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The liver plays a pivotal role in whole-body carbohydrate, lipid, and protein metabolism. One of the key regulators of glucose and lipid metabolism are hepatokines, which are found among the liver secreted proteins, defined as liver secretome. To elucidate the composition of the human liver secretome and identify hepatokines in primary human hepatocytes (PHH), we conducted comprehensive protein profiling on conditioned medium (CM) of PHH. Secretome profiling using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS) identified 691 potential hepatokines in PHH. Subsequently, pathway analysis assigned these proteins to acute phase response, coagulation, and complement system pathways. The secretome of PHH was compared to the secreted proteins of the liver hepatoma cell line HepG2. Although the secretome of PHH and HepG2 cells show a high overlap, the HepG2 secretome rather mirrors the fetal liver with some cancer characteristics. Collectively, our study represents one of the most comprehensive secretome profiling approaches for PHH, allowing new insights into the composition of the secretome derived from primary human material, and points out strength and weakness of using HepG2 cell secretome as a model for the analysis of the human liver secretome. [ABSTRACT FROM AUTHOR]

Studies have linked obesity, metabolic syndrome, type 2 diabetes, cardiovascular disease (CVD), nonalcoholic fatty liver disease (NAFLD) and dementia. Their relationship to the incidence and progression of these disease states suggests an interconnected pathogenesis involving chronic low-grade inflammation and oxidative stress. Metabolic syndrome represents comorbidities of central obesity, insulin resistance, dyslipidemia, hypertension and hyperglycemia associated with increased risk of type 2 diabetes, NAFLD, atherosclerotic CVD and neurodegenerative disease. As the socioeconomic burden for these diseases has grown signficantly with an increasing elderly population, new and alternative pharmacologic solutions for these cardiometabolic diseases are required. Adipose tissue, skeletal muscle and liver are central endocrine organs that regulate inflammation, energy and metabolic homeostasis, and the neuroendocrine axis through synthesis and secretion of adipokines, myokines, and hepatokines, respectively. These organokines affect each other and communicate through various endocrine, paracrine and autocrine pathways. The ultimate goal of this review is to provide a comprehensive understanding of organ crosstalk. This will include the roles of novel organokines in normal physiologic regulation and their pathophysiological effect in obesity, metabolic syndrome, type 2 diabetes, CVD, NAFLD and neurodegenerative disorders., (© 2020 Elsevier Inc. All rights reserved.)

Fibroblast growth factor 21 (FGF21), follistatin and leukocyte cell-derived chemotaxin 2 (LECT2) are novel hepatokines that are modulated by metabolic stresses. This study investigated whether exercise intensity modulates the hepatokine response to acute exercise. Ten young, healthy men undertook three 8-h experimental trials: moderate-intensity exercise (MOD; 55% peak oxygen uptake), high-intensity exercise (HIGH; 75% peak oxygen uptake), and control (CON; rest), in a randomised, counterbalanced order. Exercise trials commenced with a treadmill run of varied duration to match gross exercise energy expenditure between trials (MOD vs HIGH; 2475 ± 70 vs 2488 ± 58 kJ). Circulating FGF21, follistatin, LECT2, glucagon, insulin, glucose and nonesterified fatty acids (NEFA) were measured before exercise and at 0, 1, 2, 4, and 7 h postexercise. Plasma FGF21 concentrations were increased up to 4 h postexercise compared with CON ( P ≤ 0.022) with greater increases observed at 1, 2, and 4 h postexercise during HIGH versus MOD ( P ≤ 0.025). Irrespective of intensity ( P ≥ 0.606), plasma follistatin concentrations were elevated at 4 and 7 h postexercise ( P ≤ 0.053). Plasma LECT2 concentrations were increased immediately postexercise ( P ≤ 0.046) but were not significant after correcting for plasma volume shifts. Plasma glucagon (1 h; P = 0.032) and NEFA (4 and 7 h; P ≤ 0.029) responses to exercise were accentuated in HIGH versus MOD. These findings demonstrate that acute exercise augments circulating FGF21 and follistatin. Exercise-induced changes in FGF21 are intensity-dependent and may support the greater metabolic benefit of high-intensity exercise.

Many researchers pay attention to novel secretory factors, such as adipokines or osteokines, secreted by the tissues that were not formerly recognized as classical endocrine organs. The liver also contributes to the onset of various kinds of pathologies of type 2 diabetes and obesity by producing and releasing secretory proteins "hepatokines." By using the information of gene expression in human livers, we rediscovered selenoprotein P (SeP) and leukocyte cell-derived chemotaxin 2 (LECT2) as hepatokines involved in the onset of glucose intolerance. SeP was previously recognized as a selenium transport protein, but we revealed that SeP causes insulin resistance in the muscle and liver. SeP also reduces VEGF signal transduction in vascular endothelial cells, contributing the impaired angiogenesis in diabetes. Importantly, SeP impairs health-promoting effects of exercise training by suppressing reactive oxygen species (ROS)/adenosine monophosphate-dependent protein kinase (AMPK) pathway in the skeletal muscle through its receptor low-density lipoprotein receptor-related protein 1 (LRP1). LECT2, previously-reported as a neutrophil chemotactic protein, promotes skeletal muscle insulin resistance in obesity. Further studies are necessary to develop new diagnostic or therapeutic procedures targeting hepatokines to combat type 2 diabetes or obesity.

The aim of this study was to compare the effects of 8 weeks of aerobic versus resistance training programs on serum fetuin-A, fetuin-B, and fibroblast growth factor-21 (FGF-21) levels in males with type 2 diabetes mellitus. Participants (n = 34) were randomly assigned to a resistance training group (RTG; n = 12), an aerobic training group (ATG; n = 11), or a control group (n = 11). The ATG completed 30-45 min of aerobic running training at 65%-75% of the maximum heart rate. The RTG completed three sets of 10 repetitions maximum of leg press, bench press, knee extension, seated cable row, knee flexion, military press, and calf rise. Blood samples were taken before and after the training period to assess dependent variables. After 8 weeks, both the ATG and the RTG reduced fetuin-A (p < 0.05) and fetuin-B (p < 0.05), but increased FGF-21 (p < 0.05). Moreover, the RTG showed greater decrease than the ATG in fetuin-A (-18.3% vs. -7.9%), fetuin-B (-29.2% vs. -11.45%), and a lower increase in FGF-21 (42.2% vs. 25.1%), respectively. Aerobic and resistance exercise training significantly decreased serum fetuin-A, and fetuin-B, and increased FGF-21 levels in males with type 2 diabetes mellitus. However, more significant alterations in serum factors were observed from resistance training. Thus, resistance training may be considered a more suitable training strategy.

Type 2 diabetes is characterized by a deterioration of glucose tolerance, which associates insulin resistance of glucose uptake by peripheral tissues and increased endogenous glucose production. Here we report that the specific suppression of hepatic glucose production positively modulates whole-body glucose and energy metabolism. We used mice deficient in liver glucose-6 phosphatase that is mandatory for endogenous glucose production. When they were fed a high fat/high sucrose diet, they resisted the development of diabetes and obesity due to the activation of peripheral glucose metabolism and thermogenesis. This was linked to the secretion of hepatic hormones like fibroblast growth factor 21 and angiopoietin-like factor 6. Interestingly, the deletion of hepatic glucose-6 phosphatase in previously obese and insulin-resistant mice resulted in the rapid restoration of glucose and body weight controls. Therefore, hepatic glucose production is an essential lever for the control of whole-body energy metabolism during the development of obesity and diabetes.