Current Medicinal Chemistry - Volume 24, Issue 10, 2017

Lipoprotein (a) [Lp(a)] is a low-density lipoprotein (LDL)-like particle with an additional apolipoprotein, apolipoprotein (a), [apo(a)] attached to apolipoprotein B. Recent epidemiologic and Mendelian randomization studies have provided evidence that Lp(a) is causally related to the pathogenesis of atherosclerosis and cardiovascular disease (CVD). The risk association between Lp(a) concentrations and CVD is still controversial but seems to be continuous and without an obvious threshold Lp(a) level. Circulating concentrations of Lp(a) are genetically determined; desirable levels are < 50 mg/dl. A plasma concentration of 60 mg/dl is associated with an odds ratio for coronary heart disease of about 1.5 after adjustment for other cardiovascular risk factors. Extended-release niacin is an option for decreasing elevated Lp(a) levels (by ~20-30%) but it is often poorly tolerated. Dietary measures, exercise and lipid-lowering drugs such as statins and ezetimibe are without significant effect. In patients with severe progressive CVD and very high Lp(a) levels, lipoprotein apheresis can decrease Lp(a) concentrations. The method is expensive and impractical for most patients and its feasibility depends mainly on the healthcare reimbursement system. Since no established treatment reduces Lp(a) without influencing other lipoproteins, there has been no trial that evaluated whether decreasing Lp(a) concentrations translates to clinical benefits. Recently, an antisense oligonucleotide against apo(a), IONIS-APO(a)Rx, has been shown to selectively decrease Lp(a) by almost 80%. A phase 2 study with this drug has been completed in late 2015 and results are expected to be published soon.

The limited distribution of lipoprotein (a) (Lp(a)) to humans, Old World primates and to the European hedgehog, has raised considerable interest and speculation regarding its possible physiological role. Lp(a) has variable circulating concentrations (<0.1 – >100 mg/ml) which are highly genetically determined in humans. These characteristics gave rise to several theories concerning the origins and evolution of Lp(a). Lp(a) has a protective role after injury since Lp(a) particles bind to macrophages and platelets membrane receptors, leading to fibrin activation and injury healing. On the other hand, Lp(a) seems to be implicated in the formation of atheromatic plaques but also in cerebrovascular events and stenosis of the aortic valve. The main genetic factor determining plasma Lp(a) levels is the Lp(a) gene (LPA). Most Caucasian people have normal plasma Lp(a) concentrations, but there is important distribution variation according to race. Women seem to have increased Lp(a) levels compared with men, while diabetes mellitus type 2 favours lower plasma Lp(a) levels. Nutrition, hormones and several drugs may also influence circulating Lp(a) levels.

Cardiovascular disease (CVD) continues to be the first cause of mortality in developed countries. Moreover, far from diminishing, the cardiovascular risk factors leading towards the development of CVD are on the rise. Therefore, the preventive and therapeutic management which is currently in place is clearly not enough to stop this pandemic. In this context, a major resurgence in interest in lipoprotein (a) [Lp(a)] has occurred in light of its association with CVD. This series aims to review the basic and clinical aspects of Lp(a) biology. Specifically, the present review considers the current situation regarding the influence of lifestyle, hormones and other physiological or pathological conditions on Lp(a) plasma concentrations which might mitigate the harmful effects of this lipoprotein.

Lipoprotein (a) [Lp(a)] is an independent but moderate, predictor for coronary heart disease (CHD) prevalence and severity. Several established and emerging cardiovascular (CV) risk factors including age, gender, ethnicity, smoking, dyslipidemia, hypertension, obesity, type 2 diabetes mellitus, alcohol consumption, arterial stiffness and hyperuricemia have been linked to Lp(a) metabolism. Apart from CHD, Lp(a) has been also associated with non-cardiac vascular diseases and diseases associated with increased CV risk such as chronic kidney disease, metabolic syndrome, non-alcoholic fatty liver disease, erectile dysfunction, obstructive sleep apnea syndrome, inflammatory bowel diseases and human immunodeficiency virus infection. The above data are discussed in the present narrative review. Several guidelines suggest the clinical use of Lp(a) in (re)defining vascular risk, especially in asymptomatic individuals at intermediate or high CV risk and those with a family history of premature CHD. By improving individuals risk stratification, Lp(a) may contribute to a better secondary prevention strategy. However, there is still a need to establish a standardized method to measure Lp(a) as well as selective potent therapies for lowering Lp(a). This will support conducting large randomized trials in order to establish whether lowering circulating Lp(a) levels will result in a significant reduction in CV events.

This review covers recent discoveries of phytoconstituents, herbal extracts and some semi-synthetic compounds for treating metabolic syndrome with AMPK activation as one of their mechanisms of action. Recent researches have demonstrated AMPK activation to ameliorate multiple components of metabolic syndrome by regulating a balance between anabolic and catabolic cellular reactions. The review attempts to delineate the AMPK activation by natural agents from the perspective of its functional consequences on enzymes, transcription factors and signaling molecules and also on other potential factors contributing in the amelioration of metabolic syndrome.