The corticotropin releasing factor system in the liver: expression, actions and possible implications in hepatic physiology and pathology

Abstract

The corticotropin-releasing factor (crF) system plays a crucial regulatory role in the adaptation to exogenous and endogenous stress stimuli, as well as homeostasis. Apart from the central nervous system (cNs), the members of this neuropeptide family extend their actions in the periphery, where they may affect various body systems independently, stimulating peripheral crF receptors via vagal and/or autocrine/paracrine pathways. Here, we review all findings concerning the expression and role of the crF system in human liver, but also in other species. Direct and indirect regulatory data are also analyzed in order to draw conclusions about possible physiological/pathophysiological implications. Although data supporting any clinical significance are still limited and further research in the field is necessary, scientific interest in the crF system is particularly active, with multiple ongoing clinical studies evaluating the activity of crF ligands in medical conditions involving other organs. Thus, new knowledge with therapeutic potential appears to be steadily accumulating.

Social dominance‐related major urinary proteins and the regulatory mechanism in mice

“…The expression of CRH system is not restricted to the brain. Recent research found its expression in the periphery, including in the liver (Paschos et al 2013). This suggests that the CRH system might exert a direct influence on the expression of MUPs in hepatocytes.…”

“…Corticosterone, a glucocorticoid related to stress in mice, is the end product of the hypothalamic-pituitaryadrenal (HPA) axis, initiated by corticotropin releasing hormone (CRH) with 2 closely associated G-protein coupled receptors, CRHR1 and CRHR2 (Muller et al 2001;Huising et al 2010). CRH ligands and receptors, expressed mainly in the pituitary and brain, are also widely expressed and function in the periphery, particularly in the liver (Charalampopoulos et al 2006;Gu et al 2010;Paschos et al 2013;Cong & Ni 2014).…”

The Corticotropin-Releasing Factor Family: Physiology of the Stress Response

“…Similarly, significant differences in distribution of CRFRs between rodents and primates have been reported (329,538). In the periphery, CRFR1 is found in the skin, GI tract, lymphatic tissues, and testis (19,73,403,461,574,613 8) (630). In addition, two reporter mouse lines have been generated (293,339) and repeatedly used to address CRFR1 expression in the brain (192,193,209,249,500,530,590,617,655).…”

UCN2: a new candidate influencing pancreatic β-cell adaptations in pregnancy

“…These neuroendocrine peptides are best known for their involvement in regulating the physiological and behavioural responses to stress, through the cognate G-protein-coupled receptors (GPCRs), CRH receptor 1 (CRHR1) and CRH receptor 2 (CRHR2) (Chen et al 1993, Lovenberg et al 1995, Weninger et al 1999, Bakshi et al 2002, as part of the hypothalamic-pituitary-adrenal (HPA) axis. More recent evidence suggests additional, diverse, extra-hypothalamic roles for these peptides in peripheral organs (Paschos et al 2013, Chatoo et al 2018, Chatzaki et al 2019. Thus, CRH expression has been reported in the adrenal gland and the gastrointestinal tract (Suda et al 1984); UCN1 is expressed in heart, skin and adipose tissue (Kimura et al 2002, Seres et al 2004, Wierzbicka et al 2017; and UCN2 and UCN3 have been detected in peripheral blood cells, skeletal muscle, pancreas and gestational tissues such as foetal membranes and placental villi (Petraglia et al 2010).…”