CD1d-dependent Activation of NKT Cells Aggravates Atherosclerosis

Adaptive and innate immunity have been implicated in the pathogenesis of atherosclerosis. Given their abundance in the lesion, lipids might be targets of the atherosclerosis-associated immune response. Natural killer T (NKT) cells can recognize lipid antigens presented by CD1 molecules. We have explored the role of CD1d-restricted NKT cells in atherosclerosis by using apolipoprotein E–deficient (apoE−/−) mice, a hypercholesterolemic mouse model that develops atherosclerosis. ApoE−/− mice crossed with CD1d−/− (CD1d−/−apoE−/−) mice exhibited a 25% decrease in lesion size compared with apoE−/− mice. Administration of α-galactosylceramide, a synthetic glycolipid that activates NKT cells via CD1d, induced a 50% increase in lesion size in apoE−/− mice, whereas it did not affect lesion size in apoE−/−CD1d−/− mice. Treatment was accompanied by an early burst of cytokines (IFNγ, MCP-1, TNFα, IL-2, IL-4, IL-5, and IL-6) followed by sustained increases in IFNγ and IL-4 transcripts in the spleen and aorta. Early activation of both T and B cells was followed by recruitment of T and NKT cells to the aorta and activation of inflammatory genes. These results show that activation of CD1d-restricted NKT cells exacerbates atherosclerosis

Inhibition of Intestinal Bile Acid Transporter Slc10a2 Improves Triglyceride Metabolism and Normalizes Elevated Plasma Glucose Levels in Mice

Interruption of the enterohepatic circulation of bile acids increases cholesterol catabolism, thereby stimulating hepatic cholesterol synthesis from acetate. We hypothesized that such treatment should lower the hepatic acetate pool which may alter triglyceride and glucose metabolism. We explored this using mice deficient of the ileal sodium-dependent BA transporter (Slc10a2) and ob/ob mice treated with a specific inhibitor of Slc10a2. Plasma TG levels were reduced in Slc10a2-deficient mice, and when challenged with a sucrose-rich diet, they displayed a reduced response in hepatic TG production as observed from the mRNA levels of several key enzymes in fatty acid synthesis. This effect was paralleled by a diminished induction of mature sterol regulatory element-binding protein 1c (Srebp1c). Unexpectedly, the SR-diet induced intestinal fibroblast growth factor (FGF) 15 mRNA and normalized bile acid synthesis in Slc10a2−/− mice. Pharmacologic inhibition of Slc10a2 in diabetic ob/ob mice reduced serum glucose, insulin and TGs, as well as hepatic mRNA levels of Srebp1c and its target genes. These responses are contrary to those reported following treatment of mice with a bile acid binding resin. Moreover, when key metabolic signal transduction pathways in the liver were investigated, those of Mek1/2 - Erk1/2 and Akt were blunted after treatment of ob/ob mice with the Slc10a2 inhibitor. It is concluded that abrogation of Slc10a2 reduces hepatic Srebp1c activity and serum TGs, and in the diabetic ob/ob model it also reduces glucose and insulin levels. Hence, targeting of Slc10a2 may be a promising strategy to treat hypertriglyceridemia and diabetes

The Liver-Selective Thyromimetic T-0681 Influences Reverse Cholesterol Transport and Atherosclerosis Development in Mice

Liver-selective thyromimetics have been reported to efficiently reduce plasma cholesterol through the hepatic induction of both, the low-density lipoprotein receptor (LDLr) and the high-density lipoprotein (HDL) receptor; the scavenger receptor class B type I (SR-BI). Here, we investigated the effect of the thyromimetic T-0681 on reverse cholesterol transport (RCT) and atherosclerosis, and studied the underlying mechanisms using different mouse models, including mice lacking LDLr, SR-BI, and apoE, as well as CETP transgenic mice.T-0681 treatment promoted bile acid production and biliary sterol secretion consistently in the majority of the studied mouse models, which was associated with a marked reduction of plasma cholesterol. Using an assay of macrophage RCT in mice, we found T-0681 to significantly increase fecal excretion of macrophage-derived neutral and acidic sterols. No positive effect on RCT was found in CETP transgenic mice, most likely due to the observed decrease in plasma CETP mass. Studies in SR-BI KO and LDLr KO mice suggested hepatic LDLr to be necessary for the action of T-0681 on lipid metabolism, as the compound did not have any influence on plasma cholesterol levels in mice lacking this receptor. Finally, prolonged treatment with T-0681 reduced the development of atherosclerosis by 60% in apoE KOs on Western type diet. In contrast, at an earlier time-point T-0681 slightly increased small fatty streak lesions, in part due to an impaired macrophage cholesterol efflux capacity, when compared to controls.The present results show that liver-selective thyromimetics can promote RCT and that such compounds may protect from atherosclerosis partly through induction of bile acid metabolism and biliary sterol secretion. On-going clinical trials will show whether selective thyromimetics do prevent atherosclerosis also in humans

New trends in globalization of science and engineering education

Three decades ago most research and design were conducted in each country independently. But the world has become quite different since then. Global changes in technology and society changed the concept of an engineer. There is the need for engineers who can work effectively in changing global and technical environments. Less interest has been paid to the globalization of science and technology. This article reviews the stimulus, that impact the engineering profession and gives the recommendations concerning the profession of engineering, the technology and innovation

Mice Abundant in Muricholic Bile Acids Show Resistance to Dietary Induced Steatosis, Weight Gain, and to Impaired Glucose Metabolism.

High endogenous production of, or treatment with muricholic bile acids, strongly reduces the absorption of cholesterol. Mice abundant in muricholic bile acids may therefore display an increased resistance against dietary induced weight gain, steatosis, and glucose intolerance due to an anticipated general reduction in lipid absorption. To test this hypothesis, mice deficient in steroid 12-alpha hydroxylase (Cyp8b1-/-) and therefore abundant in muricholic acids were monitored for 11 weeks while fed a high fat diet. Food intake and body and liver weights were determined, and lipids in liver, serum and feces were measured. Further, responses during oral glucose and intraperitoneal insulin tolerance tests were evaluated. On the high fat diet, Cyp8b1-/- mice displayed less weight gain compared to wildtype littermates (Cyp8b1+/+). In addition, liver enlargement with steatosis and increases in serum LDL-cholesterol were strongly attenuated in Cyp8b1-/- mice on high fat diet. Fecal excretion of cholesterol was increased and there was a strong trend for doubled fecal excretion of free fatty acids, while excretion of triglycerides was unaltered, indicating dampened lipid absorption. On high fat diet, Cyp8b1-/- mice also presented lower serum glucose levels in response to oral glucose gavage or to intraperitoneal insulin injection compared to Cyp8b1+/+. In conclusion, following exposure to a high fat diet, Cyp8b1-/- mice are more resistant against weight gain, steatosis, and to glucose intolerance than Cyp8b1+/+ mice. Reduced lipid absorption may in part explain these findings. Overall, the results suggest that muricholic bile acids may be beneficial against the metabolic syndrome

Stimulation of murine biliary cholesterol secretion by thyroid hormone is dependent on a functional ABCG5/G8 complex

Secretion of cholesterol into bile is important for the elimination of cholesterol from the body. Thyroid hormone (TH) increases biliary cholesterol secretion and hepatic gene expression of adenosine triphosphate (ATP)-binding cassette, subfamily G (WHITE), member 5 (ABCG5) and ATP-binding cassette, subfamily G (WHITE), member 8 (ABCG8), two half-transporters that act as a heterodimeric complex promoting sterol secretion. In addition, nuclear liver x receptor-alpha (LXRa), also regulated by TH, induces gene expression of ABCG5/G8. We here investigated if the TH-induced stimulation of biliary cholesterol secretion is mediated by the ABCG5/G8 complex in vivo, and if so, whether LXRa is involved. Mice homozygous for disruption of Abcg5 (Abcg5(-/-)) or Lxra (Lxra(-/-)) and their wild-type counterparts were treated with triiodothyronine (T3) for 14 days and compared to untreated mice of corresponding genetic backgrounds. Bile was collected by gallbladder cannulation, and liver samples were analyzed for gene expression levels. Basal biliary cholesterol secretion in Abcg5(-/-) mice was 72% lower than in Abcg5(+/+) mice. T3 treatment increased cholesterol secretion 3.1-fold in Abcg5(+/+) mice, whereas this response was severely blunted in Abcg5(-/-) mice. In contrast, biliary cholesterol secretion in T3-treated Lxra(+/+) and Lxra(-/-) mice was increased 3.5- and 2.6-fold, respectively, and did not differ significantly. Conclusions: TH-induced secretion of cholesterol into bile is largely dependent on an intact ABCG5/G8 transporter complex, whereas LXRa is not critical for this effect. (HEPATOLOGY 2012;56:18281837