Katsunori Ishikawa

Thiazolidinedione derivative improves fat distribution and multiple risk factors in subjects with visceral fat accumulation—double-blind placebo-controlled trial

BACKGROUND It has been clarified that visceral fat accumulation leads to atherosclerosis through multiple risk factors such as insulin resistance, glucose intolerance, hyperlipidemia and hypertension. So far, it has been reported that a thaizolidinedione derivative, troglitazone, improves the insulin resistance in subjects with diabetes, glucose intolerance and obesity. However, it has not been reported yet that troglitazone affects fat distribution in subjects concomitant with visceral fat accumulation and multiple risk factors. METHODS Twenty-nine subjects with visceral fat accumulation who had at least two risk factors including glucose intolerance, hyperlipidemia and hypertension were investigated. They were randomly assigned to receive either 200 or 400 mg per day of troglitazone or placebo for 12 weeks. A 75 g oral glucose tolerance test (OGTT) was performed before and after the treatment for 12 weeks. Fasting plasma glucose, insulin, HbA(1c), total serum cholesterol (T-chol), triglyceride (TG), HDL-cholesterol (HDL-C), and blood pressure, as well as the number of risk factors were measured periodically during the treatment. The change of the abdominal fat distribution was evaluated using computed tomographic scanning (CT scan) at the umbilicus level. RESULTS After the treatment for 12 weeks, the area under the curve (AUC) of plasma glucose from a 75 g OGTT decreased dose-dependently. HbA(1c) and TG decreased significantly in the high-dose troglitazone group (400 mg per day) compared with the placebo group (P<0.05). Systolic blood pressure was significantly lower in subjects with hypertension in the pooled troglitazone group than in the placebo group (P<0.05). Therefore, the number of risk factors decreased with the troglitazone treatment. The ratio of visceral fat area (VFA) to subcutaneous fat area (SFA) (V/S ratio) decreased in the troglitazone groups due to decreased VFA and increased SFA. CONCLUSION These results suggest that thiazolidinedione derivative may be a useful drug to improve multiple risk factors by changing the fat distribution in subjects with visceral fat accumulation.

Familial type I hyperlipoproteinemia caused by apolipoprotein C-II deficiency

A study was made on the clinical and biochemical features of siblings of patients with hyperchylomicronemia and its inherited relationship. It was not a case of the classical type of familial LPL deficiency, but of familial apolipoprotein C-II deficiency. The first patient with apolipoprotein C-II deficiency was reported by Breckenridge et al. and our patients provide the basis for the second report of this new disease. Our observations in this study strongly suggest that familial apolipoprotein C-II deficiency is transmitted by an autosomal recessive mode of inheritance and heterozygotes of this disorder have no abnormalities of plasma lipid and lipoproteins in spite of the reduced plasma apolipoprotein C-II.

Coronary artery disease in heterozygous familial hypercholesterolemia

Serum lipids, lipoproteins and Achilles tendon thickness in 52 patients with heterozygous familial hypercholesterolemia (FH) were investigated in order to clarify what are the important factors for the development of coronary artery disease (CAD) in heterozygous FH patients. There were no significant differences in the average concentration of total cholesterol and triglyceride between the patients with and those without CAD. The HDL cholesterol (HDL-C) level was significantly lower in patients with CAD than in those without, and the HDL-C value was within the normal range in most of the patients with heterozygous FH, if not associated with CAD. Although most of the males aged over 50 years had CAD and a decreased level of HDL-C, many of the aged females were without signs of CAD. The HDL-C value of heterozygous FH patients with CAD was significantly lower compared with the age-matched group without CAD. The Achilles tendon was thicker in patients with CAD than in those without CAD, both for males and females, although it was less closely correlated with the incidence of CAD than HDL-C or the atherogenic index. A forecast concerning the development of CAD in heterozygous FH may be possible if we consider multiple parameters, such as HDL-C, atherogenic index, Achilles tendon thickness, etc.

Studies on drug-induced lipodosis (V). Changes in the lipid composition of rat liver and spleen following the administration of 4,4′-diethylaminoethoxyhexestrol

Administration of 4,4′-diethylamino-ethoxyhexestrol increased total phospholipids and free cholesterol in rat liver. An elevation of a peculiar glycerophospholipid, lysobisphosphatidic acid, was marked both in liver and spleen. An increase in phosphatidylinositol was also noticed in spleen. However these changes in rats were not so marked as in human cases. There was an accumulation of a substance in rat tissue which was identified as a derivative of the drug, while the intact drug accumulated in large amount in human cases. Differences in the effect of 4,4′-diethylaminoethoxyhexestrol on lipid metabolism between human and rat seem to be related to the difference in drug digesting ability between these two animal species.

Apo A-I and Apo A-II inhibit hepatic triglyceride lipase from human postheparin plasma

Summary The effect of apolipoprotein A-I and A-II on hepatic triglyceride lipase activity was studied. Purification of apolipoprotein A-I and A-II was carried out by gel filtration with Sephadex G-200 in 6 M urea. Hepatic triglyceride lipase was purified from human postheparin plasma by heparin-Sepharose affinity chromatography. We demonstrated that both apolipoprotein A-I and A-II substantially inhibited hepatic triglyceride lipase. It suggests that these apolipoproteins play an important role in the inhibition of hepatic triglyceride lipase activity by whole serum.

Accumulation of hydrocarbon in a patient with adrenoleukodystrophy.

SummaryThe lipid composition of tissues from a patient with adrenoleukodystrophy was examined. Cholesterol esters of both brain and adrenal tissues contained increased proportions of fatty acids longer than C22 in agreement with previous reports. During this study, thin-layer chromatographic analysis of the neutral lipid fraction from the cerebral white matter and the adrenal gland revealed an unknown spot, which was identified as hydrocarbon of n-alkanes (CnH2n+2, n=16–33) by means of gas-liquid chromatography and gas chromatography/mass spectrometry. There may be a relationship between the accumulation of hydrocarbons and the change in fatty acid metabolism that is the fundamental disorder of ALD, as: (1) the fatty acids abnormally accumulated in cerebral white matter and adrenal gland coincided in chain length (i.e. C24–C26) with the main peaks of n-alkane in the same tissues, and (2) an abnormal accumulation of n-alkanes occurred in the diseased tissues where cholesterol esters with very long chain fatty acids were markedly increased.ZusammenfassungIm Gewebe eines Patienten mit Adrenoleukodystrophie wurde die Zusammensetzung der Fette untersucht. Die Cholesterolester sowohl von Gehirn wie auch von Nebennierengewebe enthielten einen höheren Anteil an Fettsäuren einer Kettenlänge von über C 22. Dies stimmt mit früheren Berichten überein. In der vorliegenden Untersuchung konnte in der Dünnschichtchromatographie der Neutralfettfraktion aus der weißen Substanz des Gehirnes und aus der Nebenniere ein Anteil nachgewiesen werden, der mittels Gaschromatographie und gaschromatographischen Massenspektrometrie als Wasserkohlenstoff des n-alkanes (CnH2n+2, n=16−33) identifiziert wurde. Es dürfte eine Beziehung zwischen der Zunahme des Wasserkohlenstoffes und den Veränderungen im Fettstoffwechsel bei der Adrenoleukodystrophie stehen. Die in abnormer Menge in der weißen Substanz des Gehirnes und in der Nebenniere anfallenden Fettsäuren entsprechen in der Länge der Ketten (C 24–C 26) den Haupt-Peaks des n-alkanes in den entsprechenden Geweben. Im weiteren war gerade in jenen Geweben eine abnorme Ansammlung von n-alkanen nachweisbar, in welchen Cholesterolester mit sehr langen Fettsäureketten stark vermehrt waren.