Hepatokines and Adipokines in Metabolic Syndrome

Hepatokines and adipokines are secretory proteins derived from hepatocytes and adipocytes, respectively. These proteins play a main role in the pathogenesis of metabolic syndrome (MetS), characterized by obesity, dysglycemia, insulin resistance, dyslipidemia, and hypertension. Adipose tissue and liver are important endocrine organs because they regulate metabolic homeostasis as well as inflammation because they secrete adipokines and hepatokines, respectively. These adipokines and hepatokines communicate their action through different autocrine, paracrine and endocrine pathways. Liver regulates systemic homeostasis and also glucose and lipid metabolism through hepatokines. Dysregulation of hepatokines can lead to progression toward MetS, type 2 diabetes (T2D), inflammation, hypertension, and other diseases. Obesity is now a worldwide epidemic. Increasing cases of obesity and obesity-associated metabolic syndrome has brought the focus on understanding the biology of adipocytes and the mechanisms occurring in adipose tissue of obese individuals. A lot of facts are now available on adipose tissue as well. Adipose tissue is now given the status of an endocrine organ. Recent evidence indicates that obesity contributes to systemic metabolic dysfunction. Adipose tissue plays a significant role in systemic metabolism by communicating with other central and peripheral organs via the production and secretion of a group of proteins known as adipokines. Adipokine levels regulate metabolic state of our body and are potent enough to have a direct impact upon energy homeostasis and systemic metabolism. Dysregulation of adipokines contribute to obesity, T2D, hypertension and several other pathological changes in various organs. This makes characterization of hepatokines and adipokines extremely important to understand the pathogenesis of MetS. Hepatokines such as fetuin-A and leukocyte cell-derived chemotaxin 2, and adipokines such as resistin, leptin, TNF-?, and adiponectin are some of the most studied proteins and they can modulate the manifestations of MetS. Detailed insight into the function and mechanism of these adipokines and hepatokines in the pathogenesis of MetS can show the path for devising better preventative and therapeutic strategies against this present-day pandemic.

Expression of liver-specific ZP domain-containing protein in mouse models of obesity / 上海交通大学学报（医学版）

Objective: To study the expression of liver-specific ZP domain-containing protein (LZP) in mouse models of obesity. Methods: The gene and protein expression of LZP in different tissues of C57BL/6J mice were detected by realtime-PCR and Western blotting respectively. C57BL/6J mice were treated with high fat diet (HFD) to establish the model of diet-induced obesity and ob/ob mice were also treated with HFD. The body mass and blood glucose were monitored during the experiment, then the liver weight and fat mass were measured at the end of the study. Hematoxylin-eosin staining of liver was performed to observe the morphology of liver. The expression of LZP in liver of model mice was also detected by realtime-PCR and Western blotting, respectively. Results: The expression of LZP mRNA was mainly found in liver, while a lower gene expression level was also observed in several other tissues such as spleen and testis by realtime-PCR. The protein expression of LZP was detected in liver in C57BL/6J mice by Western blotting. Compared with normal diet group, the group treated with HFD had significantly increased body mass and total fat mass, higher blood glucose, increased liver mass and more serious hepatic steatosis (all P<0.05), while the expression of LZP in liver was reduced (P<0.05). Similarly, body mass and blood glucose were increased significantly in ob/ob mice (both P<0.05), though the expression of LZP was decreased compared with wild type littermates (P<0.05). Conclusion: Mouse models of obesity display decreased expression of LZP in liver, indicating that LZP may play a role in metabolic homeostasis in obese individuals.

Exendin-4 Inhibits the Expression of SEPP1 and Fetuin-A via Improvement of Palmitic Acid-Induced Endoplasmic Reticulum Stress by AMPK

BACKGROUND: Selenoprotein P (SEPP1) and fetuin-A, both circulating liver-derived glycoproteins, are novel biomarkers for insulin resistance and nonalcoholic fatty liver disease. However, the effect of exendin-4 (Ex-4), a glucagon-like peptide-1 receptor agonist, on the expression of hepatokines, SEPP1, and fetuin-A, is unknown. METHODS: The human hepatoma cell line HepG2 was treated with palmitic acid (PA; 0.4 mM) and tunicamycin (tuni; 2ug/ml) with or without exendin-4 (100 nM) for 24 hours. The change in expression of PA-induced SEPP1, fetuin-A, and endoplasmic reticulum (ER) stress markers by exendin-4 treatment were evaluated using quantitative real-time reverse transcription polymerase chain reaction and Western blotting. Transfection of cells with AMP-activated protein kinase (AMPK) small interfering RNA (siRNA) was performed to establish the effect of exendin-4-mediated AMPK in the regulation of SEPP1 and fetuin-A expression. RESULTS: Exendin-4 reduced the expression of SEPP1, fetuin-A, and ER stress markers including PKR-like ER kinase, inositol-requiring kinase 1alpha, activating transcription factor 6, and C/EBP homologous protein in HepG2 cells. Exendin-4 also reduced the expression of SEPP1 and fetuin-A in cells treated with tunicamycin, an ER stress inducer. In cells treated with the AMPK activator 5-aminoidazole-4-carboxamide ribonucleotide (AICAR), the expression of hepatic SEPP1 and fetuin-A were negatively related by AMPK, which is the target of exendin-4. In addition, exendin-4 treatment did not decrease SEPP1 and fetuin-A expression in cells transfected with AMPK siRNA. CONCLUSION: These data suggest that exendin-4 can attenuate the expression of hepatic SEPP1 and fetuin-A via improvement of PA-induced ER stress by AMPK.

Increased Selenoprotein P Levels in Subjects with Visceral Obesity and Nonalcoholic Fatty Liver Disease

BACKGROUND: Selenoprotein P (SeP) has recently been reported as a novel hepatokine that regulates insulin resistance and systemic energy metabolism in rodents and humans. We explored the associations among SeP, visceral obesity, and nonalcoholic fatty liver disease (NAFLD). METHODS: We examined serum SeP concentrations in subjects with increased visceral fat area (VFA) or liver fat accumulation measured with computed tomography. Our study subjects included 120 nondiabetic individuals selected from participants of the Korean Sarcopenic Obesity Study. In addition, we evaluated the relationship between SeP and cardiometabolic risk factors, including homeostasis model of insulin resistance (HOMA-IR), high sensitivity C-reactive protein (hsCRP), adiponectin values, and brachial-ankle pulse wave velocity (baPWV). RESULTS: Subjects with NAFLD showed increased levels of HOMA-IR, hsCRP, VFA, and several components of metabolic syndrome and decreased levels of adiponectin and high density lipoprotein cholesterol than those of controls. Serum SeP levels were positively correlated with VFA, hsCRP, and baPWV and negatively correlated with the liver attenuation index. Not only subjects with visceral obesity but also those with NAFLD exhibited significantly increased SeP levels (P<0.001). In multiple logistic regression analysis, the subjects in the highest SeP tertile showed a higher risk for NAFLD than those in the lowest SeP tertile, even after adjusting for potential confounding factors (odds ratio, 7.48; 95% confidence interval, 1.72 to 32.60; P=0.007). CONCLUSION: Circulating SeP levels were increased in subjects with NAFLD as well as in those with visceral obesity and may be a novel biomarker for NAFLD.