Identifying a regulator of the bioactive signaling lipid lysophosphatidylserine

Author interview: Arnab Chakraborty obtained his dual majors in Chemical Engineering and Biological Sciences from BITS Pilani. He is now pursuing his PhD at IISER Pune in Dr Siddhesh Kamat’s lab, working on different aspects of the signaling lipid lysophosphatidylserine.

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Lab: Dr. Siddhesh S Kamat, IISER Pune

Research Summary: Lysophosphatidylserine (lyso-PS) is a potent hormone-like signaling lysophospholipid, regulating many facets of mammalian biology. We identified the serine hydrolase ABHD6 as a lyso-PS lipase in the Liver and Kidney.

What was the core problem you aimed to solve with this research?

Studying the enzymes involved in controlling lyso-PS levels is essential since dysregulation in its metabolism is associated with several human neurological and autoimmune diseases.

Despite the physiological importance and causal relation with human pathophysiology, little is known about the metabolism of lyso-PS in tissues other than the nervous and immune systems. To address this problem, we attempted to identify one (or more) lipase(s) capable of degrading lyso-PS in different mammalian tissues.

How did you go about solving this problem? 

To bridge this knowledge gap, we determined whether peripheral tissues (tissues other than the brain) in mammals have lyso-PS lipase activity (the ability to degrade the parent lyso-PS molecule). Using tissue fractionation (into a membrane and soluble fraction) and substrate profiling assays (a test to determine how much lyso-PS is degraded), we found that all mouse tissues except the muscle possess lyso-PS lipase activity enriched in the membrane fraction, and this activity is largely contributed by one (or more) lipase(s) (enzymes that break down lipids) from the metabolic serine hydrolase (mSH) family of enzymes. Further, we wanted to see if ABHD12, the major lyso-PS lipase in the brain, also performed the same function in these peripheral tissues. To this effect, we used ABHD12 knockout (KO) mice and found that this lyso-PS lipase can regulate lyso-PS concentrations only in the brain and no other tissue. Using a focused inhibitor screen (using small molecules that would render enzymes catalytically inactive), we found that another lipase from the mSH enzyme family, the α/β-hydrolase domain-containing protein # 6 (ABHD6), is possibly a lyso-PS lipase in the mouse liver and kidneys. By pharmacologically inhibiting ABHD6, we showed that this lipase controls concentrations of lyso-PS in vivo in primary hepatocytes (cells harvested directly from a mouse liver) and the liver and kidneys of mice. Finally, we showed that recombinant ABHD6 (overexpressed enzyme) possesses robust lyso-PS lipase activity and thus functionally annotate ABHD6 as a major lyso-PS lipase in these mammalian tissues.

This is the first report of identification of a lyso-PS metabolic enzyme outside the nervous or immune system. – Dr. Siddhesh S Kamat

How would you explain your research outcomes (Key findings) to the non-scientific community?

As we use language to communicate with other humans, cells in our body use chemicals to talk (signal) to each other. One such molecule that is used by our body for signaling is a lipid (fat) called lysophosphatidylserine, or lyso-PS, in short. When we have an immune response (upon infection or injury), lyso-PS signals different types of immune cells, e.g., signaling mast cells to release histamine (which is the molecule against which we take allergy medications). Hence, it has multiple roles in ensuring that our body produces an appropriate immune response. Researchers have previously seen that imbalances in levels of this signaling molecule lead to a variety of disease conditions, such as PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract) and HSP (hereditary spastic paraplegia), which are diseases that affect the nervous system.

We wanted to search for enzymes (active proteins) that control the level of lyso-PS in different tissues because these are the key to maintaining a balance in the signaling levels.

Through our study, we identified ABHD6 (the name of an enzyme) as a lyso-PS lipase (lipases are enzymes that break down lipids) in the liver and kidneys. We showed this using cells taken from mouse livers first and then eventually in the liver and kidneys of live mice. Down the line, if patients have any imbalances in lyso-PS levels and, hence, immune response-related symptoms in the liver or kidneys, our work opens up ABHD6 as a therapeutic target for the same.

What are the potential implications of your findings for the field and society?

Using a focused inhibitor screen in conjunction with follow-up pharmacological studies in primary hepatocytes and mice, we identified ABHD6 as a major lyso-PS lipase in the liver and kidney, where it selectively regulates concentrations of lyso-PS and no other lysophospholipid.

Our findings thus showed how lyso-PS is metabolized in peripheral tissues and have opened new avenues for studying this emerging signaling lysophospholipid in the context of systemic metabolism and metabolic diseases in humans. Furthermore, it opens up ABHD6 as a therapeutic target for potential lyso-PS imbalance-related phenotypes in the liver or kidneys. We also showed that other peripheral tissues like the lungs, heart, and spleen also have lyso-PS lipase activity; hence, this study presents a blueprint to identify and characterize such enzymes in these tissues.

What was the exciting moment during your research?

I will share two anecdotes of small milestones during the progress of this project.

Initially, screening candidate lipases from different peripheral tissues was the most daunting task because the number of active enzymes in tissues is in the order of hundreds, and we wanted to narrow it down to one or two lyso-PS lipases. Eventually, we used a probe-based experiment to figure out the enzyme superfamily and an inhibitor screen against that enzyme superfamily. The exciting moment for me was going through all the peaks on the mass spectrometer software, with the gradual realization that this experiment led to the culmination of a couple of years of screening; the data indicated that ABHD6 was our major candidate lipase.

Finally, to see if ABHD6 is indeed relevant to lyso-PS metabolism in mammalian physiology, we decided to perform an in-vivo experiment by dosing mice with an inhibitor of ABHD6. The results were exciting to us since we could see an accumulation of lyso-PS lipids in the liver and kidneys after only four hours of dosing. This experiment strongly suggested that ABHD6 controls the levels of lyso-PS (by degrading it into a fatty acid) in the liver and kidneys since, upon its inhibition (in just four hours of treatment), we see an aberrant lyso-PS metabolism in these tissues.

Reference: Chakraborty, A. et al. Identification of ABHD6 as a lysophosphatidylserine lipase in the mammalian liver and kidneys. Journal of Biological Chemistry 301, 108157 (2025). https://www.jbc.org/article/S0021-9258(25)00004-3/fulltext

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