Biomedical subjects

Kenji Harada

Publications and source records attributed to Kenji Harada.

44 records · Page 3Linked to original sources

PubMed2002

Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)/Lep(ob) mice.

Obesity is a common nutritional problem often associated with diabetes, insulin resistance, and fatty liver (excess fat deposition in liver). Leptin-deficient Lep(ob)/Lep(ob) mice develop obesity and those obesity-related syndromes. Increased lipogenesis in both liver and adipose tissue of these mice has been suggested. We have previously shown that the transcription factor sterol regulatory element-binding protein-1 (SREBP-1) plays a crucial role in the regulation of lipogenesis in vivo. To explore the possible involvement of SREBP-1 in the pathogenesis of obesity and its related syndromes, we generated mice deficient in both leptin and SREBP-1. In doubly mutant Lep(ob/ob) x Srebp-1(-/-) mice, fatty livers were markedly attenuated, but obesity and insulin resistance remained persistent. The mRNA levels of lipogenic enzymes such as fatty acid synthase were proportional to triglyceride accumulation in liver. In contrast, the mRNA abundance of SREBP-1 and lipogenic enzymes in the adipose tissue of Lep(ob)/Lep(ob) mice was profoundly decreased despite sustained fat, which could explain why the SREBP-1 disruption had little effect on obesity. In conclusion, SREBP-1 regulation of lipogenesis is highly involved in the development of fatty livers but does not seem to be a determinant of obesity in Lep(ob)/Lep(ob) mice.

Adipose Tissue↗

PubMed2002

Left anterior descending coronary artery flow and its relation to age in children.

Recent advances in Doppler and color echocardiographic techniques enable coronary flow dynamics to be estimated even in children. To assess quantitatively left anterior descending coronary artery (LAD) volumetric flow and to determine its relation to age and left ventricular (LV) mass, healthy children participated in a study that used high-frequency transthoracic echocardiography. We also studied whether Doppler echocardiography can reliably measure LAD flow in a clinical setting. In 57 healthy children, 2-dimensional echocardiography was used to measure the diameter and cross-sectional area of the LAD and LV mass. LAD peak flow velocity, flow velocity integral, and flow volume were measured by Doppler echocardiography. We then calculated the ratio of LAD cross-sectional area to LV mass and the ratio of LAD flow volume to LV mass. In 12 patients with Kawasaki disease, LAD flow velocity and flow velocity integral were measured by Doppler echocardiography at the time of Doppler guide wire examination. There were significant correlations between echocardiographic and Doppler guide wire methods for flow velocity and flow velocity integral (r = 0.77 and 0.83, P <.01, respectively). The LAD flow velocity decreased significantly with age (r = -0.43, P <.01). The LAD flow volume per minute increased significantly with age (r = 0.55, P <.01). However, LAD flow volume/LV mass ratio in younger infants was high and decreased significantly with age (r = -0.66, P <.01). This study shows that LAD flow patterns can be reliably assessed by transthoracic Doppler echocardiography in the majority of pediatric subjects. In the current study, the LAD flow velocity and the ratio of LAD flow volume to LV mass in infants was high and decreased with age, suggesting high myocardial perfusion. High LAD peak velocity in infants may be related with high resting coronary flow. Age-related changes in the LAD flow characteristics must be taken into consideration in the study of the coronary circulation in children.

Adolescent↗

PubMed2002

Blood flow in the left anterior descending coronary artery in children with ventricular septal defect.

High-frequency echocardiography offers a noninvasive approach for imaging left anterior descending coronary artery (LAD) blood flow from a transthoracic window. The purpose of this study was to assess the effects of left ventricular (LV) volume overload on LAD flow in pediatric patients with ventricular septal defect (VSD). The study subjects consisted of 38 children with VSD and 15 healthy children. LV mass, LAD diameter, and LAD flow were measured by using transthoracic echocardiography, then LAD diameter and LV mass were indexed for body surface area. Pulmonary to systemic flow ratios (Qp/Qs) were obtained by cardiac catheterization. The Qp/Qs ratios ranged from 1.2 to 3.1 (mean 2.1 +/- 0.5). The mean LAD flow velocities, flow velocity integrals, and flow volumes were significantly higher in the patients than in the control subjects. LAD flow velocity and flow volume showed significant positive correlations with Qp/Qs, LV mass, and LV end-diastolic volume. Stepwise regression analysis revealed that Qp/Qs was the most important determinant of both LAD flow velocity (r(2) = 0.45, P < .0001) and LAD flow volume (r(2) = 0.44, P < .0001). The ratios of LAD flow volume to LV mass did not differ between the 2 groups. In 8 patients who underwent surgical treatment, LAD flow velocity, flow velocity integral, and flow volume decreased significantly after surgery. The current results suggest that patients with VSD have a higher resting coronary blood flow, and that LAD flow pattern is dependent on LV volume overload and changes after surgery.

Blood Flow Velocity↗

PubMed2002

Coronary flow reserve assessment by Doppler echocardiography in children with and without congenital heart defect: comparison with invasive technique.

To evaluate whether transthoracic Doppler echocardiography can reliably measure coronary flow velocity (CFV) and CFV reserve (CFVR) in the left anterior descending coronary artery (LAD) in children, we examined 12 patients who had a history of Kawasaki disease without stenosis or aneurysm formation of coronary artery and 9 patients who had congenital heart disease (ventricular septal defect in 6, patent ductus arteriosus in 2, tricuspid atresia in 1). The pulmonary-to-systemic flow ratio ranged from 1.7 to 2.8. CFV in the proximal LAD was measured by transthoracic Doppler echocardiography at the time of Doppler guidewire examination. CFV in the proximal LAD was measured at baseline and hyperemic conditions by both transthoracic Doppler echocardiography and Doppler guidewire techniques. CFVR was defined as "the ratio of peak hyperemic to basal CFV in the proximal LAD." Clear envelopes of basal and hyperemic CFV in the proximal LAD were obtained in 19 of 21 patients by transthoracic Doppler echocardiography. There was a significant correlation between transthoracic Doppler echocardiography and Doppler guidewire methods for the measurements of CFV (r = 0.84, P <.0001). The mean difference between the 2 methods was -0.5 +/- 5.9 cm/s. CFVR from transthoracic Doppler echocardiography correlated well with that from Doppler guidewire examinations (r = 0.83, P <.0001). The mean difference between the 2 methods was 0.06 +/- 0.24. Noninvasive measurement of CFV and CFVR in the proximal LAD using transthoracic Doppler echocardiography accurately reflects invasive measurement of CFV and CFVR by Doppler guidewire method in pediatric patients with various heart diseases.

Adenosine Triphosphatases↗

PubMed2002

A kindred of familial acromegaly without evidence for linkage to MEN-1 locus.

Familial acromegaly (FA) is a rare inherited disease characterized by clustering of somatotrophic adenomas and acromegaly within a family without other manifestations of multiple endocrine neoplasia-type 1 (MEN-1). The genetic basis of this pituitary-specific phenotype is largely unknown, and its relationship to the MEN-1 locus on chromosome 11q13 also remains unclear. To test the hypothesis that FA results from a germline mutation of the MEN-1 locus, we performed a linkage analysis in a Japanese family with 2 members showing manifestations of acromegaly due to somatotroph adenomas. We also examined the adenoma of one patient for loss of heterozygosity (LOH) at 11q13 locus and for the presence of mutations of codon 201 and 227 in the gene for Gsalpha. Our results provided no evidence that either germline alterations of the MEN-1 locus, LOH at 11q13, or somatic mutation of Gsalpha plays a causative role in the development of somatotroph adenomas in our FA family. Together with the previous reports, these results suggest that there are at least two distinct subgroups of FA: one that results from a mutation in MEN-1 locus and the other whose causative gene is located outside the 11q13 locus.

Acromegaly↗

PubMed2002

Left ventricular systolic and diastolic function during early neonatal period using transthoracic echocardiography.

To examine the effects of ductal closure on left ventricular (LV) systolic and diastolic function during the early neonatal periods, 45 normal term neonates delivered after uncomplicated pregnancies (mean 39 weeks) were studied using two-dimensional and Doppler echocardiography. We measured ductus arteriosus size, arterial blood pressures, ascending aortic size, LV dimensions, and transmitral flow velocity patterns and calculated LV output and rate-corrected fiber shortening fraction (mVcfc) at 2, 12, 24, and 120 hours after birth. The inner diameter of the ductus arteriosus was 4.3 +/- 0.7mm at 2 hours, 2.1 +/- 0.6 mm at 12 hours, and had closed in 42 of 45 neonates at 24 hours. LV output and LV end-diastolic dimension showed the highest level at 2 hours of age. However, the mVcfc did not change from 2 to 120 hours of age. The peak velocity during early diastole (peak E) was significantly greater at 2 hours than at 12 hours. The peak velocity during atrial contraction (peak A) remained unchanged during this period. The normalized peak filling rate at isovolumic relaxation time did not change over 120 hours. The present study demonstrated changes in LV systolic function and LV diastolic filling during the early neonatal period. LV systolic and diastolic function was preserved under the hemodynamic changes associated with the early neonatal period.

Cardiac Output↗

PubMed2002

Lipolysis in the absence of hormone-sensitive lipase: evidence for a common mechanism regulating distinct lipases.

Hormone-sensitive lipase (HSL) is presumed to be essential for lipolysis, which is defined as the mobilization of free fatty acids from adipocytes. In the present study, we investigated the effects of various lipolytic hormones on the lipolysis in adipocytes derived from mouse embryonic fibroblasts (MEF adipocytes) prepared from HSL-deficient mice (HSL-/-). HSL-/- MEF differentiated into mature adipocytes in a manner indistinguishable from that of wild-type mice. Both isoproterenol (ISO) and tumor necrosis factor (TNF)-alpha stimulated the rate of lipolysis in HSL-/- MEF adipocytes, although to a lesser extent than in wild-type cells, and these lipolytic activities were inhibited by H-89, a cAMP-dependent protein kinase inhibitor, and troglitazone, respectively. Thus, the responses of the residual lipolytic activity to lipolytic hormones and TNF-alpha were well conserved in the absence of HSL. Extracts from HSL-/- MEF adipocytes hydrolyzed triacylglycerol (TG) but not cholesterol ester, indicating that the residual lipolytic activity was mediated by another TG-specific lipase. The TG lipase activity, which was decreased in cytosolic fraction in response to ISO, was increased in fat cake fraction. Therefore, translocation of the TG lipase may explain, at least partially, the ISO-stimulated lipolysis in HSL-/- adipocytes. In conclusion, lipolysis is mediated not only by HSL but also by the non-HSL TG lipase, whose responses to lipolytic hormones are similar to those of HSL. We propose that both lipases are regulated by common mechanism of lipolysis.

Adipocytes↗

PubMed2002

Transcriptional activities of nuclear SREBP-1a, -1c, and -2 to different target promoters of lipogenic and cholesterogenic genes.

Recent studies on the in vivo roles of the sterol regulatory element binding protein (SREBP) family indicate that SREBP-2 is more specific to cholesterogenic gene expression whereas SREBP-1 targets lipogenic genes. To define the molecular mechanism involved in this differential regulation, luciferase-reporter gene assays were performed in HepG2 cells to compare the transactivities of nuclear SREBP-1a, -1c, and -2 on a battery of SREBP-target promoters containing sterol regulatory element (SRE), SRE-like, or E-box sequences. The results show first that cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c. Second, an E-box containing reporter gene is much less efficiently activated by SREBP-1a and -1c, and SREBP-2 was inactive in spite of its ability to bind to the E-box. Third, promoters of lipogenic enzymes containing variations of SRE (SRE-like sequences) are strongly activated by SREBP-1a, and only modestly and equally by both SREBP-1c and -2. Finally, substitution of the unique tyrosine residue within the basic helix-loop-helix (bHLH) portion of nuclear SREBPs with arginine, the conserved residue found in all other bHLH proteins, abolishes the transactivity of all SREBPs for SRE, and conversely results in markedly increased activity of SREBP-1 but not activity of SREBP-2 for E-boxes. These data demonstrate the different specificity and affinity of nuclear SREBP-1 and -2 for different target DNAs, explaining a part of the mechanism behind the differential in vivo regulation of cholesterogenic and lipogenic enzymes by SREBP-1 and -2, respectively.

ATP Citrate (pro-S)-Lyase↗