ReviewKeynoteEmerging strategies of targeting lipoprotein lipase for metabolic and cardiovascular diseases
Introduction
Homeostatic balance of fat absorption, synthesis and breakdown is crucial to the metabolic health of humans. The dietary lipids absorbed via the small intestine and the lipids carried in the form of lipoproteins generated by the liver are the major contributors to circulatory lipid levels and comprise the exogenous and endogenous pathways of lipid transport, respectively. The circulatory lipids in exogenous and endogenous lipid transport pathways converge on a catabolic enzyme named lipoprotein lipase (LPL). The enzymatic activity of LPL is central to the maintenance of plasma lipid levels in check in the face of excessive fat intake or dysregulated lipid metabolism in the liver. As such, LPL has slowly but definitively emerged as a drug target in dyslipidemia.
Lipases are the orchestrators of fat digestion and absorption, metabolism of lipoproteins and mobilization of stored depots of fats to oxidative tissues in conditions of nutrient demand. The catalytic reaction that facilitates the role of LPL in these processes is the hydrolytic cleavage of the ester bonds of the triacylglycerols (TGs) to form glycerol and free fatty acids. This hydrolytic processing of lipids known as lipolysis is carried out in the gastrointestinal tract (pancreatic lipase, gastric lipase, among others), intracellularly [adipose triglyceride lipase (ATGL), hormone-sensitive lipase, among others], as well as in circulatory blood vessels. In the vasculature, the key lipases are LPL, endothelial lipase (EL) and hepatic lipase (HL). These three lipases differ in the relative ratios of their triglyceride lipase to phospholipase activity [1]. Although all three enzymes are involved in triglyceride metabolism, the current review will focus on LPL as a drug target in metabolic diseases.
Section snippets
LPL: structure, function and regulation
LPL is primarily synthesized in the heart, skeletal muscle and adipose tissue. Other tissues with measurable LPL activity include lungs, lactating mammary glands, brain, kidney and macrophages. In all tissues, LPL is found lining the capillary endothelial lumen and its main function is to hydrolyze the core triglycerides in the triglyceride-rich lipoproteins such as the chylomicrons and the very-low-density lipoproteins (VLDLs) yielding glycerol and free fatty acids (FFAs) for uptake by
Pharmacological targeting of LPL
The recognition of LPL as a drug target has existed for several decades. LPL modulation has been shown to be a pleiotropic effect of several clinically used drugs in metabolic disorders. However, a clinically useful drug with LPL activation as its centerpiece mechanistic effect has not yet been achieved. Only recently, the emergence of ANGPTL proteins and a renewed interest in APO proteins has reinvigorated the quest for a LPL-targeted drug. Strategies to target LPL have yielded a wide range of
Concluding remarks
Over the past 5–10 years, LPL has attracted significant pharmacological attention in the treatment of metabolic disease and the downstream cardiovascular sequelae. Increased efforts of understanding of LPL physiology in recent years have led to identification of ANGPTL proteins GPIHB1 and LMF1 as key players in LPL biology, revitalizing the interest in LPL as a drug target. The pursuit of the approaches outlined in this manuscript and development of other novel modalities of targeting LPL are
Prabodh Sadana, PhD, is an Assistant Professor in the Department of Pharmaceutical Sciences at Northeast Ohio Medical University. Dr Sadana obtained his doctorate in pharmacology from the University of Tennessee studying transcriptional regulation of genes involved in fatty acid oxidation and glucose metabolism. Dr Sadana underwent postdoctoral training in chemical biology at the St Jude Children's Research Hospital, studying the development of novel small molecules regulating nuclear hormone
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Prabodh Sadana, PhD, is an Assistant Professor in the Department of Pharmaceutical Sciences at Northeast Ohio Medical University. Dr Sadana obtained his doctorate in pharmacology from the University of Tennessee studying transcriptional regulation of genes involved in fatty acid oxidation and glucose metabolism. Dr Sadana underwent postdoctoral training in chemical biology at the St Jude Children's Research Hospital, studying the development of novel small molecules regulating nuclear hormone receptors involved in metabolic pathways. Dr Sadana's current research focuses on the molecular pathways of regulation of lipid metabolism and the development of novel small-molecule approaches in the treatment of dyslipidemias.