Lipoproteins transport lipids in the circulation and are key drivers in the progression and etiology of cardiovascular disease (CVD). Increased low-density lipoprotein cholesterol (LDL-c) is a well-established risk factor for CVD and is effectively treated with statins. Together with treatments for increased blood glucose and hypertension, statins have contributed to a major improvement in the management of CVD. However, although conventional lipid-lowering treatment goals have been reached, there is still major residual risk for cardiovascular events. Only 25 % of all coronary events are prevented by reaching statin treatment LDL-c goals [1]. A significant part of the residual risk is correlated to non-LDL-c dyslipidemia i.e. independent risk factors such as increased non-fasting plasma triacylglycerol (TG) and low high-density lipoprotein cholesterol (HDL-c) [2, 3]. Especially diabetics display an atherogenic dyslipidemia with elevated plasma TG levels, lowered HDL-c levels as well as prolonged- and elevated postprandial plasma lipid levels. Together these characteristics significantly contributes to the 3-4 times higher prevalence of CVD in this patient group.

Available pharmacological agents, e.g. niacin and fibrates, for the treatment of non-LDL-c dyslipidemia are linked to severe side-effects (e.g. flushing and rhabdomyolysis) and an inability to improve clinical outcomes when combined with statins according to the recently published AIM-HIGH and ACCORD studies. Several new agents affecting TG and HDL-c are now in clinical trials, but some already finished trials have been disappointing e.g. CETP-inhibitors. Thus, there is a great need for novel treatments of dyslipidemia in high risk patients, such as diabetics displaying atherogenic dyslipidemia. Since CVD is the leading cause for morbidity and mortality worldwide, even a minor further reduction in risk will affect millions of people, increasing life expectancy and quality of life.

Lipoprotein metabolism is balanced through influx of dietary lipids in the form of chylomicrons and hepatic very low-density lipoproteins (VLDL) and the clearance of these TG-rich lipoproteins and their remnants by lipases and lipoprotein receptors. Plasma TG levels are regulated by lipoprotein lipase (LPL) which is the principal enzyme in blood lipid metabolism [4]. Together with several cofactors, inhibitors and activators it constitutes the ‘LPL system’. The LPL system responds quickly, and tissue specific, to changes in nutritional status [5]. This allows inflow of lipids to adipose tissue for storage during nutritional excess and inflow to heart and skeletal muscle during fasting and/or physical activity. Most of the quick change in LPL activity is due to post-transcriptional regulation of the enzyme. LPL exerts its catalytic effect at the luminal side of the capillary endothelium hydrolyzing TG, carried by lipoproteins, into fatty acids for concomitant use or storage by the underlying tissue. The mature LPL enzyme is secreted as an active, non-covalent and rather unstable homodimer by parenchymal cells (e.g. adipocytes and myocytes) and reaches the capillary lumen after endothelial transcytosis by GPIHBP1 [6]. The instability of LPL might be a necessity for quick and precise regulation. The mature dimer enzyme is secreted in abundance but through partly unknown factors it is split into monomeric catalytically inactive LPL which is quickly cleared by the liver. On the luminal side of the endothelium LPL is sequestered to its site of action and stabilized through interaction with negatively charged heparan sulfate proteoglycans (HSPG) and possibly GPIHBP1.

Since LPL is the principal enzyme in lipoprotein metabolism, regulating primarily TG clearance but also de novo HDL formation, which is confirmed by the inverse correlation between plasma TG levels and HDL-c levels [7]. It has therefore been an attractive target for pharmacological stimulation for many decades (schematic overview figure 1). The powerful catalytic activity of LPL modulates plasma lipid levels leading to a decrease in atherosclerotic lesions in various animal disease models [8]. In accordance, genetic knock-out of inhibiting factors, e.g. apoCIII and ANGPTLs, protect against development of atherosclerosis. In contrast, when LPL activity is low or not present hyperchylomicronemia will occur. These lipoproteins have been considered too large to enter the intimal space and cause lipid accumulation. However, recent data in animal models have shown that LPL or GPIHBP1 genetic deficiencies significantly aggravate progression of atherosclerosis. Humans with a defect LPL inhibitor function present a more favorable lipid profile and lower risk for CVD [9].

It has been shown that LPL activity is hampered in patients with type II diabetes indicating that LPL is associated with diabetic dyslipidemia and possibly the increased risk for CVD in these patients [10]. Taken together, the data above and the fact that the human gain of function LPL-mutation S447X, correlates with lower risk for CVD [11], provides evidence that increased LPL activity is desirable.

The enzyme is a non-covalently bound homodimer which is stimulated by the cofactor apoCII. Only in case of genetic apoCII deficiency, co-factor stimulation is considered to be a limiting factor for LPL action. Together with the instability of the functional dimer, this has hindered therapeutic development, although attempts have been made to impact this system. There are currently no drugs available or under known development that affects the LPL system directly. To date, a handful potential LPL- inhibitors/inactivators have been identified; the ANGPTL-gene family being one of the most significant ones. In drug discovery it is generally the first rate-limiting step in a process that is the most attractive target. In blood lipid metabolism that target is LPL.

  • 1. Fruchart, J.C., et al., The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol, 2008. 102(10 Suppl): p. 1K-34K.

  • 2. Nordestgaard, B.G., et al., Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA : the journal of the American Medical Association, 2007. 298(3): p. 299-308.

  • 3. Assmann, G., H. Schulte, and P. Cullen, New and classical risk factors--the Munster heart study (PROCAM). European journal of medical research, 1997. 2(6): p. 237-42.

  • 4. Olivecrona, T., Olivecrona, G., The ins and outs of adipose tissue: Cellular lipid metabolism, C. Ehnholm, Editor 2009, Springer-Verlag Berlin: Heidelberg. p. 315-369.

  • 5. Bergo, M., et al., Down-regulation of adipose tissue lipoprotein lipase during fasting requires that a gene, separate from the lipase gene, is switched on. J Biol Chem, 2002. 277(14): p. 11927-32.

  • 6. Davies, B.S., et al., GPIHBP1 is responsible for the entry of lipoprotein lipase into capillaries. Cell metabolism, 2010. 12(1): p. 42-52.

  • 7. Brewer, H.B., Jr., Hypertriglyceridemia: changes in the plasma lipoproteins associated with an increased risk of cardiovascular disease. The American journal of cardiology, 1999. 83(9B): p. 3F-12F.

  • 8. Stein, Y. and O. Stein, Lipoprotein lipase and atherosclerosis. Atherosclerosis, 2003. 170(1): p. 1-9.

  • 9. Pollin, T.I., et al., A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science, 2008. 322(5908): p. 1702-5.

  • 10. Taskinen, M.R. and E.A. Nikkila, Lipoprotein lipase activity of adipose tissue and skeletal muscle in insulin-deficient human diabetes. Relation to high-density and very-low-density lipoproteins and response to treatment. Diabetologia, 1979. 17(6): p. 351-6.

  • 11. Hokanson, J.E., Functional variants in the lipoprotein lipase gene and risk cardiovascular disease. Current opinion in lipidology, 1999. 10(5): p. 393-9.


2014 Jul 25;450(2):1063-9. doi: 10.1016/j.bbrc.2014.06.114. Epub 2014 Jun 28.
Identification of a small molecule that stabilizes lipoprotein lipase in vitro and lowers triglycerides in vivo. Larsson M, Caraballo R, Ericsson M, Lookene A, Enquist PA, Elofsson M, Nilsson SK, Olivecrona G.


2015 Oct 20;103:191-209. doi: 10.1016/j.ejmech.2015.08.058. Epub 2015 Sep 2
Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo. Caraballo R, Larsson M, Nilsson SK, Ericsson M, Qian W, Nguyen Tran NP, Kindahl T, Svensson R, Saar V, Artursson P, Olivecrona G, Enquist PA, Elofsson M.