Autophagie ist ein lysosomaler Degradationsprozess, der wesentlich zur zellulären Homöostase über die Eliminierung von Aggregaten und Bereitstellung von Wachstumssubstraten beiträgt. Defekte in der Autophagie wurden mit einer Vielzahl von Tumoren in verschiedenen Organen assoziiert. Eine Rolle in der duktalen Pankreaskarzinogenese (PDAC) wurde ebenfalls beschrieben, wobei detaillierte mechanistische Untersuchungen noch ausstehen.

Aims: Diabetes mellitus type 2 (DM 2) and its complications include intracellular accumulation of damaged and misfolded proteins, while protective heat shock proteins (HSP) are repressed. We aim to identify HSP-regulated liver-to-periphery signalling pathways effecting the development and progression of long term diabetic complications.

Background: Cyclooxygenase-2 (COX-2) over-expression and subsequent prostaglandin E2 (PGE2) production are frequently associated with human non-small-cell lung cancer (NSCLC) and are involved in tumor proliferation, invasion, angiogenesis, and resistance to apoptosis. Here, we report that ciglitazone downregulates PGE2 in NSCLC cells.Methods: PGE2 ELISA assay and COX-2 ELISA assay were performed for measuring PGE2 and COX-2, respectively, in NSCLC. The mRNA level of COX-2 was measured by semi-quantitative RT-PCR. The transient transfection experiments were performed to measure COX-2 and peroxisome proliferator-response element (PPRE) promoter activity in NSCLC. Western blots were unitized to measure PGE synthase (PGES) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) protein expression.Results: COX-2 ELISA assays suggested that ciglitazone-dependent inhibition of PGE2 occurs through the suppression of COX-2. Ciglitazone treatment suppressed COX-2 mRNA expression and COX-2 promoter activity while upregulating PPRE promoter activity. Ciglitazone did not modify the expression of enzymes downstream of COX-2 including PGES and 15-PGDH. Utilization of a dominant-negative PPARγ showed that the suppression of COX-2 and PGE2 by ciglitazone is mediated via non-PPAR pathways.Conclusion: Taken together, our findings suggest that ciglitazone is a negative modulator of COX-2/PGE2 in NSCLC.

Hypertriglyceridemia forms a hallmark of the metabolic syndrome and represents an independent risk factor for the development of coronary heart disease. Plasma lipid levels are controlled through a complex interplay between different tissues, the molecular basis of which remains largely unknown. Given the importance of transcriptional regulation in metabolic control, we investigated the role of nuclear receptor co-factor receptor interacting protein 140 (RIP140) in the liver, a key organ in energy homeostasis. Here we show that an acute, liver-specific depletion of RIP140 caused dramatically increased blood triglyceride levels. In contrast, hepatic triglyceride content in these animals was decreased in the absence of RIP140, suggesting that the observed hypertriglyceridemia was not the consequence of increased hepatic VLDL production. Interestingly, RIP140 knockdown in the liver reduced expression of apolipoprotein A5 (ApoA5), the serum levels of which have been shown to be inversely correlated with circulating blood triglycerides. Indeed, RIP140 knockdown in a murine hepatocyte cell line decreased ApoA5 promoter activity in transient transfection studies. Conversely, RIP140 over-expression induced ApoA5 expression in these cells, strengthening the notion that RIP140 acts as a direct transcriptional co-activator on the ApoA5 promoter. ApoA5 has been shown to control blood lipid levels, at least in part, by accelerating the hydrolysis of triglycerides by lipoprotein lipase (LPL) in adipose and muscle tissue. By influencing hepatic ApoA5 release, transcriptional control via RIP140 in the liver might, therefore, provide a novel mechanism of metabolic tissue crosstalk and the development of dyslipidemia associated with the metabolic syndrome.

Glucose homeostasis in mammals is maintained, in large parts, through the hypothalamic-pituitary-hormonal axis (HPA) resulting in the regulation of adrenal glucocorticoid production. Glucocorticoids are critical mediators of liver-specific glucose metabolism the molecular mechanisms of which remain largely unclear and, consequently, represented the focus of this study.

The occurrence of a fatty liver phenotype is closely linked to elevated glucocorticoid levels as associated with obesity, extensive fasting or glucocorticoid therapy. However, despite its clinical importance, the molecular determinants of glucocorticoid-induced fatty liver development remain largely enigmatic.

According to recent estimates of the World Health Organization the number of people diagnosed with diabetes type II – now 150 million worldwide – will double by 2025. While it is certain that a dysregulation of lipid metabolism contributes to the outbreak of the disease the molecular mechanisms are still unclear.

As a result of the worldwide epidemic of insulin-resistant type II diabetes, the characterization of new therapeutic targets has become a major challenge for current biomedical research. Hyperglycemia and dyslipidemia represent hallmarks of the diabetic pathophysiology and importantly contribute to the vascular complications in diabetic patients.