Functional characterization of alpha/beta hydrolase domain-containing 6

Alpha/beta hydrolase domain-containing 6 (ABHD6) belongs to the large superfamily of a/ß hydrolases constituting approximately 1 % of all proteins encoded by mammalian genomes. These proteins exhibit similar topology of the core structure characterized by 5-8 central beta-sheets connected by alpha-helices, and the same location of two (Ser, His) of the three residues comprising the catalytic triad. Members of this family play key roles in diverse physiological processes and many uncharacterized proteins are supposed to exhibit hydrolytic activity. However, the substrate preference and the physiological function of most family members are unknown. ABHD6 was originally identified as brain monoacylglycerol (MG) lipase capable of degrading the signaling lipid molecule 2-arachidonoylglycerol (2-AG). This MG species acts as endogenous activator of cannabinoid receptors (endocannabinoid) and its biological effects are mimicked by 9 -tetrahydrocannabinol (THC), the major psychoactive component of marijuana. Further studies revealed that ABHD6 is differentially expressed in cancer cell lines and highly present in Ewing tumors indicating that it might be an interesting diagnostic or therapeutic target. Moreover, it was reported that ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. This finding was surprising since most of the 2-AG degrading activity detected in brain preparations was ascribed to monoglyceride lipase (MGL or MAGL) and MGL-deficient mice exhibit a strong increase in 2-AG levels (20- to 50-fold). Yet, a recent study using a compound which inhibits ABHD6 and fatty acid amide hydrolase (FAAH), but not MGL, supports the observation that ABHD6 is involved in EC degradation. This study demonstrates that it is possible to increase 2-AG levels in neurons, even when MGL is fully active. It is assumed that ABHD6 is active in specific subcellular compartments and responsible for the fine-tuned modulation of 2-AG levels. However, the in vivo function of this enzyme remains to be investigated and it unknown whether the enzyme also hydrolyzes other substrates than MG. The objective of this project is to characterize the physiological function of ABHD6 in vivo. We aim to investigate the consequences of ABHD6-deficieny on lipid metabolism in mouse lines lacking the enzyme totally or in specific tissues.

Alpha/beta hydrolase domain-containing 6 (ABHD6) is a lipid-degrading enzyme, whose function is incompletely characterized. Currently, it is believed that ABHD6 plays a role in the degradation of signaling lipids, which control important aspects of metabolism and contribute to the pathogenesis of diverse diseases. It has been shown that inactivation prevents obesity and type 2 diabetes in mice. Furthermore, ABHD6 is increased in some tumor types and affects metastatic seeding of tumor cells. Therefore, ABHD6 represents a pharmacologically interesting enzyme, whose detailed investigation can unveil important insights into physiological and pathophysiological processes.This project is based on the observation that ABHD6 is capable of degrading the lysosomal lipid bis(monoacylglycero)phosphate (BMP). Lysosomes function as cellular stomach and contain digestive enzymes, whose purpose is to break down food for the cell. The function of BMP in lysosomes is that it activates digestive enzymes and therefore contributes to the effective degradation of macromolecules. Currently, very little is known about the synthesis and degradation of BMP. We thus focused on basic aspects of BMP metabolism and the role of ABHD6 in this process. Our data demonstrate that BMP is regulated by the nutritional state and dietary composition. Cholesterol- and triglyceride-rich diets increase concentrations in the liver and induce the release of BMP into the circulation. Inactivation of ABHD6 strongly promotes BMP release. We conclude that diet-induced metabolic disease is associated with robust changes in BMP metabolism and that ABHD6 substantially contributes to BMP degradation. Currently, it is unknown whether BMP concentrations correlate with human metabolic disorders. However, based on our mouse studies, it is reasonable to assume that metabolic diorders such as obesity, insulin resistance, and liver steatosis are associated with lysosomal stress and increased release of BMP into the circulation. We believe that further exploration of the basics of BMP metabolism will reveal important insights into the pathogenesis of lysosomal dysfunction and metabolic disease.