Within the last twenty years the view on reactive oxygen species (ROS) has changed; they are no longer only considered to be harmful but also necessary for cellular communication and homeostasis in different organisms ranging from bacteria to mammals. In the latter, ROS were shown to modulate diverse physiological processes including the regulation of growth factor signaling, the hypoxic response, inflammation and the immune response. During the last 60–100 years the life style, at least in the Western world, has changed enormously. This became obvious with an increase in caloric intake, decreased energy expenditure as well as the appearance of alcoholism and smoking; These changes were shown to contribute to generation of ROS which are, at least in part, associated with the occurrence of several chronic diseases like adiposity, atherosclerosis, type II diabetes, and cancer. In this review we discuss aspects and problems on the role of intracellular ROS formation and nutrition with the link to diseases and their problematic therapeutical issues.

The hypoxia-inducible factor α-subunits (HIFα) are key transcription factors in the mammalian response to oxygen deficiency. The HIFα regulation in response to hypoxia occurs primarily on the level of protein stability due to posttranslational hydroxylation and proteasomal degradation. However, HIF α-subunits also respond to various growth factors, hormones, or cytokines under normoxia indicating involvement of different kinase pathways in their regulation. Because these proteins participate in angiogenesis, glycolysis, programmed cell death, cancer, and ischemia, HIFα regulating kinases are attractive therapeutic targets. Although numerous kinases were reported to regulate HIFα indirectly, direct phosphorylation of HIFα affects HIFα stability, nuclear localization, and transactivity. Herein, we review the role of phosphorylation-dependent HIFα regulation with emphasis on protein stability, subcellular localization, and transactivation.

Objective— Small-molecule hypoxia-inducible factor prolyl 4-hydroxylase (HIF-P4H) inhibitors are being explored in clinical studies for the treatment of anemia. HIF-P4H-2 (also known as PHD2 or EglN1) inhibition improves glucose and lipid metabolism and protects against obesity and metabolic dysfunction. We studied here whether HIF-P4H-2 inhibition could also protect against atherosclerosis. Approach and Results— Atherosclerosis development was studied in low-density lipoprotein (LDL) receptor–deficient mice treated with an oral HIF-P4H inhibitor, FG-4497, and in HIF-P4H-2-hypomorphic/C699Y-LDL receptor–mutant mice, all mice being fed a high-fat diet. FG-4497 administration to LDL receptor–deficient mice reduced the area of atherosclerotic plaques by ≈50% when compared with vehicle-treated controls and also reduced their weight gain, insulin resistance, liver and white adipose tissue (WAT) weights, adipocyte size, number of inflammation-associated WAT macrophage aggregates and the high-fat diet–induced increases in serum cholesterol levels. The levels of atherosclerosis-protecting circulating autoantibodies against copper-oxidized LDL were increased. The decrease in atherosclerotic plaque areas correlated with the reductions in weight, serum cholesterol levels, and WAT macrophage aggregates and the autoantibody increase. FG-4497 treatment stabilized HIF-1α and HIF-2α and altered the expression of glucose and lipid metabolism and inflammation-associated genes in liver and WAT. The HIF-P4H-2-hypomorphic/C699Y-LDL receptor–mutant mice likewise had a ≈50% reduction in atherosclerotic plaque areas, reduced WAT macrophage aggregate numbers, and increased autoantibodies against oxidized LDL, but did not have reduced serum cholesterol levels. Conclusions— HIF-P4H-2 inhibition may be a novel strategy for protecting against the development of atherosclerosis. The mechanisms involve beneficial modulation of the serum lipid profile and innate immune system and reduced inflammation.

SummaryPlasminogena ctivator inhibitor-1 (PAI-1) controls the regulation of thefibrinolytic system in blood by inhibiting both urokinase-type and tissue-type plasminogenactivators. Enhanced levelsofP AI-1 aref oundinpatientswith type 2diabetesmellitus which is associated with adysbalance in glucose and lipid homeostasis. Especiallyad efectivei nsulin response in the liver contributestothe developmentofhyperglycemia, dyslipidemia and peripheral insulin resistance and maycontributetohepatic overexpression of PAI-1 in diabetes type 2. Furthermore,asubstantialu pregulationo fP AI-1 expression has also been showni na Keywords Fibrinolysis inhibitors, gene expression,plasminogen activator inhibitors, transcription factors,h ypoxia variety of liver injurym odels.Thus,the liver appearst oben ot onlyam ajor site of PAI-1 synthesis in response to hormonal changes, but also in response to avariety of other pathological events. PAI-1 expression in liver largelydepends on activation of signalling pathways and transcriptionalregulators whichmay be the basis foranew levelofcross-talk between differentsignalling pathways and thus mayr epresent attractivet herapeutic candidates.This article will primarilyfocusonthe regulation of PAI-1 expression in liver cells and discuss potential cross-talksb etween metabolic,hormonal and environmental signals.

Resveratrol, a polyphenol derived from grapes, exerts important effects on glucose and lipid metabolism, yet detailed mechanisms mediating these effects remain unknown. The liver plays a central role in energy homeostasis, and glucokinase (GK) is a key enzyme involved in glucose utilization. Resveratrol activates SIRT1 (sirtuin 1), which promotes deacetylation of the forkhead transcription factor FoxO1. Previously, we reported that FoxO1 can suppress and that HNF-4 can stimulate GK expression in the liver. Here, we examined the role of FoxO1 and HNF-4 in mediating resveratrol effects on liver GK expression. Resveratrol suppressed hepatic GK expression in vivo and in isolated hepatocytes, and knocking down FoxO1 with shRNAs disrupted this effect. Reporter gene, gel shift, supershift assay, and chromatin immunoprecipitation studies show that FoxO1 binds to the GK promoter and that the interplay between FoxO1 and HNF-4 within the GK promoter is essential for mediating the effects of resveratrol. Resveratrol promotes deacetylation of FoxO1 and enhances its recruitment to the FoxO-binding element. Conversely, resveratrol suppresses recruitment of HNF-4 to its binding site, and knockdown of FoxO1 blocks this effect of resveratrol. Coprecipitation and chromatin immunoprecipitation studies show that resveratrol enhances interaction between FoxO1 and HNF-4, reduces binding of HNF-4 to its own site, and promotes its recruitment to the FoxO site in a FoxO1-dependent manner. These results provide the first evidence that resveratrol represses GK expression via FoxO1 and that the interaction between FoxO1 and HNF-4 contributes to these effects of resveratrol.The liver is a key organ in energy homeostasis, and glucokinase (GK) 3 plays a major role in promoting hepatic glucose utilization and maintenance of blood glucose homeostasis.Compared with other hexokinases, GK has a smaller molecular mass (100 versus 52 kDa, respectively) and a lower affinity for glucose, with an S 0.5 for glucose in the range of about 7-8 mmol/liter. Although GK binds to a regulatory protein (GKRP) and exists as a monomer, it displays sigmoidal kinetics with a Hill coefficient of about 1.5-1.7, indicating cooperativity with its substrate, glucose (1-3). These characteristics allow GK to react with glucose across the range of physiological glucose concentrations reached in vivo. Although GK is expressed predominantly in hepatocytes and pancreatic ␤-cells, it also is expressed in some neuroendocrine cells of the gastrointestinal tract and the brain, where it also may contribute to glucose sensing (4).In the liver, GK is expressed predominantly in the less aerobic perivenous zone (5), and its expression is stimulated by insulin (6). Previous studies indicate that several transcription factors, including USF-1 and -2 (upstream stimulatory factor-1 and -2) (7, 8), HIF-1 (hypoxia-inducible factor-1) (9), PPAR␥ (peroxisome proliferator-activated receptor-␥) (10), sterol regulatory element binding protein-1c (11,12), and hepatocyte nuclear factor-4␣ (HNF-4␣) (...