No abstract

Peroxisome proliferator-activated receptors (PPARs) control the transcription of genes involved in lipid metabolism. Activation of PPAR ␦ may have antiatherogenic effects through the increase of plasma HDL, theoretically promoting reverse cholesterol transport from peripheral tissues toward the liver for removal via bile and feces. Effects of PPAR ␦ activation by GW610742 were evaluated in wild-type and Abca1-deficient ( Abca1 ؊ / ؊ ) mice that lack HDL. Treatment with GW610742 resulted in an ‫ف‬ 50% increase of plasma HDL-cholesterol in wild-type mice, whereas plasma cholesterol levels remained extremely low in Abca1 ؊ / ؊ mice. Yet, biliary cholesterol secretion rates were similar in untreated wild-type and Abca1 ؊ / ؊ mice and unaltered upon treatment. Unexpectedly, PPAR ␦ activation led to enhanced fecal neutral sterol loss in both groups without any changes in intestinal Abca1 , Abcg5 , Abcg8 , and 3-hydroxy-3-methylglutaryl-coenzyme A reductase expression. Moreover, GW610742 treatment resulted in a 43% reduction of fractional cholesterol absorption in wild-type mice, coinciding with a significantly reduced expression of the cholesterol absorption protein NiemannPick C1-like 1 ( Npc1l1 ) in the intestine. PPAR ␦ activation is associated with increased plasma HDL and reduced intestinal cholesterol absorption efficiency that may be related to decreased intestinal Npc1l1 expression. Thus, PPAR ␦ is a promising target for drugs aimed to treat or prevent atherosclerosis. -van der Veen, J. N., J. K. Kruit, R. Havinga, J. Plasma levels of HDL-cholesterol are inversely related to the development of atherosclerosis (1). This protective effect has been attributed to a role of HDL in reverse cholesterol transport (RCT), defined as the flux of excess cholesterol from peripheral cells to nascent HDL particles followed by transport to the liver. The liver is able to secrete cholesterol into bile, either as free cholesterol or after conversion into bile salts, for removal via the feces. Stimulation of HDL-mediated cholesterol efflux is considered an attractive approach to diminish the development of atherosclerosis.ABCA1 is considered to be essential in RCT (2). ABCA1 is ubiquitously expressed and probably involved in the formation of pre ␤ -HDL particles and the efflux of cholesterol from peripheral tissues toward HDL (3). HDL is considered a major source for bile-destined cholesterol (4). However, we recently demonstrated that, despite the absence of HDL, hepatobiliary cholesterol flux and fecal sterol excretion are not affected in Abca1-deficient ( Abca1 Ϫ / Ϫ ) mice (5, 6). The ABCG5/ABCG8 heterodimer was recently shown to be of crucial importance for hepatobiliary cholesterol secretion and for transport of cholesterol from enterocytes back into the intestinal lumen, thereby promoting net cholesterol removal from the body (7,8).Several genes involved in the control of cholesterol meAbbreviations: Abca1 Ϫ / Ϫ , Abca1-deficient; FPLC, fast-protein liquid chromatography; Hmgr, 3-hydroxy-3-methylglutaryl-coenzyme...

van Straten EME, Bloks VW, Huijkman NCA, Baller JFW, van Meer H, Lü tjohann D, Kuipers F, Plö sch T. The liver X-receptor gene promoter is hypermethylated in a mouse model of prenatal protein restriction. Am J Physiol Regul Integr Comp Physiol 298: R275-R282, 2010. First published November 4, 2009 doi:10.1152/ajpregu.00413.2009.-Prenatal nutrition as influenced by the nutritional status of the mother has been identified as a determinant of adult disease. Feeding low-protein diets during pregnancy in rodents is a well-established model to induce programming events in offspring. We hypothesized that protein restriction would influence fetal lipid metabolism by inducing epigenetic adaptations. Pregnant C57BL/6J mice were exposed to a protein-restriction protocol (9% vs. 18% casein). Shortly before birth, dams and fetuses were killed. To identify putative epigenetic changes, CG-dinucleotiderich region in the promoter of a gene (CpG island) methylation microarrays were performed on DNA isolated from fetal livers. Two hundred four gene promoter regions were differentially methylated upon protein restriction. The liver X-receptor (Lxr) alpha promoter was hypermethylated in protein-restricted pups. Lxr alpha is a nuclear receptor critically involved in control of cholesterol and fatty acid metabolism. The mRNA level of Lxra was reduced by 32% in fetal liver upon maternal protein restriction, whereas expression of the Lxr target genes Abcg5/Abcg8 was reduced by 56% and 51%, respectively, measured by real-time quantitative PCR. The same effect, although less pronounced, was observed in the fetal intestine. In vitro methylation of a mouse Lxra-promoter/luciferase expression cassette resulted in a 24-fold transcriptional repression. Our study demonstrates that, in mice, protein restriction during pregnancy interferes with DNA methylation in fetal liver. Lxra is a target of differential methylation, and Lxra transcription is dependent on DNA methylation. It is tempting to speculate that perinatal nutrition may influence adult lipid metabolism by DNA methylation, which may contribute to the epidemiological relation between perinatal/neonatal nutrition and adult disease.programming; epigenetics; CpG island methylation microarray AN OVERWHELMING BODY OF EVIDENCE links fetal (mal)nutrition to the development of chronic diseases at adult age [developmental origins of health and disease hypothesis (4, 5)]. Epidemiological data show that children small for gestational age, who were undernourished during intrauterine development, have a higher risk of developing cardiovascular diseases or the metabolic syndrome in adulthood (3). In humans, fetal malnutrition is related to external factors (starvation, malnutrition, drug consumption of the mother) or to internal factors, such as placental dysfunction leading to reduced routing of nutrients to the fetus (32).Knowledge of underlying mechanisms of metabolic programming may help to design strategies to halt the current epidemic in metabolic diseases. For this purpose, several animal mo...

Effects of acute inhibition of glucose-6-phosphatase activity by the chlorogenic acid derivative S4048 on hepatic carbohydrate fluxes were examined in isolated rat hepatocytes and in vivo in rats. Fluxes were calculated using tracer dilution techniques and mass isotopomer distribution analysis in plasma glucose and urinary paracetamol-glucuronide after infusion of [U-13 C]glucose, [2-13 C]glycerol, [1-2 H]galactose, and paracetamol. In hepatocytes, glucose-6-phosphate (Glc-6-P) content, net glycogen synthesis, and lactate production from glucose and dihydroxyacetone increased strongly in the presence of S4048 (10 M). In livers of S4048-treated rats (0.5 mg kg ؊1 min ؊1 ; 8 h) Glc-6-P content increased strongly (؉440%), and massive glycogen accumulation (؉1260%) was observed in periportal areas. Total glucose production was diminished by 50%. The gluconeogenic flux to Glc-6-P was unaffected (i.e. 33.3 ؎ 2.0 versus 33.2 ؎ 2.9 mol kg ؊1 min ؊1 in control and S4048-treated rats, respectively). Newly synthesized Glc-6-P was redistributed from glucose production (62 ؎ 1 versus 38 ؎ 1%; p < 0.001) to glycogen synthesis (35 ؎ 5% versus 65 ؎ 5%; p < 0.005) by S4048. This was associated with a strong inhibition (؊82%) of the flux through glucokinase and an increase (؉83%) of the flux through glycogen synthase, while the flux through glycogen phosphorylase remained unaffected. In livers from S4048-treated rats, mRNA levels of genes encoding Glc-6-P hydrolase (ϳ9-fold), Glc-6-P translocase (ϳ4-fold), glycogen synthase (ϳ7-fold) and L-type pyruvate kinase (ϳ 4-fold) were increased, whereas glucokinase expression was almost abolished. In accordance with unaltered gluconeogenic flux, expression of the gene encoding phosphoenolpyruvate carboxykinase was unaffected in the S4048-treated rats. Thus, acute inhibition of glucose-6-phosphatase activity by S4048 elicited 1) a repartitioning of newly synthesized Glc-6-P from glucose production into glycogen synthesis without affecting the gluconeogenic flux to Glc-6-P and 2) a cellular response aimed at maintaining cellular Glc-6-P homeostasis.

It is concluded that Hx is able to induce proteinuria associated with MCD-like alterations in rat kidney in vivo.