Table 1.
Liver-specific signaling molecules. Hormones and metabolites acting via NRs (A) and NR-independent hormones (B) are listed.
| Hormone | Site of Synthesis | Receptor(s) | Site of Action | Function |
|---|---|---|---|---|
| A | ||||
| Bile acid | Liver | FXR, PXR, VDR, GPCRs (TGR5, Sphingosine 1-phosphate receptor (S1P2)) | Liver, intestine | Bile acid homeostasis, lipid, glucose, and energy homeostasis [51] |
| Bilirubin | Plasma | CAR, PXR, PPARα | Liver | Conjugation and secretion of bilirubin [94], an increase of FA oxidation, and decrease of lipid accumulation [15] |
| Fatty acids (FAs) | Liver, Adipose tissue | PPARα, PPARβ/δ, PPARγ | PPARα: liver, muscle, BAT, heart; PPARβ/δ: ubiquitous; PPARγ: adipose tissue, weak in Liver |
PPARα: increase of fatty acid oxidation (FAO), a decrease of glucose uptake; PPARβ/δ: increase of FAO and glucose metabolism, decrease of inflammation [95]; PPARγ: might be involved in FA uptake and DAG synthesis [33] |
| Glucocorticoids (corticosterone, cortisol) | Adrenal cortex | GRs | Liver | Gluconeogenesis by lipolysis and ketogenesis [38,41] |
| Oxysterol | Liver | LXRα/LXRβ | Liver | Activation of LXRα, regulation of cholesterol metabolism [96]; LXR-induced Srebp-1c increases de novo lipogenesis [50] |
| Thyroid hormones (T3, T4) | Thyroid | TRα, TRβ | Liver, kidney, bone, heart | Cholesterol metabolism, stimulation of FAO, activation of de novo lipogenesis, and glucose homeostasis [97] |
| B | ||||
| Adiponectin (adipokine) | White adipose tissue (WAT) | Adiponectin receptor 1 and 2 (AdipoR1/2) | Liver, skeletal muscle, WAT | Suppression of glucose production in the liver via activation of AMPK [67] |
| Adrenaline, noradrenaline | Adrenal medulla | Adrenoreceptors alpha1, alpha2, and beta | Liver | Glycogenolysis, increase of blood glucose [65,66] |
| Angiopoietin-like proteins (ANGPTL3, ANGPTL 6) * | Liver | - | Plasma | Increase of plasma TG level in mice via lipoprotein lipase inhibition [84]; activation of Angptl6 has been associated with protection from HFD-induced obesity, insulin resistance, and hepatic steatosis [87] |
| β-aminoisobutyric acid (BAIBA) | Skeletal muscle | AMPK, transcription factors | Liver, WAT, skeletal muscle | Improvement of hepatic lipid metabolism via PPAR-mediated β-oxidation [69,70] |
| Fetuin A (α2-HS-Glycoprotein) * | Liver | - | Plasma | Inhibition of insulin receptor tyrosine kinase [71] |
| Fibroblast growth factor 21 (FGF21) * | Liver | - | Plasma | Fasting-induced hormone enhancing insulin sensitivity, lowering body weight, and increasing gluconeogenesis [98] |
| Ghrelin | Stomach | Ghrelin receptor (GHSR1a) | Liver, Agouti-related protein (ARGP)/neuropeptide Y (NPY) neurons, adipocytes | Increase of triglycerides by induction of lipogenesis-related gene expression [64] |
| Glucagon | Pancreas | Glucagon receptor | Mainly liver, kidney | Gluconeogenesis [99] |
| Insulin | Pancreas | Insulin receptor | liver | Lipogenesis, cholesterol uptake, and synthesis [100] |
| Insulin-like growth factors-1 and -2 (IGFs) * | Liver | IGF receptors -1 and -2 | Plasma | IGF-1 decreases blood glucose levels, and improves insulin sensitivity [88,89,90]. IGF-2 can be a key factor in steatosis initiation [91] |
| Leptin | Adipose tissue, small intestine | Leptin receptor | Liver, hypothalamus, and several other tissues | Lack of hepatic leptin leads to increased lipid accumulation in the liver [62] |
| Selenoprotein P (SeP) * | Liver | - | Plasma | Glycoprotein; hepatic expression has been linked to insulin resistance [80] |
| Sex-hormone-binding globulin (SHBG) * | Liver | SHBG-receptor | Plasma | Circulating levels of SHBG are a biomarker for insulin resistance and type II diabetes [93] |
* hepatokines.