Adiponectin Stimulates Apolipoprotein A-1 Gene Expression in HepG2 Cells via AMPK, PPARα, and LXRs Signaling Mechanisms.

Adiponectin is an adipose tissue hormone, participating in energy metabolism and involved in atherogenesis. Previously, it was found that adiponectin increases expression of the APOA1 (apolipoprotein A-1) gene in hepatocytes, but the mechanisms of this effect remained unexplored. Our aim was to investigate the role of adiponectin receptors AdipoR1/R2, AMP-activated protein kinase (AMPK), nuclear peroxisome proliferator-activated receptor alpha (PPARα) and liver X receptors (LXRs) in mediating the action of adiponectin on hepatic APOA1 expression in human hepatoma HepG2 cells. The level of APOA1 expression was determined by RT-qPCR and ELISA. We showed that the siRNA-mediated knockdown of genes coding for AdipoR1, AdipoR2, AMPK, PPARα, and LXRα and ß prevented adiponectin-induced APOA1 expression in HepG2 cells and demonstrated that interaction of PPARα and LXRs with the APOA1 gene hepatic enhancer is important for the adiponectin-dependent APOA1 transcription. The results of this study point out to the involvement of both types of adiponectin receptors, AMPK, PPARα, and LXRs in the adiponectin-dependent upregulation of the APOA1 expression.

Immunohistochemical analysis of adiponectin in atherosclerotic lesions of human aorta.

BACKGROUND: Metabolic syndrome, a cluster of interrelated disorders including abdominal obesity, insulin resistance, dyslipidemia, and hypertension (HTN) plays an important role in development of atherosclerotic lesions in arterial wall. Dysregulation of adipose tissue hormones (adipokines) production is a possible link between abdominal obesity and other manifestations of metabolic syndrome. Adiponectin is a well-known adipokine which affects metabolism and inflammatory response. However, data on its role in atherogenesis are still controversial. The aim of this study is to investigate whether adiponectin is present in atherosclerotic lesions of human aorta. METHODS: Thirty-five autopsy segments from abdominal, thoracic aortas, and aortic arch of four men (mean age: 57 years) were fixed and stained for lipids [Oil Red O (ORO)], cells [hematoxylin-eosin (H&E)], and adiponectin [indirect immunoperoxidase assay (IPA) method]. Samples of both stable and unstable plaques were selected for analysis. Human adipose tissue, THP-1 monocytes/macrophages, and human endothelial hybrid cell line (EA.hy926) were chosen for detection of adiponectin messenger ribonucleic acid (mRNA) using reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Adiponectin accumulations were found inside endothelial cells covering both stable and unstable atherosclerotic plaques. Focal depositions of adiponectin were also found in fibrous caps of stable lesions and atheromatous core of both stable and unstable plaques and also in adventitia. RT-PCR revealed mRNA expression of adiponectin gene in adipose tissue, but not in mononuclears and endothelial cells. CONCLUSION: Adiponectin is present in aortic plaques of humans, but is not synthesized in endothelial cells and mononuclears, at least in culture conditions. Detection of adiponectin in atherosclerotic lesions can serve as indirect evidence of possible participation of this adipokine in atherogenesis.

Association of adipokines with metabolic disorders in patients with schizophrenia: Results of comparative study with mental healthy cohort.

AIM: The role of adipose tissue hormones, adipokines, in formation of metabolic disorders in schizophrenia is not fully understood. The aim was to investigate the association of leptin and adiponectin plasma levels with metabolic parameters in antipsychotic treated patients with schizophrenia and in the group of age, gender and body mass index matched mental healthy persons. METHODS: One hundred patients with diagnosis of schizophrenia, who took antipsychotic medication, and equal number of control subjects, were enrolled for cross-sectional evaluation. Fasting blood plasma levels of glucose, lipids, insulin, adiponectin, leptin concentrations and insulin resistance HOMA index were determined. RESULTS: In both groups plasma leptin concentration positively correlated with body mass index, insulin plasma level and HOMA index, while adiponectin level had negative correlations with adiposity measures and positive associations with high density lipoprotein cholesterol content. At the same time, in schizophrenia group, but not in control subjects, leptin level positively associated with cholesterol and triglycerides concentrations and adiponectin negatively correlated with plasma insulin content, HOMA index and triglycerides levels. After controlling for confounders significant correlations remained for leptin concentration with HOMA index and plasma triglycerides level in schizophrenic patients and for adiponectin concentration with plasma high density lipoprotein cholesterol concentrations in both studied groups. CONCLUSIONS: Both adipokines associate with metabolic parameters in antipsychotic treated patients with schizophrenia. Leptin can play more specific role in pathogenesis of metabolic syndrome in schizophrenic persons than in mental healthy subjects.

Familial hypercholesterolemia in St-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia.

BACKGROUND: Familial hypercholesterolemia is a human monogenic disease caused by population-specific mutations in the low density lipoprotein (LDL) receptor gene. Despite thirteen different mutations of the LDL receptor gene were reported from Russia prior to 2003, the whole spectrum of disease-causing gene alterations in this country is poorly known and requires further investigation provided by the current study. METHODS: Forty-five patients with clinical diagnosis of FH were tested for the apolipoprotein B (apoB) mutation R3500Q by restriction fragment length analysis. After exclusion of R3500Q mutation high-sensitive fluorescent single-strand conformation polymorphism (SSCP) analysis and automatic DNA sequencing were used to search for mutations in the LDL receptor gene. RESULTS: We found twenty one rare sequence variations of the LDL receptor gene. Nineteen were probably pathogenic mutations, and two (P518P, T705I) were considered as neutral ones. Among the mutations likely to be pathogenic, eight were novel (c.670-671insG, C249X, c.936-940del5, c.1291-1331del41, W422X, c.1855-1856insA, D601N, C646S), and eleven (Q12X, IVS3+1G>A, c.651-653del3, E207X, c.925-931del7, C308Y, L380H, c.1302delG, IVS9+1G>A, V776M, V806I) have already been described in other populations. None of the patients had the R3500Q mutation in the apoB gene. CONCLUSIONS: Nineteen pathogenic mutations in the LDL receptor gene in 23 probands were identified. Two mutations c.925-931del7 and L380H are shared by St.-Petersburg population with neighbouring Finland and several other mutations with Norway, Sweden or Denmark, i.e. countries from the Baltic Sea region. Only four mutations (c.313+1G>A, c.651-653del3, C308Y and W422X) were recurrent as all those were found in two unrelated families. By this study the number of known mutations in the LDL receptor gene in St.-Petersburg area was increased nearly threefold. Analysis of all 34 low density lipoprotein receptor gene mutations found in St.-Petersburg argues against strong founder effect in Russian familial hypercholesterolemia.