Current Drug Targets (v.10, #4)
Editorial [Hot Topic: One Century of Triglycerides, but there is Still Lots to Learn(Guest Editors: K. Anagnostopoulou, D.P. Mikhailidis and G. Kolovou)] by K. Anagnostopoulou, D. Mikhailidis, Genovefa Kolovou (299-301).
In 1901 Eijkman developed a method to test the presence of lipase in animal fat . In 1912 Wells and Corper tested 5 different esters of ethyl butyrate, triacetin and olive oil and suggested that all esters are attacked by the same enzyme . Triglycerides (TGs) were first described by Trussell and Weed in 1937 . Since then, serum TG concentrations are often measured in clinical practice. However, Garber and Avins believe that their use in screening for cardiovascular risk should be rather experimental than practical . Other researchers also believe that low and high density lipoprotein cholesterol concentrations are better markers of cardiovascular risk . The relevance of low density lipoprotein cholesterol has been emphasized by survival trials of statins [5,6]. A causal role for TGs in coronary heart disease has been never conclusively proved and TGs have not been found in atherosclerotic plaques. The biological variability in fasting TGs, which can be easily influenced by a fat meal for the next 4-8 h (nonfasting hyperlipidaemia, discussed in this issue by Nordestgaard et al.) , and the failure of many investigators to control for confounding by high density lipoprotein cholesterol, which has a strong inverse correlation with serum TGs, exaggerate this problem. Hypertriglyceridaemia may be due to genetic factors (primary hypertriglyceridaemia) or to causes like medication or disease (secondary hypertriglyceridaemia) . The primary and secondary causes of hypertriglyceridaemia are considered in the current issue by Kolovou et al. . There are indirect mechanisms by which TGs may promote the progression of atherosclerosis, such as endothelial function, thrombogenesis and low and high density lipoprotein particle size (smaller, denser and more atherogenic) . In this issue Tziomalos et al. consider these mechanisms and the role of TGs in the progression of atherosclerosis . In 1994, the PROCAM study presented evidence for an independent contribution from TGs to coronary risk . In a cohort from the Physicians' Health Study, TGs were a strong and independent risk factor for cardiovascular disease, independently of high density lipoprotein cholesterol . Moreover, data from a meta-analysis showed that for every 1 mmol/l (88 mg/dl) increase in TG concentration, the relative risk of coronary heart disease increased by 14and#x25; in men and 37and#x25; in women . Additionally, available prospective studies in Western populations consistently indicate moderate and highly significant associations between TG values and coronary heart disease risk . A large number of studies have shown that treatment with hypolipidaemic drugs significantly reduces deaths from coronary heart disease but a large proportion of cardiovascular events are still not prevented [16-19]. Hypolipidaemic and non-hypolipidaemic drugs affecting hypertriglyceridaemia (e.g. weight reducing, diabetes mellitus, antihypertensives) are discussed in the current issue by AS Wierzbicki . A multi-factorial intervention for all risk factors, including weight reduction, dietary modification and increased physical exercise, is also discussed by Manfredini et al. . The authors focus on the influence of diet, sedentary lifestyle and negative habits (such as excessive alcohol intake and smoking) on hypertriglyceridaemia as well as the effects of lifestyle change. This points to the need for a better understanding of lipid metabolism. An extensive review on TG properties and metabolism is presented by Karantonis et al. .
Triacylglycerol Metabolism by Haralabos Karantonis, Tzortzis Nomikos, Constantinos Demopoulos (302-319).
Apart from being the main energy reserves of the human body, triacylglycerols take part in metabolic processes that determine the rate of fatty acid oxidation, the plasma levels of free fatty acids, the biosynthesis of other lipid molecules and the metabolic fate of lipoproteins. Allosteric, hormonal, nutritional and transcriptional signals activate shortterm and long-term regulatory mechanisms that assure the storage of triacylglycerols (TAGs) under states of excess energy and their mobilization under conditions of metabolic stress. New enzymes and novel regulatory mechanisms, involved in triacylglycerol metabolism, have been recently discovered and new details on the fine tuning of their metabolic reactions are coming to light. This knowledge will help us understand the biochemical basis of several diseases for the pathogenesis of which triacylglycerols play a role.
Triglycerides and Vascular Risk: Insights from Epidemiological Data and Interventional Studies by Konstantinos Tziomalos, Vasilios Athyros, Asterios Karagiannis, Genovefa Kolovou, Dimitri Mikhailidis (320-327).
The role of elevated triglyceride (TG) levels in the pathogenesis of atherosclerosis is controversial. Some studies suggest that TG might play a direct role in the development of vascular disease. Elevated TG levels are also associated with other vascular risk factors and may therefore represent an indirect marker of a high risk state. Another issue is that laboratory measurements of TG levels frequently show a substantial variability. Accumulating epidemiological data show that there is an independent association of TG levels with vascular risk. Some interventional studies also suggested that lowering TG levels might prevent vascular events. It appears that TG might be more important as therapeutic targets against a background of optimal low density lipoprotein cholesterol (LDL-C) levels. In this context, statins that are more effective in reducing TG levels, fibrates that can safely be combined with statins or fixed fibrate and statin combinations, as well as new, better tolerated nicotinic acid formulations might prove to be particularly beneficial.
Nonfasting Hyperlipidemia and Cardiovascular Disease by B. Nordestgaard, A. Langsted, J. Freiberg (328-335).
Most humans are in the nonfasting or postprandial state in the majority of a 24 hour cycle; however, lipids, lipoproteins, and apolipoproteins are usually measured in the fasting state. Recent studies demonstrate that these values at most change minimally in response to normal food intake, changes that are clinically unimportant. Also, elevated levels of nonfasting triglycerides as a marker of elevated remnant lipoprotein cholesterol associate strongly with increased risk of myocardial infarction, ischemic stroke, and early death. The mechanism behind these findings likely involves entrance of remnant lipoproteins into the arterial intima with subsequent retention leading to atherogenesis, while low HDL cholesterol levels may be an innocent bystander. Finally, nonfasting levels of total cholesterol, non-HDL cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, HDL cholesterol, apolipoprotein A1, total cholesterol/HDL cholesterol, and apolipoprotein B/apolipoprotein A1 all associate with increased risk of cardiovascular disease. These new data open the possibility that nonfasting rather than fasting lipid profiles can be used for cardiovascular risk prediction. If implemented, this would simplify blood sampling for lipid measurements for millions of patients worldwide. Furthermore, the results also highlight the need for randomized double-blind trials of new and established drugs to reduce nonfasting triglycerides and remnant lipoprotein cholesterol, with the ultimate aim of reducing risk of cardiovascular disease and early death.
Primary and Secondary Hypertriglyceridaemia by Genovefa Kolovou, Katherine Anagnostopoulou, Peggy Kostakou, Helen Bilianou, Dimitri Mikhailidis (336-343).
Familial hypertriglyceridaemia is inherited in an autosomal dominant manner. The responsible genetic abnormality is unknown but recently, a novel gene encoding apolipoprotein AV has been linked to familial hypertriglyceridaemia. All patients develop the same phenotype with elevated levels of very low density lipoproteins (VLDL) in plasma. The main disorder of this dyslipidaemia is decreased intestinal absorption of biliary acids, leading to a compensatory increase of VLDL production. In familial hypertriglyceridaemia, a marked increase in plasma triglyceride (TG) levels can cause acute pancreatitis. Moreover, patients with other genetic factors, like familial chylomicronaemia, familial combined hyperlipidaemia, familial dysbetalipoproteinaemia and other rare disorders (e.g. Tangier disease and fish eye disease) may present increase of TG levels or cholesterol levels or both. Secondary hypertriglyceridaemias include hypothyroidism, kidney abnormalities (e.g. nephrotic syndrome or chronic kidney failure), diabetes mellitus, heavy alcohol consumption and obesity. In men and postmenopausal women, it seems that estrogen deficiency is responsible for higher TG levels compared with premenopausal women postprandially. In every state -fasting or postprandial-, women demonstrate lower plasma TG levels compared with men. This fact is due not only to increased muscular TG uptake and storage but also to higher TG clearance. Many studies demonstrated an age impact on plasma TG increase and larger variation of fasting TG levels caused by age. Also, hypertriglyceridaemia (TG > 150 mg/dl; 1.7 mmol/l) is one of the diagnostic criteria of metabolic syndrome. Finally, several drugs may increase TG levels (e.g. chlorthalidone or beta-blockers).
Influence of Lifestyle Measures on Hypertriglyceridaemia by F. Manfredini, S. D'Addato, L. Laghi, A. Malagoni, S. Mandini, B. Boari, C. Borghi, R. Manfredini (344-355).
Hypertriglyceridaemia is a common dyslipidaemia encountered in clinical practice. People with hypertriglyceridaemia are frequently obese, insulin-resistant, hypertensive or diabetic, all of which are risk factors for cardiovascular diseases. Hypertriglyceridaemia also contributes to metabolic syndrome, in which an atherogenic diet, sedentary lifestyle, overweight/obesity and genetic factors interact. A multi-factorial intervention for all risk factors is necessary, including weight reduction, dietary modification and increased physical exercise. This review focuses on the influence of diet, sedentary lifestyle and negative habits (such as excessive alcohol intake, smoking and drug addiction) on hypertriglyceridaemia as well as the effects of lifestyle change.
Potential Options to Treat Hypertriglyceridaemia by Adie Viljoen, Anthony Wierzbicki (356-362).
Hypertriglyceridaemia is associated with insulin resistance, hypertension, obesity and diabetes. The management of hypertriglyceridaemia and atherogenic dyslipidaemias increasingly involves the use of several drugs for different aspects of the metabolic syndrome. This review highlights the agents for treatment of blood pressure, weight and blood pressure that reduce triglycerides as a number of drugs used to treat these co-morbidities also lower triglycerides as additional effects beyond their primary actions. Lipid - lowering drugs particularly fibrates and niacin and to a lesser degree statins and omega-3 fatty acids reduce plasma triglyceride levels. Additional reductions can be gained from the appropriate choice of therapies for co-morbid condition as the optimal combinations may offer benefits in improving cardiovascular risk as well as compliance.
Chalcones Derivatives Acting as Cell Cycle Blockers: Potential Anti Cancer Drugs? by Boumendjel Ahcene, Ronot Xavier, Boutonnat Jean, Ahcene Boumendjel, Xavier Ronot, Jean Boutonnat (363-371).
Chalcones (1,3-diphenylpropen-1-ones) are naturally occurring compounds belonging to the flavonoid family and are largely investigated in various therapeutic area and especially as antitumor drugs. In the latter field, the literature survey indicates that effect on the cell cycle is one of the most important targets domains of chalcones. In this review, we will shed light on: a) the structural criteria responsible for the cell cycle perturbations, b) the activity of chalcones on cell cycle molecular players or regulators c) the correlation between the chalcone-structure and proteins involved directly or not in cell cycle regulation and apoptosis by enhancement of proapoptotic molecules expression. We will discuss some perspectives related on how can we deal with chemical modification of chalcones to come up with more potent compounds to provide new ways for cancer treatment.
Mitochondrial Serine Protease HtrA2/Omi as a Potential Therapeutic Target by Md. Bhuiyan, Kohji Fukunaga (372-383).
Deregulation of apoptosis has been shown to contribute to the development of many diseases, including ischemia/ reperfusion injury of organs, different types of cancer formation, as well as neurodegenerative and autoimmune disorders. Recently, the mitochondrial serine protease High temperature requirement A2 (HtrA2)/Omi has drawn attention as it played pivotal role in different pathological conditions. We critically discussed the rationale for therapeutically targeting HtrA2 signaling in pathological conditions and explore the molecular mechanisms of HtrA2 inhibition as a novel therapeutic strategy. The precise mode of action and importance of HtrA2 in mitochondrial quality control as well as in apoptosis in mammalian cells has been recently studied through biochemical, structural and genetic studies. This review introduces HrtA2 from its molecular origins, discusses its modulation and potential as a novel drug target, and considers future therapeutic perspectives.