Importance of the non-physiological activation of the mineralocorticoid receptor for progression and development of complication in cirrhosis
Anatomy and Physiology
Final Report Abstract
Cirrhosis is the final stage in the natural course of all chronic liver diseases. In recent years, the number of patients with liver cirrhosis has increased worldwide, which is also reflected in increasing hospitalization numbers of patients with liver cirrhosis in Germany. Recent studies have suggested that mineralocorticoid receptor (MR) activation may contribute to the progression of cirrhosis. Hypoxia, a common feature in cirrhosis, has been found to induce MR activation in hepatocytes. However, the impact of non-physiological MR activation remains poorly understood. We investigated the effect of cirrhosis-induced MR activation in hepatocytes. RNA sequencing followed by gene ontology term enrichment analysis was performed on liver samples from rats treated for 12 weeks with or without CCl4 and for the last four weeks with or without eplerenone (MR antagonist). In cirrhosis eplerenone reverses the downregulation of genes annotated to the GOterm “Monocarboxylic acid metabolic process” (PPARα, PDK4, AMACR, ABCC2 and Lipin1). We confirmed that non-physiological activation of the MR in hepatocytes is induced by hypoxia in vitro but not by acidosis or lipopolysaccharides, both additional changes in the micromilieu in cirrhotic livers. We investigated if the change in gene expression by eplerenone in cirrhotic livers can be mimicked by hypoxia and if those changes lead to alterations of glucose and lipid metabolism in primary rat hepatocytes (pRH) and human HepG2 cells. Hypoxia reduces the mRNA and protein content of the PPARα, PDK4 and ABCC2 in pRH and HepG2 cells. This effect can be partially reversed by eplerenone. Those proteins are key regulators of cellular glucose and lipid metabolism. Hypoxia induced increase in glucose consumption and lactate production in HepG2 cells was partially reduced by eplerenone treatment. Furthermore, hypoxia associated lipid accumulation in hepatocytes is at least partially provoked by MR activation. Taken together, our findings suggest that non-physiological MR activation may play a role in the dysregulation of glucose and lipid metabolism in hepatocytes thereby contributing to the development of chronic liver disease and cirrhosis. Therefore, MR antagonists may have therapeutic potential in the treatment of liver diseases.
Publications
-
Hypoxia induces activation of Mineralocorticoid receptor. Posterpräsentation, Europhysiology, Copenhagen
Mohib, M.M.; Rabe, S.; Zipprich, A., Gekle, M. & Schreier, B.
-
Hypoxia induces ligand independent activation of mineralocorticoid receptor. Forschungstag Medizinische Fakultät Halle
Mohib, M.M.; Rabe, S.; Zipprich, A.; Gekle, M. & Schreier, B.
-
Mineralocorticoid receptors in non‐alcoholic fatty liver disease. British Journal of Pharmacology, 179(13), 3165-3177.
Schreier, Barbara; Zipprich, Alexander; Uhlenhaut, Henriette & Gekle, Michael
-
Hypoxia induces activation of Mineralocorticoid receptor that leads to lipid accumulation in liver that leads to liver cirrhosis. Abstract, Jahrestagung der deutschen, physiologischen Gesellschaft, Berlin
Mohib, M.M.; Rabe, S.; Nolze, A.; Zipprich, A.; Gekle, M. & Schreier, B.
