Metabolic disease and ABHD6 alter the circulating bis(monoacylglycerol)phosphate profile in mice and humans

Abstract

Bis(monoacylglycerol)phosphate (BMP) is a phospholipid that is crucial for lipid degradation and sorting in acidic organelles. Genetic and drug-induced lysosomal storage disorders (LSDs) are associated with increased BMP concentrations in tissues and in the circulation. Data on BMP in disorders other than LSDs, however, are scarce, and key enzymes regulating BMP metabolism remain elusive. Here, we demonstrate that common metabolic disorders and the intracellular BMP hydrolase α/β-hydrolase domain-containing 6 (ABHD6) affect BMP metabolism in mice and humans. In mice, dietary lipid overload strongly affects BMP concentration and FA composition in the liver and plasma, similar to what has been observed in LSDs. Notably, distinct changes in the BMP FA profile enable a clear distinction between lipid overload and drug-induced LSDs. Global deletion of ABHD6 increases circulating BMP concentrations but does not cause LSDs. In humans, nonalcoholic fatty liver disease and liver cirrhosis affect the serum BMP FA composition and concentration. Furthermore, we identified a patient with a loss-of-function mutation in the ABHD6 gene, leading to an altered circulating BMP profile. In conclusion, our results suggest that common metabolic diseases and ABHD6 affect BMP metabolism in mice and humans.

The Current State-of-the Art of LRRK2-Based Biomarker Assay Development in Parkinson’s Disease

“…Another potential alternative LRRK2 related biomarker is BMP [bis(monoacylglycero)phosphate], also known as lysobisphosphatidic acid (LBPA), which is an anionic phospholipid found exclusively on the intra-lumenal vesicles of late endosomes and lysosomes (Bissig and Gruenberg, 2013). BMP can also be secreted into biofluids, where it may be enriched on exosomes (Miranda et al, 2018) or apolipoprotein particles, like HDL (Grabner et al, 2019). BMP promotes electrostatic interactions between intralumenal vesicles and lysosomal lipases and their regulators (e.g., saposins) in order to facilitate glycosphingolipid degradation (Gallala and Sandhoff, 2011).…”

Bis(monoacylglycero)phosphate, an important actor in the host endocytic machinery hijacked by SARS-CoV-2 and related viruses

“…However, acyl chain turnover was demonstrated comparable to other phospholipids [ 41 ]. Phospholipase activities able to metabolize BMP have been described depending on the acidic environment and substrate presentation [ 42 , 43 ], including a pancreatic-lipase related protein 2 (PLRP2) also found in lysosome [ 44 , 45 ] and recently the monoacylglycerol hydrolase α/β hydrolase domain-containing 6 ABHD6 [ 46 , 47 ].

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“…In most cell types, BMP is characterized by a high proportion of unsaturated fatty acids, such as oleic acid. Also polyunsaturated fatty acids, such as docosahexaenoic acid, are enriched in BMP of rat uterine stromal cells, macrophages, liver and brain [ 31 , 41 , 47 , [56] , [57] , [58] , [59] ]. The BMP polyunsaturation coupled to its cone-shape structure and its negative charge are crucial for the dynamic of endolysosomal membranes, favoring membrane invagination and the formation of ILVs.…”

“…Recent studies have highlighted the role of BMP for the maintenance of metabolic homeostasis and the importance of its physiological regulation. Fasting stimulates lysosomal biogenesis and BMP content [ 57 ] whereas high fat diet increases hepatic and circulating BMP concentrations [ 47 ]. All these active membrane exchanges and trafficking can be hijacked by viruses.…”

Metabolic regulation of the lysosomal cofactor bis(monoacylglycero)phosphate in mice

“…Genetic as well as drug-induced lysosomal storage disorders are associated with increased BMP concentrations in tissues and in the circulation which is utilized in clinical practice as biomarker for the diagnosis of these disorders (10). We recently demonstrated that also high-fat induced metabolic disease is associated with elevated hepatic and circulating BMP concentrations (11). Furthermore, published data demonstrate that excessive dietary lipids cause lysosomal lipid storage and BMP accumulation in the kidney (12).…”