Peroxisome proliferator-activated receptors in atherosclerosis and inflammation--an update.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor subfamily of transcription factors with pleiotropic effects on intra- and extracellular lipid metabolism, glucose homeostasis, cell proliferation, control of inflammation, and atherosclerosis. Three PPARs, namely alpha, delta, and gamma have been identified with distinct tissue distribution patterns and metabolic functions. PPAR-alpha is predominantly expressed in brown adipose tissue, liver, kidney, duodenum, heart, skeletal muscle, and vascular endothelial cells and is involved in the control of lipoprotein metabolism, fatty acid oxidation, and the cellular uptake of fatty acids. PPAR-gamma is highly expressed in brown and white adipose tissues and, to lesser extent, in large intestine, retina, and some parts of the immune system, and plays a critical role in adipocyte differentiation and fat deposition. PPAR-delta shows a widespread tissue distribution but its regulation and functions are not yet known. Considerable evidence indicates that PPARs (PPAR-alpha and PPAR-gamma) have beneficial effects in inflammatory diseases, including atherosclerosis, through regulation of cytokine production, adhesion molecule expression on the endothelial cells, fibrinolysis, and modulation of monocyte-derived macrophages. In this review, the general and specific roles of the PPAR isotypes and their implications in the control of vascular inflammation and atherosclerosis are discussed.

The RXR agonist LG100268 causes hepatomegaly, improves glycaemic control and decreases cardiovascular risk and cachexia in diabetic mice suffering from pancreatic beta-cell dysfunction.

AIMS/HYPOTHESIS: Although retinoid X receptor (RXR) and peroxisome proliferator activated receptor-gamma (PPARgamma) agonists have antidiabetic effects in hyperinsulinaemic animals, little information exists on their effects after pancreatic beta-cell failure. Thus, we examined if RXR and PPARgamma agonists alter distinct metabolic pathways in animals suffering from impaired insulin secretion. METHODS: Adverse side effects and antidiabetic responses were measured in db/db mice treated from 14-16 weeks of age with the RXR agonist, LG100268, and/or the PPARgamma agonists, BRL49653 or GW1929. RESULTS: In animals treated with LG100268 or BRL49653, serum glucose, glycohaemoglobin and the cardiovascular risk factor, fibrinogen, decreased to the same extent. Both of these agonists were equally effective at increasing insulin accumulation in beta cells, although neither agent had an effect on serum insulin concentrations. In contrast, the RXR agonist was less effective than the PPARgamma agonists at lowering serum triglycerides and non-esterified fatty acids and increasing interscapular brown fat and body weight. Further, LG100268 increased serum alkaline phosphatase and liver mass, hepatic fat accumulation, lauric acid hydroxylase activity, catalase-immunostaining and peroxisomal number more than the PPARgamma agonists. Moreover, co-treatment with the RXR and PPARgamma agonists reduced glucose, triglycerides, non-esterified fatty acids and cholesterol more than either agent alone. CONCLUSION/INTERPRETATION: These data suggest 1) RXR and PPARgamma agonists decrease islet degeneration, cardiovascular risk and cachexia during later stages of diabetes, 2) RXR agonists are less effective than PPARgamma agonists at decreasing serum lipids and causing weight gain and 3) RXR agonists have a more pronounced effect on liver metabolism (e.g. peroxisome accumulation and hepatomegaly) than PPARgamma agonists.

Use of Ca2+ modulation to evaluate biliary excretion in sandwich-cultured rat hepatocytes.

Previous work in our laboratory has indicated that biliary excretion of a substrate in sandwich-cultured hepatocytes can be quantitated by measurement of substrate accumulation in the presence and absence of extracellular Ca2+. The present study was designed to examine the effects of Ca2+ on taurocholate accumulation and tight junction integrity in cultured hepatocytes. Kinetic modeling was used to characterize taurocholate disposition in the hepatocyte monolayers in the presence and absence of extracellular Ca2+. The accumulation of taurocholate in freshly isolated hepatocytes, which lack an intact canalicular network, was the same in the presence and absence of extracellular Ca2+. Electron microscopy studies showed that Ca2+ depletion increased the permeability of the tight junctions to ruthenium red, demonstrating that tight junctions were the major diffusional barrier between the canalicular lumen and the extracellular space. Cell morphology and substrate accumulation studies in the monolayers indicated that Ca2+ depletion disrupted the tight junctions in 1 to 2 min. The integrity of the disrupted tight junctions was not re-established completely after reincubation in the presence of Ca2+ for 1 h. The accumulation of taurocholate was described best by a two-compartment model (cytosol and bile) with Michaelis-Menten kinetics for both uptake and biliary excretion. In summary, Ca2+ depletion does not alter hepatocyte transport properties of taurocholate. Ca2+ modulation may be a useful approach to study biliary excretion of substrates in sandwich-cultured hepatocytes.

Retinal pigment epithelial dystrophy in Briard dogs.

The eyes of normal Briard dogs, Briards affected with inherited retinal pigment epithelial dystrophy (RPED) and a range of normal crossbred and beagle dogs were examined and the histopathology of RPED in the Briard was compared with the histopathological features of ageing in the normal canine retina. RPED was characterised by the accumulation of auto-fluorescent lipofuscin-like inclusions in the retinal pigment epithelium (RPE), which initially involved only non-pigmented RPE cells overlying the tapetum but subsequently spread to all pigmented RPE cells. Secondary neuro-retinal degeneration was characterised by a gradual loss of the outer nuclear layer and the subsequent atrophy and degeneration of the inner retina. The loss of primary photoreceptors in the peripheral retina was accompanied by the migration of photoreceptor nuclei and appeared to resemble severe changes due to ageing. Intra-vitreal radiolabelled leucine was used to examine the rate of turnover of the outer segments of the rods in some Briards, but no significant variations were found. The activity of acid phosphatase in RPE was assayed in vitro and showed comparable regional variations in Briard and crossbred dogs. The results suggest that RPED in the Briard is unlikely to be due either to an increased rate of turnover of rod outer segments (and thus an increased phagocytic load) or to a primary insufficiency of lysosomal enzyme.