Myokines: Crosstalk and Consequences on Liver Physiopathology

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease mainly characterized by the hepatic accumulation of lipid inducing a deregulation of β-oxidation. Its advanced form is non-alcoholic steatohepatitis (NASH), which, in addition to lipid accumulation, induces hepatocellular damage, oxidative stress and fibrosis that can progress to cirrhosis and to its final stage: hepatocellular carcinoma (HCC). To date, no specific therapeutic treatment exists. The implications of organ crosstalk have been highlighted in many metabolic disorders, such as diabetes, metabolic-associated liver diseases and obesity. Skeletal muscle, in addition to its role as a reservoir and consumer of energy and carbohydrate metabolism, is involved in this inter-organs' communication through different secreted products: myokines, exosomes and enzymes, for example. Interestingly, resistance exercise has been shown to have a beneficial impact on different metabolic pathways, such as lipid oxidation in different organs through their secreted products. In this review, we will mainly focus on myokines and their effects on non-alcoholic fatty liver disease, and their complication: non-alcoholic steatohepatitis and HCC.

Keywords: HCC; NAFLD; NASH; diabetes; inter-organ crosstalk; metabolic disease; myokines.

Figure 1

Effects of myokines on glucose metabolism. This figure represents the beneficial and deleterious effects of different myokines on the different pathways involved in glucose metabolism: insulin sensitivity, glycogenesis, glycolysis, and gluconeogenesis. FGF21: Fibroblast growth factor 21; G6PC: Glucose-6-phosphatase catalytic subunit; GLUT2: Glucose transporter 2; IRS1/2: Insulin receptor substrate 1/2; LIF: Leukemia inhibitory factor; mTORC1: Mammalian target of rapamycin complex 1; PCK1: phosphoénol pyruvate carboxykinase; PGC1α: Peroxysome proliferator-activated receptor gamma co-activator 1-alpha.

Figure 2

Effects of myokines on lipid metabolism. This figure highlights the beneficial and deleterious effects of different myokines on the different pathways involved in lipid metabolism: fatty acid transport, de-novo lipogenesis, fatty acid β-oxidation and lipid droplet secretion. Acaca: acétyl-CoA carboxylase 1; BAIBA: β-aminoisobutyric acid; CD36: Cluster of differentiation 36; FABP: Fatty acid binding protein; FATP: Fatty acid transport protein; Fasn: Fatty acid synthase; IL-6: Interleukine 6; IL-15: Interleukine 15; LIF: Leukemia inhibitory factor; PPARα: Peroxisome proliferator-activated receptor alpha; SREBP: sterol regulatory element binding protein; STAT3: Signal transducer and activator of transcription 3.

Figure 3

Effects of myokines on NASH hallmarks. This figure represents the beneficial, but also the deleterious effects of different myokines on the different hallmarks of NASH: inflammation and fibrosis. HIF-1: Hypoxia inducible factor 1; IGFRIR: Insulin growth factor I receptor; IL-15: Interleukine 15; JNK-1: c-Jun N-terminal kinase 1; NK: Natural killer; α-SMA: Alpha-smooth muscle actin; TNF: Tumor necrosis factor.

Figure 4

Effects of myokines on hepatocellular carcinoma. This figure puts a light on the beneficial and deleterious effects of different myokines on the different pathways involved in the development of hepatocellular carcinoma: hepatic dysfunction, fibrosis, HCC cell invasion, migration and metastasis. gp130: Glycoprotein 130; HCC: Hepatocellular carcinoma; IL-6: Interleukine 6; IL-15: Interleukine 15; NK: Natural killer.