The Role of Catecholamines in Pathophysiological Liver Processes

Abstract

Over the last few years, the number of research publications about the role of catecholamines (epinephrine, norepinephrine, and dopamine) in the development of liver diseases such as liver fibrosis, fatty liver diseases, or liver cancers is constantly increasing. However, the mechanisms involved in these effects are not well understood. In this review, we first recapitulate the way the liver is in contact with catecholamines and consider liver implications in their metabolism. A focus on the expression of the adrenergic and dopaminergic receptors by the liver cells is also discussed. Involvement of catecholamines in physiological (glucose metabolism, lipids metabolism, and liver regeneration) and pathophysiological (impact on drug-metabolizing enzymes expression, liver dysfunction during sepsis, fibrosis development, or liver fatty diseases and liver cancers) processes are then discussed. This review highlights the importance of understanding the mechanisms through which catecholamines influence liver functions in order to draw benefit from the adrenergic and dopaminergic antagonists currently marketed. Indeed, as these molecules are well-known drugs, their use as therapies or adjuvant treatments in several liver diseases could be facilitated.

Keywords: dopamine; epinephrine; hepatic cells; norepinephrine; sympathetic innervation.

Figure 5

Impact of catecholamines on liver regeneration. Increase of plasma catecholamines after partial hepatectomy can participate in liver regeneration by enhancing the EGF effect on hepatocyte proliferation and through the proliferation/differentiation of various hepatic cell types (→ activation; —| inhibition). AC: adenylate cyclase; ADR: adrenergic receptor; EGF: epidermal growth factor; EGFR: EGF receptor; HPC: hepatic progenitor cells; TG2: transglutaminase 2. Adapted from [94].

Figure 1

Metabolism of epinephrine (E) and norepinephrine (NE) in the liver. Adrenal glands, mesenteric organs, and liver sympathetic innervation are the main sources of E and NE in the liver. The last step of metabolism for metanephrine (MN) and normetanephrine (NMN) extracted from the circulation are also performed in the liver. Thus, E, NE, MN, and NMN are uptaken by hepatocytes and metabolized in VMA. VMA is then eliminated in the urine. AD: aldehyde reductase; ADH: alcohol dehydrogenase; ALDH: aldehyde dehydrogenase; MAO: monoamine oxidases; COMT: catechol-O-methyltransferase; TH: tyrosine hydroxylase; AADC: aromatic L-aminoacid decarboxylase; DBH: dopamine-β-hydroxylase; PNMT: phenylethanolamine N-methyltransferase; DHPG: 3,4-dihydroxyphenylglycol; MHPG: 4-hydroxy-3methoxyphenylglycol; VMA: vanillyl mandelic acid (Solid arrow: main pathway; dotted arrow: minor pathway).

Figure 2

Catecholamines receptors. Catecholamines can activate adrenergic receptors (ADRs), composed of 9 receptors (α_1A, α_1B, α_1D, α_2A, α_2B, α_2C, β₁, β_2, and β₃), or dopamine receptors (DRDs), composed of 5 receptors (DRD1 to 5). Each receptor is coupled to G proteins alpha (q/11; i/o; s; s/olf) that can activate or inhibit effectors such as phospholipase C (PLC), adenylate cyclase (AC), or ion channels.

Figure 3

Analysis of ADRA1A, ADRA2A, and ADRB2 expression using the single cell-RNA sequencing of normal human liver. Plot gene expression in the t-SNEP map of single-cell transcriptomes obtained from 9 normal human liver tissues was accessible on the open web interface (http://human-liver-cell-atlas.ie-freiburg.mpg.de/; accessed on 3 March 2022). ADRA1A, ADRA2A, and ADRB2 expression were analyzed. PTPRC was used as a marker of leukocytes, CD163 as a marker of macrophage and Kupffer cell populations, EPCAM as a marker of the cholangiocyte population, and CYP3A4 as a marker of the hepatocyte population [46].

Figure 4

Impact of epinephrine on hepatic gluconeogenesis and glycogenolysis. Epinephrine (EPI) activates or inhibits some metabolic enzymes involved in glycogenolysis and gluconeogenesis (→ activation; —| inhibition). EPI: epinephrine; PC: pyruvate carboxylase; PEPCK: phosphoenolpyruvate carboxykinase; TCA cycle: tricarboxylic acid cycle.

Figure 6

Summary of catecholamines liver effects during a high fat diet or obesity (A) and on HCC progression (B). (A) During high fat diet or obesity, an increase in liver sympathetic activity is observed during the onset of the pathology. This increase could lead to early events characterized by an increase in gluconeogenesis, an activation of stellate cells, cytokine production by Kupffer cells, and an increase in lipid content in hepatocytes. All of these phenomena could induce a local inflammation responsible for the reverse destruction of liver sympathetic fibers as well as fibrosis and steatohepatitis. These results suggest that α/β-antagonists could have a beneficial effect in the early stages of steatosis/fibrosis. (B) In hepatocellular carcinoma, a decrease in the expression of α₁-ADR and MAO and an increase in the expression of β₂-ADR are observed. High sympathetic innervation of the tumor tissue has also been observed but remains to be validated by other studies. In vitro and in vivo studies have also shown that several processes involved in cancer progression are activated by catecholamines. MAO: monoamine oxidase, EMT: epithelial to mesenchymal transition, sFRP1: secreted frizzled-related protein 1.