo1 deficient primary hepatocytes. These results demonstrate that glucagon inhibits mitochondrial biogenesis and function in a Foxo1-dependent manner. Disclosure W. Yang: None. H. Yan: None. Q. Pan: None. Z. Shen: None. S.A. Dahanayaka: None. C. Wu: None. Y. Sun: None. S. Guo: None.