We have discovered a novel compound, NO-1886, which possesses a powerful lipoprotein lipase (LPL) activity-increasing action. Administration of NO-1886 increased LPL activity in the postheparin plasma, adipose tissue, and myocardium of rats, and produced a reduction in plasma triglyceride levels with concomitant elevation ofHDL cholesterol levels. Administration of NO-1886 increased LPL enzyme mass in postheparin plasma and mRNA activity in epididymal adipose tissue, and it was concluded that the mode of action of this compound is stimulation of tissue LPL synthesis. We also conducted longterm studies to assess the impact of increases in LPL activity and HDL levels on the development of atherosclerotic lesions in rats. Administration of NO-1886 for as long as 90 d significantly decreased the degrere of atherosclerotic changes in the coronary arteries of vitamin D2-treated, cholesterol-fed rats. Statistical analysis indicated that increased concentration of HDL is the factor contributing mostly to the prevention ofcoronary artery sclerosis. In summary, the results of our study indicate that compound NO-1886 increases LPL activity, causing an elevation in HDL levels, and that long-term administration of NO-1886 to rats with experimental atherosclerosis provides significant protection against the development of coronary artery lesions. (J. Clin. Invest. 1993. 92:411417.)

Twenty-four hours after intratympanic administration of gadolinium contrast material (Gd), the Gd was distributed mainly in the perilymphatic space. Three-dimensional FLAIR can differentiate endolymphatic space from perilymphatic space, but not from surrounding bone. The purpose of this study was to evaluate whether 3D inversion-recovery turbo spin echo (3D-IR TSE) with real reconstruction could separate the signals of perilymphatic space (positive value), endolymphatic space (negative value) and bone (near zero) by setting the inversion time between the null point of Gd-containing perilymph fluid and that of the endolymph fluid without Gd. Thirteen patients with clinically suspected endolymphatic hydrops underwent intratympanic Gd injection and were scanned at 3 T. A 3D FLAIR and 3D-IR TSE with real reconstruction were obtained. In all patients, low signal of endolymphatic space in the labyrinth on 3D FLAIR was observed in the anatomically appropriate position, and it showed negative signal on 3D-IR TSE. The low signal area of surrounding bone on 3D FLAIR showed near zero signal on 3D-IR TSE. Gd-containing perilymphatic space showed high signal on 3D-IR TSE. In conclusion, by optimizing the inversion time, endolymphatic space, perilymphatic space and surrounding bone can be separately visualized on a single image using a 3D-IR TSE with real reconstruction.

We evaluated the newly developed whole-brain, isotropic, 3-dimensional turbo spin-echo imaging with variable flip angle echo train (SPACE) for contrast-enhanced T(1)-weighted imaging in detecting brain metastases at 3 tesla (T). Twenty-two patients with suspected brain metastases underwent postcontrast study with SPACE, magnetization-prepared rapid gradient-echo (MP-RAGE), and 2-dimensional T(1)-weighted spin echo (2D-SE) imaging at 3T. We quantitatively compared SPACE, MP-RAGE, and 2D-SE images by using signal-to-noise ratios (SNRs) for gray matter (GM) and white matter (WM) and contrast-to-noise ratios (CNRs) for GM-to-WM, lesion-to-GM, and lesion-to-WM. Two blinded radiologists evaluated the detection of brain metastases by segment-by-segment analysis and continuously-distributed test. The CNR between GM and WM was significantly higher on MP-RAGE images than on SPACE images (P<0.01). The CNRs for lesion-to-GM and lesion-to-WM were significantly higher on SPACE images than on MP-RAGE images (P<0.01). There was no significant difference in each sequence in detection of brain metastases by segment-by-segment analysis and the continuously-distributed test. However, in some cases, the lesions were easier to detect in SPACE images than in other sequences, and also the vascular signals, which sometimes mimic lesions in MP-RAGE and 2D-SE images, were suppressed in SPACE images. In detection of brain metastases at 3T magnetic resonance (MR) imaging, SPACE imaging may provide an effective, alternative approach to MP-RAGE imaging for 3D T(1)-weighted imaging.

The DNA sequences were determined for the lipoprotein lipase (LPL) gene from five unrelated Japanese patients with familial LPL deficiency. The results demonstrated that all five patients are homozygotes for distinct point mutations dispersed throughout the LPL gene. Patient 1 has a G-to-A transition at the first nucleotide of intron 2, which abolishes normal splicing.Patient 2 has a nonsense mutation in exon 3 (Tyr" -> Stop) and patient 3 in exon 8 (Trp"2 --Stop). The latter mutation emphasizes the importance of the carboxy-terminal portion of the enzyme in the expression of LPL activity. Missense mutations were identified in patient 4 (Asp2'-Glu) and patient 5 (Arg'3 His) in the strictly conserved amino acids. Expression study of both mutant genes in COS-1 cells produced inactive enzymes, establishing the functional significance of the two missense mutations. In these patients, postheparin plasma LPL mass was either virtually absent (patients 1 and 2) or significantly decreased (patients 3-5). To detect these mutations more easily, we developed a rapid diagnostic test for each mutation. We also determined the DNA haplotypes for patients and confirmed the occurrence of multiple mutations on the chromosomes with an identical haplotype. These results demonstrate that familial LPL deficiency is a heterogeneous genetic disease caused by a wide variety of gene mutations. (J. Clin. Invest.

We investigated the role of the overexpression of lipoprotein lipase (LPL) in lipoprotein abnormalities in transgenic mice with streptozotocin-induced diabetes mellitus. Before the induction of diabetes, LPL activity was 4.6-fold in skeletal muscle and 2.0-fold higher in the heart in transgenic mice than in their nontransgenic littermates. LPL activity in skeletal muscles in diabetic nontransgenic mice and cardiac LPL activity in diabetic nontransgenic and transgenic mice were decreased. Body weights were similarly reduced, and no appreciable amount of adipose tissue was observed in diabetes in both groups. The plasma triglyceride level was lower in diabetic transgenic mice than in diabetic nontransgenic mice (33.2 +/- 22.5 versus 185.3 +/- 57.4 mg/dL). Induction of diabetes was associated with a significant increase in the plasma cholesterol level in nontransgenic mice (90.0 +/- 11.1 versus 163.9 +/- 39.3 mg/dL) but much less in transgenic mice. Our results indicate that overexpression of LPL in transgenic mice inhibited diabetes-associated hypertriglyceridemia and hypercholesterolemia but did not affect the loss of body weight induced by diabetes.