Effects of cilostazol on lipid and fatty acid metabolism

Abstract Cilostazol is a selective inhibitor of phosphodiesterase III with anti-platelet-aggregatory and vasodilating properties. Randomised, double-blind, placebo-controlled trials in 2702 patients with intermittent claudication demonstrated that cilostazol significantly increased walking distances compared with placebo. Furthermore, the agent has beneficial effects on the serum lipid profile and fatty acid composition in plasma. Consequently, cilostazol may be useful to prevent atherosclerosis from progressing by ameliorating lipid and fatty acid metabolism.     

游离脂肪酸混合物对肝细胞脂毒性及脂代谢相关基因表达的影响

目的:研究游离脂肪酸(FFA)混合物对肝细胞L-02的脂毒性及脂代谢相关基因表达的影响。方法:正常肝细胞L-02分别用正常培养基和0.5、1、2 mmol/LFFA混合物(油酸和软脂酸的比例为2:1)培养24 h后,尼罗红染液室温避光染色,激光共聚焦显微镜及流式细胞仪确定细胞内脂质堆积情况。组织细胞酶法测定试剂盒测定细胞内甘油三酯含量。MTT法分析细胞存活率,Annexin V-PI凋亡检测试剂盒分析肝细胞的凋亡情况,丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)测定试剂盒分别检测培养液中ALT和AST活性。实时定量PCR技术检测脂代谢相关的脂肪分化相关蛋白(ADRP)和固醇调节元件结合蛋白1(SREBP-1)的mRNA表达情况。结果:各浓度FFAs混合物均可剂量依赖性增加肝细胞脂肪堆积和肝细胞甘油三酯含量,且1 mmol/LFFA混合物可增高肝细胞的甘油三酯含量2.6倍,与非酒精性脂肪肝病人的变化基本相同。2 mmol/LFFA混合物可降低肝细胞L-02细胞存活率并诱导细胞凋亡,而0.5 mmol/L和1 mmol/LFFA混合物对细胞无明显影响。与对照组相比,各浓度FFA混合物对细胞上清中ALT和AST活性无明显影响。1 mmol/LFFA混合物作用后可分别上调肝细胞的ADRP和SREBP-1 mRNA的表达2.660和2.758倍。结论:FFA混合物可诱导肝细胞L-02脂肪变性且2mmol/LFFA混合物可造成轻度细胞损伤。脂代谢相关基因ADRP和SREBP-1表达上调与FFA混合物诱导的脂肪变性相关。     

Oral fatty acid signaling and intestinal lipid processing: support and supposition

There is increasing recognition that specialized processes once thought to be relatively isolated to the oral cavity (e.g., taste) and intestine (e.g., nutrient absorption) are better characterized as common and continuous. This is exemplified by accumulating evidence linking oral detection of dietary fats to their intestinal processing. This review first summarizes this literature focusing on purported gustatory signaling by free fatty acid stimulation and enterocyte lipid storage and mobilization in humans. It then willfully speculates on the possible functions of this integrated system. It is proposed that it may aid absorption of fat soluble nutrients, enhance acute energy intake, sustain intestinal function during long inter-meal intervals, modulate appetite and/or detoxify ingested compounds including free fatty acids.     

Effects of fatty acids on lipid synthesis and viral RNA replication in poliovirus-infected cells.

Animal viruses profoundly modify the metabolism of lipids, the synthesis of new membranes, and membrane traffic. These alterations are related to the replication of viral genomes. Addition of oleic acid from the beginning of poliovirus infection inhibits the appearance of virus polypeptides at concentrations that do not affect translation in mock-infected HeLa cells. This inhibition is due to the blockade of viral RNA synthesis. Membranes made in poliovirus-infected cells in the presence of oleic acid differ in their buoyant density from control membranes. These results suggest that the incorporation of oleic acid into membranes leads to increased membrane fluidity and decreased buoyant density, making these membranes nonfunctional for poliovirus RNA replication.     

Human T lymphocytes require lipid as either lipoprotein or nonesterified fatty acid for in vitro activation.

Serum, which is required for activation of T cells in vitro, was fractionated to isolate and identify major supportive components. The serum activity concentrated exclusively with the lipoprotein fractions LDL and HDL. Furthermore, oleic and linoleic acids were equally active supplements, suggesting that resting T cells may require exogenous lipid because they are incapable of synthesizing fatty acid. A survey of fatty acids disclosed that all were capable of some degree of support. Titration delineated the narrow concentration range of lipid supplements successful in supporting T cell proliferation and demonstrated that concentrations must be rigidly controlled to optimize cell proliferation.     

Inhibition of fatty acid mobilization by arterial free fatty acid concentration

Subcutaneous, inguinal adipose tissue from dogs was perfused with blood in which the free fatty acid (FFA) concentration was varied corresponding to FFA/albumin molar ratios between 1 and 6. Otherwise the composition of the perfusate was kept constant. In order to stimulate lipolysis, isoprenaline and theophyllamine were added to the perfusate. A raise in arterial FFA/albumin molar ratio was without influence on lipolysis (as reflected in the release of glycerol), but reduced the FFA release indicating an increased re-esterification. At FFA/albumin ratios above 3 a marked increase in vascular resistance was seen. This increase was partly reversible within the time of a perfusion. When lipolysis is stimulated in the intact organism, the effects of increasing arterial FFA/albumin ratio on re-esterification and vascular resistance may serve as feedback mechanisms regulating FFA mobilization.     

Disorders of fatty acid composition and the processes of lipid peroxidation in chronic ischemic heart disease

The levels of lipid fractions, free and bound fatty acids, initial and end lipid peroxidation products in the blood plasma, red cell membrane resistance to hemolysis, and myocardial contractility before, during, and after therapy with lipostabil forte (0.6-1.8 g daily or 10 ml (0.5 g) i.v.) and bezafibrate (0.2 g 3 times daily) along with nitrates (10 to 30 tablets) have been examined by the routine methods in 159 patients with stable angina pectoris and postinfarction cardiosclerosis. A negative effect of high doses of nitrates on myocardial hemodynamics and fatty acid composition has been revealed, resulting in accumulation of bound fatty acids. Lipostabil has improved the patients' status, myocardial function, and lipid composition, reduced the levels of atherogenic lipids and lipid peroxidation products, as well as the concentration of fatty acids with an uneven number of C atoms, increased the fatty acid nonsaturation index and the level of medium-strand fatty acids. Improvement of the patient's condition in bezafibrate therapy has been less evident; the concentration of atherogenic lipids has been reduced, but the levels of bound fatty acids and of lipid peroxidation products has increased. Bezafibrate is recommended to be administered together with antioxidants.     

Primary role of decreased fatty acid synthesis in insulin resistance of large rat adipocytes

The ability of large fat cells from spontaneously obese rats to synthesize fatty acids from D-[1-14C]glucose, D-[6-14C]glucose, or [2-14C]pyruvate was markedly diminished compared to small fat cells from lean animals. Furthermore, fatty acid synthetase and acetyl coenzyme A carboxylase activities in dialyzed homogenates of large fat cells were inhibited by 84 and 90%, respectively, compared to small cells. Pentose shunt activity, but not glycolytic flux, was also markedly inhibited in large fat cells incubated with or without insulin. However, the NADPH oxidant vitamin K5 completely restored pentose shunt activity in large cells to the elevated levels observed in small fat cells in the presence of this agent or insulin. Furthermore, inhibition of mitochondrial oxidation and fatty acid synthesis in small cells by rotenone led to a secondary inhibition of pentose shunt activity indicating a link between these two pathways. Direct measurements of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities in fat cell homogenates showed no difference between cell types. The data provide strong support for the hypothesis that the fatty acid synthetic pathway is the primary metabolic defect in large insulin-resistant rat adipocytes, a defect which secondarily leads to inhibited pentose shunt activity.