Alterations in endo-lysosomal function induce similar hepatic lipid profiles in rodent models of drug-induced phospholipidosis and Sandhoff disease

Abstract

Drug-induced phospholipidosis (DIPL) is characterized by an increase in the phospholipid content of the cell and the accumulation of drugs and lipids inside the lysosomes of affected tissues, including in the liver. Although of uncertain pathological significance for patients, the condition remains a major impediment for the clinical development of new drugs. Human Sandhoff disease (SD) is caused by inherited defects of the β subunit of lysosomal β-hexosaminidases (Hex) A and B, leading to a large array of symptoms, including neurodegeneration and ultimately death by the age of 4 in its most common form. The substrates of Hex A and B, gangliosides GM2 and GA2, accumulate inside the lysosomes of the CNS and in peripheral organs. Given that both DIPL and SD are associated with lysosomes and lipid metabolism in general, we measured the hepatic lipid profiles in rodent models of these two conditions using untargeted LC/MS to examine potential commonalities. Both model systems shared a number of perturbed lipid pathways, notably those involving metabolism of cholesteryl esters, lysophosphatidylcholines, bis(monoacylglycero)phosphates, and ceramides. We report here profound alterations in lipid metabolism in the SD liver. In addition, DIPL induced a wide range of lipid changes not previously observed in the liver, highlighting similarities with those detected in the model of SD and raising concerns that these lipid changes may be associated with underlying pathology associated with lysosomal storage disorders.

Decrease in Myelin-Associated Lipids Precedes Neuronal Loss and Glial Activation in the CNS of the Sandhoff Mouse as Determined by Metabolomics

“…The increases in BMPs, lipids located to the inner membranes of lysosomes and late endosomes [ 9 ] most probably reflect the impairment of the endo-lysosomal degradation pathway, and the accumulation of these organelles. Similar increases have been observed previously in several lysosomal disorders including Niemann–Pick diseases, neuronal ceroid lipofuscinoses, SD and also drug-induced phospholipidosis [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. In addition, BMPs have been reported to stimulate the degradation of glycosphingolipids in lysosomes [ 9 ] and participate in the transport of cellular cholesterol and its degradation [ 9 , 28 , 29 ].…”

The Emerging and Diverse Roles of Bis(monoacylglycero) Phosphate Lipids in Cellular Physiology and Disease

“…Isomeric separation is important for mass spectrometry analyses because structural isomers are detected as identical masses and usually cannot be distinguished without additional experimental information such as retention time. Chromatographic separation of BMPs and PGs has been reported using HILIC-MS [23-25], RPLC-MS [26,27] or nanoflow LC [28]-based methods to achieve species separation by time for BMPs and PGs. Without chromatographic separation, BMPs can either be differentiated from PGs by fragmentation rules in ESI (+) mode [1] or using derivatization methods to specifically modify BMP species [29].…”

Use of 3D Human Liver Organoids to Predict Drug-Induced Phospholipidosis

“…Fatal genetic disorders such as Niemann-Pick disease and Tay-Sachs disease [9,10] associated with PL have been described in humans, as has cell membrane damage leading to cell death. And other hepatic [11,12] cardiac [13,14], renal [15,16] pulmonary [17,18], eye [19], nervous [20], and skin [21] toxicities related to PL are known.Although drug-induced PL can be detected preclinically using in vivo systems such as animal models [3,[22][23][24], these types of studies are expensive, time-consuming, can raise ethical issues, and may not have specific toxicological relevance to humans. It has also been recommended that compounds that can lead to PL in humans should be identified and screened out in the early stages of drug discovery [25].…”

“…Although drug-induced PL can be detected preclinically using in vivo systems such as animal models [3,[22][23][24], these types of studies are expensive, time-consuming, can raise ethical issues, and may not have specific toxicological relevance to humans. It has also been recommended that compounds that can lead to PL in humans should be identified and screened out in the early stages of drug discovery [25].…”