Lipoprotein Lipase- The Changed Dogma

Now and again in science, a well-accepted dogma comes to be challenged, and researchers find themselves re-evaluating years of research. The history of Lipoprotein Lipase (LPL) is just one example of this.

What is LPL?

LPL is a triglyceride hydrolyzing enzyme that has been widely studied. It can mediate interactions of lipoproteins with cell surfaces and receptors, and deficiency or low activity can lead to hypertriglyceridaemia (a risk factor for atherosclerosis) or, in severe cases, to severe pancreatitis. The enzyme has been described as a central molecule in plasma lipid metabolism.

Why is LPL so important?

LPL has a vital role in the processing of circulating dietary fat and therefore has attracted vast amounts of research over the last three decades as we increase our understanding of the role of lipid metabolism in human health.

LPL has been in the spotlight for different reasons recently, including situations that weren't even considered when LPL was first discovered.

One of these is in relation to COVID19.  There have been many studies showing that lipid metabolism during COVID19 may be perturbed.  In a paper in 2021 Masana et al (1) showed that high triglycerides in COVID were associated with severe COVID, and hypothesised that cytokines released during infection led to LPL inhibition. There have been two isolated reports of patients experiencing acute increases in triglycerides after recovering from COVID-19.  In these reports Fijen et al (2) and Shimoda et al (3) have suggested that autoantibodies raised during COVID infection may have temporarily led to inhibition of LPL activity.

In 2019, a severe reaction to the immunotherapy drug Pembroluzimab was associated with low LPL activity, leading to severe hypertriglyceridaemia. This new area of science has generated more interest in LPL. In this case links were suggested between autoantibodies raised against a protein called GP1HBP1 and the condition. GP1HBP1 works to help LPL reach its target tissues, and therefore blocking of this activity can lead to a lack of LPL functionality (4).

The changed dogma

The discovery that LPL is actually active as a monomer was supported by two further publications. 

Kristensen showed in 2020 (5) that the Fab fragment of 5D2 bound to LPL monomers that were enzymatically active.  The researchers found that regulators of LPL act on the monomer, not the dimer as previously thought. This has significant implications for future research on LPL.

In an elegant paper from 2020 Luz et al (6) used surface plasmon resonance techniques to effectively confirm what Chang had seen 22 years before – that the 5D2 antibody binds to the tryptophan rich loop of LPL.  However, with the more recent understanding of LPL structure, this confirmation simply helped to confirm old findings, but with a remarkably different conclusion.

References

(1)    Masana,L. et al (2021). Low HDL and high triglycerides predict COVID-19 severity. Sci. Rep. 11:7217

(2)   Fijen LM et al (2021) Severe acquired hypertriglyceridemia following COVID-19 BMJ Case Rep 14:e246698

(3)   Shimoda, M et al (2022) A rare case of COVID-19 pneumonia with severe hyperlipoproteinemia Oxford Medical Case Reports 4:132

(4)   Thakker,M. et al (2019) Pembrolizumab and Severe Hypertriglyceridemia Requiring

(5)   Kristensen, K.K. et al (2020) Unfolding of monomeric lipoprotein lipase by ANGPTL4: Insight into the regulation of plasma triglyceride metabolism PNAS USA 117:4337

(6)   Luz, J.G. et al (2020) The structural basis for monoclonal antibody 5D2 binding to the tryptophan-rich loop of lipoprotein lipase J. Lipid Res. 61:1347