inositol-1-4-5-trisphosphate and Hypercholesterolemia

The role of leptin in the pathomechanism of atherosclerosis, through its free radical generating ability is established. Its effect however, on the regulation of intracellular cholesterol synthesis has not been studied. The aim of the present study was to elucidate whether leptin influences endogenous cholesterol synthesis in monocytes. Furthermore, leptin signaling to HMG CoA reductase in control and hypercholesterolemic monocytes were compared. The in vitro effect of leptin was studied on freshly isolated human monocytes obtained from healthy control volunteers and patients with hypercholesterolemia. Our results can be summarized as follows: (1) Leptin is able to increase endogenous cholesterol synthesis in human monocytes in vitro. (2) The cholesterol synthesis increasing effect of the hormone is more pronounced in hypercholesterolemic monocytes with high basal cholesterol biosynthesis. (3) The leptin-induced Ca(2+) signal was involved in the enhancement of HMG CoA reductase activation in monocytes from both controls and hypercholesterolemic patients. (4) In control monocytes the Ca(2+) signal originated from intracellular pools, whereas in patients, Ca(2+)-influx and protein kinase C activation were found to be responsible for the leptin-effect. Mevalonate cycle inhibiting fluvastatin and 25-hydroxycholesterol decreased cholesterol production in leptin-stimulated monocytes. Our present study provides the first proof of the cholesterol synthesis enhancing effect of leptin through a statin-sensitive pathway in circulating monocytes. Furthermore our results suggest that leptin can be involved in the pathomechanism of atherosclerotic plaque formation also through its effect on cholesterol biosynthesis in monocytes.

Topics: Acetates; Area Under Curve; Atherosclerosis; Calcium; Calcium Signaling; Carbon Radioisotopes; Case-Control Studies; Cholesterol; Demography; Female; Humans; Hypercholesterolemia; Inositol 1,4,5-Trisphosphate; Leptin; Male; Middle Aged; Monocytes

A Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) plays an essential role in bone accrual and eye development. Here, we show that LRP5 is also required for normal cholesterol and glucose metabolism. The production of mice lacking LRP5 revealed that LRP5 deficiency led to increased plasma cholesterol levels in mice fed a high-fat diet, because of the decreased hepatic clearance of chylomicron remnants. In addition, when fed a normal diet, LRP5-deficient mice showed a markedly impaired glucose tolerance. The LRP5-deficient islets had a marked reduction in the levels of intracellular ATP and Ca(2+) in response to glucose, and thereby glucose-induced insulin secretion was decreased. The intracellular inositol 1,4,5-trisphosphate (IP3) production in response to glucose was also reduced in LRP5-- islets. Real-time PCR analysis revealed a marked reduction of various transcripts for genes involved in glucose sensing in LRP5-- islets. Furthermore, exposure of LRP5++ islets to Wnt-3a and Wnt-5a stimulates glucose-induced insulin secretion and this stimulation was blocked by the addition of a soluble form of Wnt receptor, secreted Frizzled-related protein-1. In contrast, LRP5-deficient islets lacked the Wnt-3a-stimulated insulin secretion. These data suggest that WntLRP5 signaling contributes to the glucose-induced insulin secretion in the islets.

Topics: Animals; Blood Glucose; Calcium; Cholesterol; Chylomicrons; Dietary Fats; Genes, Essential; Glucose; Glucose Intolerance; Hypercholesterolemia; Inositol 1,4,5-Trisphosphate; Insulin; Insulin Secretion; Islets of Langerhans; LDL-Receptor Related Proteins; Liver; Low Density Lipoprotein Receptor-Related Protein-5; Mice; Mice, Knockout; Polymerase Chain Reaction; Receptors, LDL; Transcription, Genetic

Angiotensin II (AII) in 1-10 nM concentrations has an in vivo immunostimulating effect on human neutrophils. The release of superoxide anions and leukotrienes (LTs) is significantly increased by 10 nM AII-stimulated neutrophils of patients with hypercholesterolaemia (HCH). These oxidizing agents may be involved in the damage of vessel walls, i.e., in atherosclerotic plaque formation. To clarify the receptor types and signal pathways in neutrophils of healthy controls and patients, inositol trisphosphate (IP(3)) production and Ca(2+) signalling were studied. Neutrophils were pretreated before AII stimulation with different inhibitory drugs. In control cells, the stimulation occurred predominantly through pertussis toxin-sensitive, type angiotensin 1 receptors. This induced IP(3) production and Ca(2+) signalling from intracellular pools. In neutrophils of hypercholesterolaemic patients, the enhanced release of oxidizing agents was dependent more on type angiotensin 2 than type angiotensin 1 receptors. After stimulation, there was no IP(3) production detected. The Ca(2+) signalling was lower than in control cells and was dependent on extracellular Ca(2+).

Topics: Angiotensin II; Calcium Signaling; Dose-Response Relationship, Drug; Humans; Hypercholesterolemia; Inositol 1,4,5-Trisphosphate; Leukotrienes; Male; Middle Aged; Neutrophils; Pertussis Toxin; Receptors, Angiotensin; Signal Transduction; Superoxides

We studied the changes in myocardial second messengers and mitochondrial calcium levels during acute coronary occlusion-reperfusion in New Zealand white male rabbits fed a high cholesterol diet with or without fish oil supplementation. Group I, control rabbits, were fed a standard laboratory rabbit chow. In addition to the standard chow, Group II rabbits received a 1% cholesterol-enriched diet for 2 weeks, while Group III rabbits were fed a 1% cholesterol and 10% fish oil supplemented diet for 2 weeks. Acute coronary occlusion for 10 min or 1 h was induced by ligating the marginal branch of the left circumflex coronary artery. The vessel was then reperfused for 1 or 4 h in short- and long-term ischemia studies respectively. In the short-term ischemia study, myocardial samples taken from the cholesterol-fed rabbits had the highest cyclic adenosine monophosphate, inositol 1,4,5-triphosphate and mitochondrial calcium levels among the normal (nonischemic) and the ischemic areas of the three groups. The cholesterol and fish oil treated rabbits significantly suppressed the elevation of cyclic adenosine monophosphate (P < 0.05 compared with the cholesterol-fed rabbits in normal and ischemic areas respectively), but did not significantly attenuate the elevation of inositol 1,4,5-triphosphate and calcium levels. In the long-term ischemia study, the cholesterol-fed rabbits had the highest levels of these three messengers among the normal areas. However, only inositol 1,4,5-triphosphate level reached statistical significance (P < 0.05 compared with control). This group of rabbits had the lowest level of cyclic adenosine monophosphate, but the highest inositol 1,4,5-triphosphate and calcium levels among the ischemic areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Calcium; Cholesterol, Dietary; Cyclic AMP; Fish Oils; Hypercholesterolemia; Inositol 1,4,5-Trisphosphate; Male; Mitochondria, Heart; Myocardial Reperfusion Injury; Myocardium; Rabbits; Second Messenger Systems