The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays an important role in cell growth and metabolism. mTOR has been postulated as a nutrient sensor, but its role in the ...regulation of fatty acid and glucose metabolism is poorly understood. For the first time, we show that mTOR inhibition in skeletal muscle cells has pronounced effects on intermediary metabolism. Rapamycin, a uniquely specific mTOR inhibitor with clinical applications, increased fatty acid oxidation by 60% accompanied by increased activities of carnitine palmitoyltransferases I and II, the former believed to be the primary intracellular regulatory enzyme of the fatty acid oxidation pathway. Furthermore, glucose transport capacity, glycogen synthesis, and glycolysis were reduced by approximately 40% under the same conditions. In addition, in the presence of rapamycin, hyperinsulinemic conditions (100 nmol/L insulin, 24 hours) were unable to suppress fatty acid oxidation in L6 myotubes. Rapamycin treatment also decreased baseline phosphorylation of mTOR residues S2448 and S2481 by 30% and almost completely abolished p70 S6 kinase phosphorylation. These results show that rapamycin causes a metabolic shift from glucose utilization to fatty acid oxidation in model muscle cells in the presence of nutrient abundance and underline the importance of mTOR as a key regulator in glucose and lipid metabolism.
A role of apolipoprotein D in triglyceride metabolism[S] Perdomo, German; Kim, Dae Hyun; Zhang, Ting ...
Journal of lipid research,
June 2010, 2010-Jun, 2010-06-00, 20100601, 2010-06-01, Letnik:
51, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Apolipoproteins (apo) are constituents of lipoproteins crucial for lipid homeostasis. Aberrant expression of apolipoproteins is associated with metabolic abnormalities. Here we characterized ...apolipoprotein D (apoD) in triglyceride metabolism. Unlike canonical apolipoproteins that are mainly produced in the liver, apoD is an atypical apolipoprotein with broad tissue distribution. We show that circulating apoD is present mainly in HDL and, to a lesser extent, in LDL and VLDL and that its plasma levels were reduced in db/db mice with visceral obesity and altered lipid metabolism. Elevated apoD production, derived from adenovirus-mediated gene transfer, resulted in significant reduction in plasma triglyceride levels in mice. This effect was attributable to enhanced LPL activity and improved catabolism of triglyceride-rich particles. In contrast, VLDL triglyceride production remained unchanged in response to elevated apoD production. These findings were recapitulated in high-fat–induced obese mice. Obese mice with elevated apoD production exhibited significantly improved triglyceride profiles, correlating with increased plasma LPL activity and enhanced postprandial fat tolerance. ApoD was shown to promote LPL-mediated hydrolysis of VLDL in vitro, correlating with its TG-lowering action in vivo. Apolipoprotein D plays a significant role in lipid metabolism. These data provide important clues to clinical observations that genetic variants of apoD are associated with abnormal lipid metabolism and increased risk of metabolic syndrome.
Background
Eltrombopag is useful for immune thrombocytopenia (ITP). However, results of clinical trials may not accurately mirror clinical practice reality. Here we evaluated eltrombopag for primary ...and secondary ITP in our ≥65‐year‐old population.
Methods
A total of 106 primary ITP patients (16 with newly diagnosed ITP, 16 with persistent ITP, and 74 with chronic ITP) and 39 secondary ITP patients (20 with ITP secondary to immune disorders, 7 with ITP secondary to infectious diseases, and 12 with ITP secondary to lymphoproliferative disorders LPD) were retrospectively evaluated.
Results
Median age of our cohort was 76 (interquartile range, IQR, 70‐81) years. 75.9% of patients yielded a platelet response including 66.2% complete responders. Median time to platelet response was 14 (IQR, 8‐21) days. Median time on response was 320 (IQR, 147‐526) days. Sixty‐three adverse events (AEs), mainly grade 1‐2, occurred. The most common were hepatobiliary laboratory abnormalities (HBLAs) and headaches. One transient ischemic attack in a newly diagnosed ITP and two self‐limited pulmonary embolisms in secondary ITP were the only thrombotic events observed.
Conclusion
Eltrombopag showed efficacy and safety in ITP patients aged ≥65 years with primary and secondary ITP. However, efficacy results in LPD‐ITP were poor. A relatively high number of deaths were observed.
There is an urgency to find new treatments for the devastating epidemic of diabetes. Pancreatic β-cells viability and function are impaired in the two most common forms of diabetes, type 1 and type ...2. Regeneration of pancreatic β-cells has been proposed as a potential therapy for diabetes. In a preliminary study, we screened a collection of marine products for β-cell proliferation. One unique compound (epoxypukalide) showed capability to induce β-cell replication in the cell line INS1 832/13 and in primary rat cell cultures. Epoxypukalide was used to study β-cell proliferation by (3)Hthymidine incorporation and BrdU incorporation followed by BrdU/insulin staining in primary cultures of rat islets. AKT and ERK1/2 signalling pathways were analyzed. Cell cycle activators, cyclin D2 and cyclin E, were detected by western-blot. Apoptosis was studied by TUNEL and cleaved caspase 3. β-cell function was measured by glucose-stimulated insulin secretion. Epoxypukalide induced 2.5-fold increase in β-cell proliferation; this effect was mediated by activation of ERK1/2 signalling pathway and upregulation of the cell cycle activators, cyclin D2 and cyclin E. Interestingly, epoxypukalide showed protection from basal (40% lower versus control) and cytokine-induced apoptosis (80% lower versus control). Finally, epoxypukalide did not impair β-cell function when measured by glucose-stimulated insulin secretion. In conclusion, epoxypukalide induces β-cell proliferation and protects against basal and cytokine-mediated β-cell death in primary cultures of rat islets. These findings may be translated into new treatments for diabetes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction
The influence of maternal body mass index (BMI) on respiratory quotient during pregnancy is not clear. We aim to evaluate longitudinal changes in energy expenditure, respiratory ...quotient, and substrate oxidation rates in normal and overweight women with uncomplicated pregnancies. We hypothesized that the threshold period in switching from a predominantly carbohydrate to a predominantly lipid metabolism may be different in normal and overweight women.
Material and methods
Forty healthy pregnant women were recruited for a prospective cohort study. They were divided into two groups, normal and overweight (BMI <25 kg/m2 or ≥25 kg/m2). Comparisons of indirect calorimetry data were performed monthly throughout pregnancy. The relationships between energy and substrate metabolism variables and maternal BMI were also analyzed.
Results
There was a significant increase in oxygen consumption (Vo2), carbon dioxide production (Vco2) and resting energy expenditure during pregnancy in both normal and overweight women. In the normal weight group, respiratory quotient decreased during the second trimester and increased in the last trimester. Respiratory quotient was lower in the overweight group in the second trimester and decreased in the last trimester; between‐group differences being significant at 20 and 36 weeks (0.85 ± 0.06 vs. 0.81 ± 0.01, p = 0.009; 0.87 ± 0.05 vs. 0.80 ± 0.03, p = 0.01, respectively). Lipid oxidation was significantly higher in overweight women at both 20 and 36 weeks (36.8 ± 19.7% vs. 55.2 ± 5.6%, p = 0.003 and 33.6 ± 18.2% vs. 59.6 ± 12.7%, p = 0.007, for normal and overweight group, respectively).
Conclusion
Prepregnancy maternal BMI influences lipid oxidation rate and respiratory quotient during pregnancy.
Abnormal fatty acid oxidation (FAO) is associated with maternal and fetal complications during pregnancy. The contribution of maternal and fetal tissues to FAO capacity during late pregnancy is ...important to understand the pathophysiology of pregnancy-associated complications. The aim of this study was to determine the expression levels of mitochondrial FAO enzymes in maternal and fetal tissues during late normal pregnancy.
We have measured by Real-time PCR the levels of long- and medium -chain acyl-CoA dehydrogenase (LCHAD and MCAD), two acyl-CoA dehydrogenases that catalyze the initial step in the mitochondrial FAO spiral.
LCHAD and MCAD were expressed in maternal skeletal muscle, subcutaneous adipose tissue, placenta, and maternal and fetal blood cells. LCHAD gene expression was four- to 16-fold higher than MCAD gene expression in placenta, adipose tissue and skeletal muscle. In contrast, MCAD gene expression was ~5-fold higher in fetal blood than maternal blood (p = 0.02), whereas LCHAD gene expression was similar between fetal blood and maternal blood (p =0.91).
LCHAD and MCAD are differentially expressed in maternal and fetal tissues during normal late pregnancy, which may represent a metabolic adaptation in response to physiological maternal dyslipidemia during late pregnancy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Activation of pancreatic β-cell proliferation has been proposed as an approach to replace reduced functional β-cell mass in diabetes. Quiescent fibroblasts exit from G0 (quiescence) to G1 through pRb ...phosphorylation mediated by cyclin C/cdk3 complexes. Overexpression of cyclin D1, D2, D3, or cyclin E induces pancreatic β-cell proliferation. We hypothesized that cyclin C overexpression would induce β-cell proliferation through G0 exit, thus being a potential therapeutic target to recover functional β-cell mass. We used isolated rat and human islets transduced with adenovirus expressing cyclin C. We measured multiple markers of proliferation: (3)Hthymidine incorporation, BrdU incorporation and staining, and Ki67 staining. Furthermore, we detected β-cell death by TUNEL, β-cell differentiation by RT-PCR, and β-cell function by glucose-stimulated insulin secretion. Interestingly, we have found that cyclin C increases rat and human β-cell proliferation. This augmented proliferation did not induce β-cell death, dedifferentiation, or dysfunction in rat or human islets. Our results indicate that cyclin C is a potential target for inducing β-cell regeneration.
Abstract Apolipoprotein D (ApoD) is an atypical apolipoprotein with an incompletely understood function in the regulation of triglyceride and glucose metabolism. We have demonstrated that elevated ...ApoD production in mice results in improved postprandial triglyceride clearance. This work studies the role of ApoD deficiency in the regulation of triglyceride and glucose metabolism and its dependence on aging. We used ApoD knockout (ApoD-KO) mice of 3 and 21 months of age. Body weight and food intake were measured. Hepatic histology, triglyceride content, lipoprotein lipase levels, and plasma metabolites were studied. Phenotypic characterization of glucose metabolism was performed using glucose tolerance test. β -Cell mass, islet volume, and islet number were analyzed by histomorphometry. Apolipoprotein D deficiency results in nonfasting hypertriglyceridemia in young ( P = .01) and aged mice ( P = .002). In young ApoD-KO mice, hypertriglyceridemia was associated with 30% to 50% increased food intake in nonfasting and fasting conditions, respectively, without changes in body weight. In addition, lipoprotein lipase levels were reduced by 35% in adipose tissue ( P = .006). In aged ApoD-KO mice, hypertriglyceridemia was not associated with changes in food intake or body weight, whereas hepatic triglyceride levels were reduced by 35% ( P = .02). Furthermore, nonfasting plasma insulin levels were elevated by 2-fold in young ( P = .016) and aged ( P = .004) ApoD-KO mice, without changes in blood glucose levels, glucose tolerance, β -cell mass, or islet number. These findings underscore the importance of ApoD in the regulation of plasma insulin levels and triglyceride metabolism, suggesting that ApoD plays an important role in the pathogenesis of dyslipidemia.
Apolipoprotein A-V (apoA-V) and apoC-III are exchangeable constituents of VLDL and HDL. ApoA-V counteracts the effect of apoC-III on triglyceride (TG) metabolism with poorly defined mechanisms. To ...better understand the effects of apoA-V on TG and cholesterol metabolism, we delivered apoA-V cDNA into livers of hypertriglyceridemic APOC3 transgenic mice by adenovirus-mediated gene transfer. In response to hepatic apoA-V production, plasma TG levels were reduced significantly as a result of enhanced VLDL catabolism without alternations in VLDL production. This effect was associated with reduced apoC-III content in VLDL. Increased apoA-V production also resulted in decreased apoC-III and increased apoA-I content in HDL. Furthermore, apoA-V-enriched HDL was associated with enhanced LCAT activity and increased cholesterol efflux. This effect, along with apoE enrichment in HDL, contributed to HDL core expansion and α-HDL formation, accounting for significant increases in both the number and size of HDL particles. As a result, apoA-V-treated APOC3 transgenic mice exhibited decreased VLDL-cholesterol and increased HDL-cholesterol levels. ApoA-V-mediated reduction of apoC-III content in VLDL represents an important mechanism by which apoA-V acts to ameliorate hypertriglyceridemia in adult APOC3 transgenic mice. In addition, increased apoA-V levels accounted for cholesterol redistribution from VLDL to larger HDL particles. These data suggest that in addition to its TG-lowering effect, apoA-V plays a significant role in modulating HDL maturation and cholesterol metabolism.
Skeletal muscle plays a major role in glucose and lipid metabolism. Active hepatocyte growth factor (HGF) is present in the extracellular matrix in skeletal muscle. However, the effects of HGF on ...glucose and lipid metabolism in skeletal muscle are completely unknown. We therefore examined the effects of HGF on deoxyglucose uptake (DOGU), glucose utilization, and fatty acid oxidation (FAO) in skeletal muscle cells. HGF significantly enhanced DOGU in mouse soleus muscles in vitro. Furthermore, HGF significantly increased: (i) DOGU in a time- and dose-dependent manner; (ii) glucose utilization; and (iii) plasma membrane expression of Glut-1 and Glut-4 in the rat skeletal muscle model of L6 myotubes. HGF-mediated effect on DOGU was dependent on the activation of phosphatidylinositol 3-kinase signaling pathway. On the other hand, HGF markedly and significantly decreased FAO in L6 myotubes without affecting the activities of carnitine palmitoyltransferase I and II. Collectively, these results indicate that HGF is a potent activator of glucose transport and metabolism and also a strong inhibitor of FAO in rodent myotubes. HGF, through its ability to stimulate glucose transport and metabolism and to impair FAO, may participate in the regulation of glucose disposal in skeletal muscle.
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