Fellows’ Research: What did your liver do when you were sleeping?
23 Oct 2019
Dr Roop Mallik, Senior Fellow, Tata Institute of Fundamental Research (TIFR), Mumbai
Dr Siddhesh Kamat, Intermediate Fellow, Indian Institute of Science Education and Research (IISER), Pune
In our recently published work, we show the fundamental mechanisms that maintain lipid homeostasis in the body and based on this understanding identify a potential target to design interventions against hyperlipidaemia—increased levels of fat in the blood.
Lipid droplets (LDs) are the organelles where cells store triglycerides (fat). Triglycerides within LDs are constantly extracted, converted into fatty molecules, secreted out into circulation, and re-converted back into LDs in target tissues. When these finely orchestrated lipid fluxes are disrupted, diabetes and cardiovascular disease follow. The centrepiece of this orchestra is the liver, an organ that controls systemic lipid metabolism. Within the liver, the action is centred on LDs inside hepatocytes because these LDs provide the triglyceride necessary for assembling very low-density lipoproteins (VLDL) that circulate around in blood as serum triglycerides. High serum triglyceride levels showing up in your blood report is bad news.
In spite of tremendous advances in cell biological techniques, we know little about how metabolic signals channel triglycerides from LDs to produce VLDL in the liver. Let us take the example of what happens when you go to bed after dinner. Glucose is in plenty, but as the night wears on, it will run out, and you must now burn fat to keep going. On such a demand, adipose tissues export triglyceride to the liver, which now gets massively bloated with LDs. However, the liver continues to secrete VLDL-triglycerides at a precisely constant rate. This remarkable elasticity of the liver prevents dangerous elevation in serum triglyceride levels on a daily basis. But, how does this work at the level of cells and molecules in the liver? To our astonishment, nobody had ever asked this question.
In this study, we show how the master hormone (Insulin), the simplest phospholipid (phosphatidic acid; PA), and the Motor protein (Kinesin) control the amount of triglyceride that is secreted from the liver into blood (See figure below). PA works as a signalling lipid to recruit Kinesin motors on LDs. LDs are therefore transported to the smooth endoplasmic reticulum inside hepatocytes, where they are catabolized to assemble VLDL particles. Most interestingly, PA appears on LDs in response to insulin. Therefore, the entire process is toned down when we fast (low insulin), and resultantly, serum triglyceride level is maintained in blood. Lastly, we show that PA-dependent recruitment of Kinesin to membranes can be inhibited with a targeted peptide. This allows external control over triglyceride secretion from hepatocytes, and is therefore a potential intervention against hyperlipidaemia and/or fatty liver.
Insulin activates intracellular transport of lipid droplets to release triglycerides from the liver. Mukesh Kumar, Srikant Ojha, Priyanka Rai, Alaumy Joshi, Siddhesh S. Kamat, Roop Mallik. Journal of Cell Biology, October 2019
Banner Image Credits: Dr Roop Mallik, Senior Fellow, Tata Institute of Fundamental Research (TIFR), Mumbai