Selective Synthesis of Perovskite Oxyhydrides Using a High-Pressure Flux Method.

Oxyhydrides with multi-anions (O2- and H-) are a recently developed material family and have attracted attention as catalysts and hydride ion conductors. High-pressure and high-temperature reactions are effective in synthesizing oxyhydrides, but the reactions sometimes result in inhomogeneous products due to insufficient diffusion of the solid components. Here, we synthesized new perovskite oxyhydrides SrVO2.4H0.6 and Sr3V2O6.2H0.8. We demonstrated that the addition of SrCl2 flux promotes diffusion during high-pressure and high-temperature reactions, and can be used for selective synthesis of the oxyhydride phases. We conducted in-situ synchrotron X-ray diffraction measurements to reveal the role of this flux and reaction pathways. We also demonstrated the electronic and magnetic properties of the newly synthesized oxyhydrides and that they work as anode materials for Li-ion batteries with excellent reversibility and high-rate characteristics, the first case with an oxyhydride. Our synthesis approach would also be effective in synthesizing various types of multi-component systems.

Hormone-sensitive lipase protects adipose triglyceride lipase-deficient mice from lethal lipotoxic cardiomyopathy.

Lipid droplets (LDs) are multifunctional organelles that regulate energy storage and cellular homeostasis. The first step of triacylglycerol hydrolysis in LDs is catalyzed by adipose triglyceride lipase (ATGL), deficiency of which results in lethal cardiac steatosis. Although hormone-sensitive lipase (HSL) functions as a diacylglycerol lipase in the heart, we hypothesized that activation of HSL might compensate for ATGL deficiency. To test this hypothesis, we crossed ATGL-KO (AKO) mice and cardiac-specific HSL-overexpressing mice (cHSL) to establish homozygous AKO mice and AKO mice with cardiac-specific HSL overexpression (AKO+cHSL). We found that cardiac triacylglycerol content was 160-fold higher in AKO relative to Wt mice, whereas that of AKO+cHSL mice was comparable to the latter. In addition, AKO cardiac tissues exhibited reduced mRNA expression of PPARα-regulated genes and upregulation of genes involved in inflammation, fibrosis, and cardiac stress. In contrast, AKO+cHSL cardiac tissues exhibited expression levels similar to those observed in Wt mice. AKO cardiac tissues also exhibited macrophage infiltration, apoptosis, interstitial fibrosis, impaired systolic function, and marked increases in ceramide and diacylglycerol contents, whereas no such pathological alterations were observed in AKO+cHSL tissues. Furthermore, electron microscopy revealed considerable LDs, damaged mitochondria, and disrupted intercalated discs in AKO cardiomyocytes, none of which were noted in AKO+cHSL cardiomyocytes. Importantly, the life span of AKO+cHSL mice was comparable to that of Wt mice. HSL overexpression normalizes lipotoxic cardiomyopathy in AKO mice and the findings highlight the applicability of cardiac HSL activation as a therapeutic strategy for ATGL deficiency-associated lipotoxic cardiomyopathies.

High-Pressure and High-Temperature Synthesis of Anion-Disordered Vanadium Perovskite Oxyhydrides.

Crystallographic order-disorder phenomena in solid state compounds are of fundamental interest due to intimate relationship between the structure and properties. Here, by using high-pressure and high-temperature synthesis, we obtained vanadium perovskite oxyhydrides Sr1-xNaxVO3-yHy (x = 0, 0.05, 0.1, 0.2) with an anion-disordered structure, which is different from anion-ordered SrVO2H synthesized by topochemical reduction. High-pressure and high-temperature synthesis from nominal composition SrVO2H yielded the anion-disordered perovskite SrVO3-yHy (y ∼ 0.4) with a significant amount of byproducts, while Na substitution resulted in the almost pure anion-disordered perovskite Sr1-xNaxVO3-yHy with an increased amount of hydride anion (y ∼ 0.7 for x = 0.2). The obtained disordered phases for x = 0.1 and 0.2 are paramagnetic with almost temperature-independent electronic conductivity, whereas anion-ordered SrVO2H is an antiferromagnetic insulator. Although we obtained the anion-disordered perovskite under high pressure, a first-principles calculation revealed that the application of pressure stabilizes the ordered phase due to a reduced volume in the ordered structure, suggesting that a further increase of the pressure or reduction of the reaction temperature leads to the anion ordering. This study shows that anion ordering in oxyhydrides can be controlled by changing synthetic pressure and temperature.

Comparative effects of insulin glulisine and lispro on postprandial plasma glucose and lipid profile in Japanese patients with type 2 diabetes mellitus.

OBJECTIVE: The control of postprandial plasma glucose (PPG) excursions is critical in the prevention of diabetic complications. Controversy remains on the differences in postprandial actions of insulin glulisine and lispro. The aim of this study was to define the differences in the efficacy of these two insulin analogues on PPG. METHODS: The study subjects were 20 in-hospital patients with type 2 diabetes mellitus (T2DM). Plasma glucose (PG) was tightly controlled with basal insulin and insulin glulisine or lispro, and then glulisine or lispro were switched to the other insulin analog every other day for 6 study days. PG was measured before breakfast and 0.5-, 1-, and 2 h-postprandial during the study. Postprandial plasma C-peptide and lipids were analyzed in the first 2 days of the study. Postprandial increments in each parameter were compared between glulisine and lispro. RESULTS: Whereas the median value of 0.5 h-Δ-PPG was comparable in glulisine and lispro, the 1 h-Δ-PPG was significantly lower with lispro than with glulisine (41 vs 53 mg/dl, respectively, p = 0.03). Similarly, the 2 h-Δ-PPG with lispro was 10 mg/dl lower than that with glulisine (35 vs 45 mg/dl, respectively, p = 0.05). In parallel with PPG, Δ-C-peptide at 1- and 2 h-postprandial were significantly lower with lispro than glulisine (0.50 vs 0.75 ng/ml, respectively, and 0.55 vs 0.75 ng/ml, respectively). The increment in LDL-C and HDL-C was significantly lower with lispro than with glulisine at 0.5 h-postprandial. CONCLUSION: Insulin lispro seems superior to glulisine in the control of PPG in Japanese patients with T2DM.

An association study of C9orf3, a novel component of the renin-angiotensin system, and hypertension in diabetes.

The renin-angiotensin system (RAS) is important in the onset and course of cardiovascular, kidney, and metabolic disorders. Previous reports showed that the RAS blockade protects organs and suppress the development of type 2 diabetes mellitus. A novel component of the RAS, namely, chromosome 9 open reading frame 3 (C9orf3), was recently identified, however, its effects are unclear. We evaluated whether the genetic variant of C9orf3 is associated with morbidity of hypertension among subjects with type 2 diabetes. We enrolled 382 subjects with type 2 diabetes, 222 of whom were diagnosed with hypertension. Human leukocyte genomic DNA was isolated and a genetic variant was analyzed for a C/T variant of C9orf3 (rs4385527) via PCR analysis. The relationship between the genotype and hypertension morbidity among subjects with diabetes was examined. The proportion of the respective C9orf3 genetic variants were as follows 247 CC, 119 CT, and 16 TT. The risk of hypertension was determined to be 1.58, with a 95% confidence interval of 1.11-2.27. Moreover, the p value was 0.012 for allelic comparison and for Armitage's trend test, with the C allele identified as the risk factor. Consequently, hypertension was markedly associated with type 2 diabetes in subjects with the C9orf3 variant, exhibiting a nearly 1.6-fold increased risk. The C variant of a new component of the RAS, C9orf3 (rs4385527) might have a considerable impact on the pathogenesis of hypertension in diabetes.

Cardiac overexpression of perilipin 2 induces atrial steatosis, connexin 43 remodeling, and atrial fibrillation in aged mice.

Atrial fibrillation (AF) is prevalent in patients with obesity and diabetes, and such patients often exhibit cardiac steatosis. Since the role of cardiac steatosis per se in the induction of AF has not been elucidated, the present study was designed to explore the relation between cardiac steatosis and AF. Transgenic (Tg) mice with cardiac-specific overexpression of perilipin 2 (PLIN2) were housed in the laboratory for more than 12 mo before the study. Electron microscopy of the atria of PLIN2-Tg mice showed accumulation of small lipid droplets around mitochondrial chains, and five- to ninefold greater atrial triacylglycerol (TAG) content compared with wild-type (WT) mice. Electrocardiography showed significantly longer RR intervals in PLIN2-Tg mice than in WT mice. Transesophageal electrical burst pacing resulted in significantly higher prevalence of sustained (>5 min) AF (69%) in PLIN2-Tg mice than in WT mice (24%), although it was comparable in younger (4-mo-old) mice. Connexin 43 (Cx43), a gap junction protein, was localized at the intercalated disks in WT atria but was heterogeneously distributed on the lateral side of cardiomyocytes in PLIN2-Tg atria. Langendorff-perfused hearts using the optical mapping technique showed slower and heterogeneous impulse propagation in PLIN2-Tg atria compared with WT atria. Cardiac overexpression of hormone-sensitive lipase in PLIN2-Tg mice resulted in atrial TAG depletion and amelioration of AF susceptibility. The results suggest that PLIN2-induced steatosis is associated with Cx43 remodeling, impaired conduction propagation, and higher incidence of AF in aged mice. Therapies targeting cardiac steatosis could be potentially beneficial against AF in patients with obesity or diabetes.

Inactivation of the Glucose-Dependent Insulinotropic Polypeptide Receptor Improves Outcomes following Experimental Myocardial Infarction.

Incretin hormones exert pleiotropic metabolic actions beyond the pancreas. Although the heart expresses both incretin receptors, the cardiac biology of GIP receptor (GIPR) action remains incompletely understood. Here we show that GIPR agonism did not impair the response to cardiac ischemia. In contrast, genetic elimination of the Gipr reduced myocardial infarction (MI)-induced ventricular injury and enhanced survival associated with reduced hormone sensitive lipase (HSL) phosphorylation; it also increased myocardial triacylglycerol (TAG) stores. Conversely, direct GIPR agonism in the isolated heart reduced myocardial TAG stores and increased fatty acid oxidation. The cardioprotective phenotype in Gipr-/- mice was partially reversed by pharmacological activation or genetic overexpression of HSL. Selective Gipr inactivation in cardiomyocytes phenocopied Gipr-/- mice, resulting in improved survival and reduced adverse remodeling following experimental MI. Hence, the cardiomyocyte GIPR regulates fatty acid metabolism and the adaptive response to ischemic cardiac injury. These findings have translational relevance for developing GIPR-based therapeutics.

Cardiac overexpression of perilipin 2 induces dynamic steatosis: prevention by hormone-sensitive lipase.

Cardiac intracellular lipid accumulation (steatosis) is a pathophysiological phenomenon observed in starvation and diabetes mellitus. Perilipin 2 (PLIN2) is a lipid droplet (LD)-associated protein expressed in nonadipose tissues, including the heart. To explore the pathophysiological function of myocardial PLIN2, we generated transgenic (Tg) mice by cardiac-specific overexpression of PLIN2. Tg hearts showed accumulation of numerous small LDs associated with mitochondrial chains and high cardiac triacylglycerol (TAG) content [8-fold greater than wild-type (WT) mice]. Despite massive steatosis, cardiac uptake of glucose, fatty acids and VLDL, systolic function, and expression of metabolic genes were comparable in the two genotypes, and no morphological changes were observed by electron microscopy in the Tg hearts. Twenty-four hours of fasting markedly reduced steatosis in Tg hearts, whereas WT mice showed accumulation of LDs. Although activity of adipose triglyceride lipase in heart homogenate was comparable between WT and Tg mice, activity of hormone-sensitive lipase (HSL) was 40-50% less in Tg than WT mice under both feeding and fasting conditions, suggesting interference of PLIN2 with HSL. Mice generated through crossing of PLIN2-Tg mice and HSL-Tg mice showed cardiac-specific HSL overexpression and complete lack of steatosis. The results suggest that cardiac PLIN2 plays an important pathophysiological role in the development of dynamic steatosis and that the latter was prevented by upregulation of intracellular lipases, including HSL.

On the top of ARB N/L type Ca channel blocker leads to less elevation of aldosterone.

The activation of the renin-angiotensin system (RAS) is one of the unfavourable characteristics of calcium channel blocker (CCB). N type calcium channel is thought to be involved in renin gene transcription and adrenal aldosterone release. Accordingly, N/L type CCB has a possibility of less elevation of plasma aldosterone concentrations (PAC) among CCBs. In a monotherapy study, we had already demonstrated that N/L type CCB leads to less activation of the RAS compared with L type CCB. The objective of this study is to substantiate the hypothesis that at the condition of additive administration on the top of an angiotensin receptor blocker (ARB), still N/L type CCB leads to less elevation of PAC compared with L type one. Subjects were 60 hypertensives administered with valsartan. As an open label study, amlodipine (L type) or cilnidipine (N/L type) were administered on the top of valsartan (ARB) in a cross-over manner. Results were as follows (valsartan+amlodipine compared with valsartan+cilnidipine): systolic blood pressure (SBP)/diastolic blood pressure (DBP) (mmHg): 132±10/76±10 compared with 131±10/77±9, P=0.95/0.48, plasma renin activity (PRA) (ng/ml·h): 2.41±2.67 compared with 2.00±1.50 P=0.20, PAC (pg/ml): 77.3±31.0 compared with 67.4±24.8, P<0.05, urinary albumin excretion (UAE) (mg/gCr): 105.9±216.1 compared with 73.9±122.2, P<0.05. Thus, PAC at cilnidipine was significantly lower than those at amlodipine in spite of the comparable BP reductions. Besides, UAE was significantly lower at cilnidipine. In conclusion, on the top of the ARB, it is suggested that cilnidipine administration might lead to less elevation of PAC and reduction in UAE compared with amlodipine.

Pioglitazone prevents tau oligomerization.

Tau aggregation and amyloid ß protein (Aß) deposition are the main causes of Alzheimer's disease (AD). Peroxisome proliferator-activated receptor γ (PPARγ) activation modulates Aß production. To test whether the PPARγ agonist pioglitazone (PIO) is also effective in preventing tau aggregation in AD, we used a cellular model in which wild-type tau protein (4R0N) is overexpressed (M1C cells) (Hamano et al., 2012) as well as primary neuronal cultures. PIO reduced both phosphorylated and total tau levels, and inactivated glycogen synthase kinase 3ß, a major tau kinase, associated with activation of Akt. In addition, PIO decreased cleaved caspase3 and C-terminal truncated tau species by caspase, which is expected to decrease tau aggregation. A fractionation study showed that PIO reduced high molecular-weight (120 kDa), oligomeric tau species in Tris Insoluble, sarkosyl-soluble fractions. Tau decrease was reversed by adding GW9662, a PPARγ antagonist. Together, our current results support the idea that PPARγ agonists may be useful therapeutic agents for AD.

Determinants of plasma renin activity: role of a human renin gene variant as a genetic factor.

The plasma renin activity (PRA) is affected by a number of environmental factors. However, significant heritability has been shown for the activity. A hypothesis that a candidate regulatory single-nucleotide polymorphism, C-5312T, of human renin gene should have a significant effect on PRA was elucidated and updating of independent determinants of PRA was attempted. Cross sectional study. Outpatient study. We enrolled consecutive 810 subjects who had consulted our hospitals for lifestyle-related diseases. Genotypes were assayed with genomic DNA for C-5312T. Among the genetic variants, the difference of PRA was evaluated. Monovariate linear regression analysis was performed to test the correlation between PRA and clinical variables. Finally, stepwise multiple regression analysis was performed to evaluate the independent determinants. On comparing 2 genotype groups, CC/CT and T allele homozygote, the geometric means of PRA were 0.778 and 0.941 ng/ml/h, respectively (F = 5.992, P = 0.015). Monovariate linear regression analysis revealed that a number of variables have a significant correlation with the activity, including urinary salt excretion. A stepwise multivariate regression analysis revealed that renin C-5312T variant (TT) is one of the independent determinants of PRA. Thus, for the first time, a human renin gene variant was associated with a significant increase in PRA as a genetic factor and the independent determinants for the activity were updated including genetic factor.

Genetic variant of the renin-angiotensin system and prevalence of type 2 diabetes mellitus: a modest but significant effect of aldosterone synthase.

Recent genome-wide association studies have identified multiple variants that confer risk of type 2 diabetes mellitus (DM). However, established associations explain only a part of the heritability. Thus, even at the genome-wide association studies era, candidate gene approach should be still useful. Recent interventional studies against the renin-angiotensin system (RAS) showed reduction in new onset of DM, implying the system is involved in the onset. We substantiated the hypothesis that genetic variants of RAS have significant association with prevalence of DM. We enrolled to the study consecutive 782 subjects who had consulted our hospitals for mainly lifestyle related diseases. They consisted of 282 (36.1 %) diabetes cases. Genotypes were assayed with genomic DNA for conventional four genes of the RAS, i.e., angiotensin converting enzyme (ACE) insertion/deletion variant, angiotensinogen (AGT) M235T variant, angiotensin II type I receptor (AT1) A1166C variant, and aldosterone synthase (CYP11B2) C-344T variant. Association between the genetic variants of the RAS and prevalence of type 2 DM was tested. A significant association of DM and CYP11B2 genotype was obtained. There was no significant association between DM and ACE, AGT and AT1 variants. A multivariate logistic regression showed that age, gender, and CYP11B2 genotype were independent factors for association to diabetes, the DM risk of CC/CT to TT being 1.40 (95 % CI 1.04-1.90, p = 0.029). Thus, it is concluded that a genetic variant of the RAS should have a modest but significant impact on the onset of type 2 diabetes mellitus.

Differential effects of α-glucosidase inhibitors on postprandial plasma glucose and lipid profile in patients with type 2 diabetes under control with insulin lispro mix 50/50.

BACKGROUND: The additive effect of α-glucosidase inhibitors (α-GIs) was investigated in patients with type 2 diabetes (T2D) under control with rapid-acting insulin analog. SUBJECTS AND METHODS: Thirty-six poorly controlled T2D patients were recruited, and plasma glucose (PG) was controlled by three times daily injection of insulin lispro mix 50/50 (Mix50) to maintain fasting PG <130 mg/dL and 2-h postprandial PG (PPG) <180 mg/dL. Another group of 20 patients was randomly assigned to either 0.3 mg of voglibose or 50 mg of miglitol, which was administered at breakfast every other day. Another group of 16 patients was assigned to a crossover study, in which each α-GI was switched every day during the 6-day study. PPG, C-peptide, and lipid profile were analyzed. RESULTS: The addition of voglibose had no effect on PPG, but miglitol blunted the PPG rise and significantly decreased 1-h and 2-h postprandial C-peptide levels compared with Mix50 alone. In addition, miglitol significantly decreased the 1-h postprandial triglyceride rise and the remnant-like particle-cholesterol rise, while it increased the 1-h postprandial high-density lipoprotein-cholesterol and apolipoprotein A-I levels in the crossover study. CONCLUSIONS: Miglitol appears to have rapid action, which appears earlier than that of lispro. The combination of miglitol and Mix50 seems effective for the control of PPG and lipid profile in T2D.

Comparative reactivity of remnant-like lipoprotein particles (RLP) and low-density lipoprotein (LDL) to LDL receptor and VLDL receptor: effect of a high-dose statin on VLDL receptor expression.

BACKGROUND: Comparison of the reactivity of remnant-like lipoprotein particles (RLP) and LDL particles to LDL receptor and VLDL receptor has not been investigated. METHODS: LDL receptor- or VLDL receptor-transfected ldlA-7, HepG2 and L6 cells were used. Human LDL and rabbit ß-VLDL were isolated by ultracentrifugation. Human RLP was isolated using an immunoaffinity mixed gel. The effect of statin on lipoprotein receptors was examined. RESULTS: Both LDL receptor and VLDL receptor recognized RLP. In LDL receptor transfectants, RLP, ß-VLDL and LDL all bound to LDL receptor. Cold RLP competed efficiently with DiI-ß-VLDL; however, cold LDL competed weakly. In VLDL receptor transfectants, RLP and ß-VLDL bound to VLDL receptor, but not LDL. RLP bound to VLDL receptor with higher affinity than ß-VLDL because of higher apolipoprotein E in RLP. LDL receptor expression was induced in HepG2 by the low concentration of statin while VLDL receptor expression was induced in L6 myoblasts at higher concentration. CONCLUSIONS: RLP are bound to hepatic LDL receptor more efficiently than LDL, which may explain the mechanism by which statins prevent cardiovascular risk by primarily reducing plasma RLP rather than by reducing LDL. Additionally, a high-dose of statins also may reduce plasma RLP through muscular VLDL receptor.

Species differences of macrophage very low-density-lipoprotein (VLDL) receptor protein expression.

Triglyceride-rich lipoproteins (TGRLs) and low-density-lipoprotein (LDL) cholesterol are independent risk factors for coronary artery disease. We have previously proposed that the very low-density-lipoprotein (VLDL) receptor is one of the receptors required for foam cell formation by TGRLs in human macrophages. However, the VLDL receptor proteins have not been detected in atherosclerotic lesions of several animal models. Here we showed no VLDL receptor protein was detected in mouse macrophage cell lines (Raw264.7 and J774.2) or in mouse peritoneal macrophages in vitro. Furthermore, no VLDL receptor protein was detected in macrophages in atherosclerotic lesions of chow-fed apolipoprotein E-deficient or cholesterol-fed LDL receptor-deficient mice in vivo. In contrast, macrophage VLDL receptor protein was clearly detected in human macrophages in vitro and in atherosclerotic lesions in myocardial infarction-prone Watanabe-heritable hyperlipidemic (WHHLMI) rabbits in vivo. There are species differences in the localization of VLDL receptor protein in vitro and in vivo. Since VLDL receptor is expressed on macrophages in atheromatous plaques of both rabbit and human but not in mouse models, the mechanisms of atherogenesis and/or growth of atherosclerotic lesions in mouse models may be partly different from those of humans and rabbits.

Effects of hormone-sensitive lipase disruption on cardiac energy metabolism in response to fasting and refeeding.

Increased fatty acid (FA) flux and intracellular lipid accumulation (steatosis) give rise to cardiac lipotoxicity in both pathological and physiological conditions. Since hormone-sensitive lipase (HSL) contributes to intracellular lipolysis in adipose tissue and heart, we investigated the impact of HSL disruption on cardiac energy metabolism in response to fasting and refeeding. HSL-knockout (KO) mice and wild-type (WT) littermates were fasted for 24 h, followed by ∼6 h of refeeding. Plasma FA concentration in WT mice was elevated twofold with fasting, whereas KO mice lacked this elevation, resulting in twofold lower cardiac FA uptake compared with WT mice. Echocardiography showed that fractional shortening was 15% decreased during fasting in WT mice and was associated with steatosis, whereas both of these changes were absent in KO mice. Compared with Langendorff-perfused hearts isolated from fasted WT mice, the isolated KO hearts also displayed higher contractile function and a blunted response to FA. Although cardiac glucose uptake in KO mice was comparable with WT mice under all conditions tested, cardiac VLDL uptake and lipoprotein lipase (LPL) activity were twofold higher in KO mice during fasting. The KO hearts showed undetectable activity of neutral cholesteryl esterase and 40% lower non-LPL triglyceride lipase activity compared with WT hearts in refed conditions accompanied by overt steatosis, normal cardiac function, and increased mRNA expression of adipose differentiation-related protein. Thus, the dissociation between cardiac steatosis and functional sequelae observed in HSL-KO mice suggests that excess FA influx, rather than steatosis per se, appears to play an important role in the pathogenesis of cardiac lipotoxicity.

Down regulation of immuno-detectable cardiac connexin-43 in BALB/c mice following acute fasting.

Acute starvation effects for connexin-43 protein expression, in the heart, had not been previously explored. Hence we examined acute fasting on the myocardial immuno-histochemical expression of connexin-43 in 3 groups of 8-week old female BALB/c mice. Groups consisted of control mice (n=5), fasting for 24 h (N=5) and 48 h (N=3). Under light microscopy all control fed cases revealed the presence of some immuno-detectable staining for connexin-43 that is either present or weakly observed in some or all of the regions of interest, that include the cross-sectional left ventricular sub-endocardium, mid-myocardium and papillary muscle. Whereas mice that underwent 24 or 48 h of acute starvation, connexin-43 expression was either difficult to detect visually (N=3) or was completely absent (N=5) at 40x magnification using a light microscope. In starved mice with no membrane staining for connexin-43 we observed an increase in the intracellular accumulation of cytoplasmic connexin-43 expression.

[A case of type 2 diabetes mellitus associated with familial hypercholesterolemia confirming the improvement of blood glucose control by colestimide].

A 65-year-old woman had been treated for type 2 diabetes mellitus, familial hypercholesterolemia and old myocardial infarction. Combination therapy of atorvastatin (40 mg/day), ethyl icosapentate (1,200 mg/day), probucol (500 mg/day) and colestimide (1 g/day) had never reached an ideal low-density lipoprotein cholesterol (LDL-C) level. However the conversion to high dose of colestimide (4 g/day) with the same dose of atorvastatin, ethyl icosapentate, and probucol obviously decreased her LDL-C level from 181.2 mg/dl to 148 mg/dl. Reduction of LDL-C level was also associated with the lowering of glycohemoglobin A1c from 10.7% to 8.7% simultaneously. Challenge tests by the cessation and resumption of only colestimide treatment clearly indicated that colestimide has both cholesterol and blood glucose lowering effect. Her body weight and appetite did not change by colestimide treatment. We think that colestimide therapy might provide a beneficial effect on atherosclerotic disease in diabetes mellitus with dyslipidemia through reduction of cholesterol and blood glucose.

Cardiac overexpression of hormone-sensitive lipase inhibits myocardial steatosis and fibrosis in streptozotocin diabetic mice.

Intracellular lipid accumulation (steatosis) and resultant lipotoxicity are key features of diabetic cardiomyopathy. Since cardiac hormone-sensitive lipase (HSL) is activated in diabetic mice, we sought to explore a pathophysiological function of cardiac HSL in the development of diabetic cardiomyopathy. Transgenic (Tg) mice with heart-specific HSL overexpression were generated, and cardiac histology, function, lipid profile, and gene expressions were analyzed after induction of diabetes by streptozotocin. Electron microscopy showed numerous lipid droplets in wild-type (Wt) hearts after 3 wk of diabetes, whereas Tg mice showed no lipid droplet accumulation. Cardiac content of acylglycerides was increased approximately 50% with diabetes in Wt mice, whereas this was blunted in Tg hearts. Cardiac lipid peroxide content was twofold lower in Tg hearts than in Wt hearts. The mRNA expressions for peroxisome proliferator-activated receptor-alpha, genes for triacylglycerol synthesis, and lipoprotein lipase were increased with diabetes in Wt hearts, whereas this induction was absent in Tg hearts. Expression of genes associated with lipoapoptosis was decreased, whereas antioxidant protein metallothioneins were increased in diabetic Tg hearts. Diabetic Wt hearts showed interstitial fibrosis and increased collagen content. However, Tg hearts displayed no overt fibrosis, concomitant with decreased expression of collagens, transforming growth factor-beta, and matrix metalloproteinase 2. Notably, mortality during the experimental period was approximately twofold lower in diabetic Tg mice compared with Wt mice. In conclusion, since HSL overexpression inhibits cardiac steatosis and fibrosis by apparently hydrolyzing toxic lipid metabolites, cardiac HSL could be a therapeutic target for regulating diabetic cardiomyopathy.