Pavol Bohov

Regulation of gene expression for lipogenic enzymes in the liver and adipose tissue of hereditary hypertriglyceridemic, insulin-resistant rats: effect of dietary sucrose and marine fish oil

Hypertriglyceridemia is closely linked to insulin resistance. Increased dietary intake of n-3 polyunsaturated fatty acids reverses both hypertriglyceridemia and insulin resistance. To evaluate molecular mechanisms responsible for the hypotriglyceridemic effects of n-3 polyunsaturated fatty acids, the expression of genes for lipogenic enzymes in liver and white and brown adipose tissue was estimated in hereditary hypertriglyceridemic rats which underwent an euglycemic hyperinsulinemic clamp. Before the clamp, animals were fed a basal or a high (63%) sucrose diet with or without fish oil for two weeks. Results were compared to data obtained from control animals subjected to the identical protocol. In hereditary hypertriglyceridemic rats, gene expression for malic enzyme was increased in liver and in brown adipose tissue but not in white adipose tissue. The high sucrose diet raised malic enzyme mRNA levels in liver of both hereditary hypertriglyceridemic and control rats, and this effect was more pronounced in brown adipose tissue. Supplementing the high sucrose diet with fish oil led to a suppression of malic enzyme gene expression in liver and brown adipose tissue of control rats. However, this inhibitory effect was not as pronounced in the hereditary hypertriglyceridemic rats. Raised levels of fatty acid synthase mRNA in liver and brown adipose tissue of control rats fed high sucrose diet were suppressed by consumption of diet high in n-3 fatty acids. On the other hand, in hereditary hypertriglyceridemic rats fed high sucrose diet, fish oil supplementation failed to suppress increased levels of fatty acid synthase mRNA in liver and in brown adipose tissue. It appears that hereditary hypertriglyceridemic rats have elevated levels of mRNA for lipogenic enzymes in liver and brown adipose tissue and dietary control leading to an alteration of hypertriglyceridemia influences gene expression of lipogenic enzymes only under special dietary circumstances.

The Effect of Hyperlipidemia on Serum Fatty Acid Composition in Type 2 Diabeticsa

Fatty acid (FA) profiles of total serum lipids were determined by capillary gas chromatography in Type 2 diabetic patients (NIDDM) with diverse types of hyperlipidemia. In patients with hypertriglyceridemia (DM-HTG) and combined hypertriglyceridemia and hypercholesterolemia (DM-HLP), a significantly different total FA composition was found compared with healthy controls or diabetics with normal serum lipids. In particular, the proportions of saturated and monounsaturated FA were increased and the proportions of n-6 polyunsaturated FA were decreased. In DM-HLP patients, PUFA n-6 metabolites and C20-C22 PUFA were also decreased. Thus, hyperlipidemia shifts significantly the serum FA composition in NIDDM patients into an atherogenic profile. More study is needed, however, to understand if serum FA changes may contribute to the increased atherogenesis commonly found in these patients.

Glucose Transport and Insulin Signaling in Rat Muscle and Adipose Tissue Effect of Lipid Availability

Studies in vivo and in vitro have accumulated substantial evidence showing that hypertriglyceridemias of exogenous origin (diets high in fat and/or simple sugar) and endogenous origin (inborn) are frequently linked to the impairment of insulin action in various peripheral tissues. I+2 Several studies have indicated that raised plasma triglyceride levels in insulin-resistant states are accompanied by accumulation of triglycerides in skeletal m~scle.3-~ Skeletal muscle is the main site of insulin-induced glucose disposal.6 This process has been shown to be related to the fatty acid composition of skeletal muscle membrane structural lipids (i.e., phospholipids).7J Increasing the percentage of longchain polyunsaturated fatty acids (PUFA) of the n-3 series in muscle membrane phospholipids improves insulin a c t i ~ n . ~ v ~ J ~ Saturated fatty acids have an opposite effect.

Hepatobiliary Disposition of 3′-Azido-3′-deoxythymidine (AZT) in the Rat: Effect of Phenobarbitone Induction*

Abstract— Isolated liver with a recirculating perfusate was used to study 3′‐azido‐3′‐deoxythymidine (AZT) disposition in phenobarbitone‐pretreated rats at 68 μm AZT concentration in the reservoir. Clearance of AZT in the livers obtained from control animals was 0·42 ± 0·01 (mean ± s.d.) mL min−1/10 g liver. Over the study period of 105 min, 12·7 ± 2·6% of the dose was excreted in bile and of this 95% was recovered as 3′‐azido‐3′‐deoxy‐5′‐O‐β‐d‐glucopyranuronosylthymidine (GAZT). The amount of GAZT found in the perfusate after 105 min of liver perfusion was < 1% of the AZT dose introduced into the reservoir. Phenobarbitone pretreatment of rats resulted in a 5·5‐fold increase of AZT clearance. In addition, the area under the perfusate concentration‐time curve (AUC0–105 min) for 3′‐amino‐3′‐deoxythymidine (AMT) and for a catabolite of unknown structure was increased 3‐ and 10‐fold, respectively, and the amount of AZT dose excreted in the bile was nearly doubled. Thus phenobarbitone was capable of stimulating both detoxification of AZT to GAZT and bioactivation of AZT to AMT, a catabolite known to be highly toxic to human bone marrow cells. This induction was the result of enhancement of AZT catabolism rather than its transport into the cells, since on incubation of AZT (0–250 μm) with rat isolated hepatocytes, a linear relationship between concentration and amount taken up by the cells was shown. In addition, the rate of AZT uptake was not influenced by KCN, dinitrophenol, or temperature, which is consistent with a simple diffusion of AZT through the hepatocellular membrane. Rats dosed intraduodenally with [3H]GAZT excreted 5·8 ± 3·3% of the GAZT dose in bile within 4 h after administration. This suggests that enterohepatic recycling is involved in AZT disposition in the rat.

Decreased blood level of β2-microglobulin in the employees of a factory which produced polychlorinated biphenyls

Under the project of evaluating the health status of the employees of CHEMKO factory (East Slovakia) which produced PCBs between 1955 and 1985, the level of beta 2-microglobulin (beta 2-m) was measured in the serum of 242 subjects from CHEMKO (Group A) and two control groups from much less polluted areas: 1,277 females from a small mountainous village (Group B), 2,179 adults from the area of a large city of Kosice (Group C). The level of thymidine kinase (TK) was measured in the groups A and B only. In addition, age-matched groups of 155 women each from all areas were evaluated. In both the whole group and the age-matched group from CHEMKO the level of beta 2-m was significantly lower (P < 0.001) than that in the respective control groups, while no difference was found in the level of TK. In conclusion, it is suggested that the decrease of beta 2-m in CHEMKO employees might be related to the immunotoxic effects of organochlorines.

High Lipid Levels in Slovak Rural Population Consequence of Thyroid Dysfunction or Nutritional Status

P. LANGER,~ E. HANZEN,~ M. TAJTAKOVA,~ z. PUTZ,~ A. KREZE,~ E. SEBOKOVA,~ P. BOHOV,~ D. G A S P E R ~ O V A , ~ M. HUCKOVA,~ AND I. KLIMES~ Institute of Experimental Endocrinology Slovak Academy of Sciences 833 06 Bratislava, Slovak Republic Institute of Clinical Endocrinology Lhbochlia, Slovak Republic dFirst Clinic of Internal Medicine Faculty of Medicine P J. safdrik University EGice, Slovak Republic Department of Clinical Chemistry Faculty Hospital Faculty of Medicine Comenius University Bratisla va , Slovak Republic