Identification of ABHD6 as a regulator of lysophosphatidylserines in the mammalian liver and kidneys

Abstract

SUMMARYLysophosphatidylserine (lyso-PS) is a potent hormone-like signaling lysophospholipid, which regulates many facets of mammalian biology and 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, here, we attempted to identify one (or more) lipase(s) capable of degrading lyso-PS in different mammalian tissues. We found that the membrane proteomic fraction of most mammalian tissues possess lyso-PS lipase activity, yet interestingly, the only bona fide lyso-PS lipase ABHD12 displays this enzymatic activity and has control over lyso-PS metabolism only in the mammalian brain. Using anin vitroinhibitor screen against membrane proteomic fractions of different tissues, we find that another lipase from the metabolic serine hydrolase family, ABHD6, is a putative lyso-PS lipase in the mouse liver and kidney. Finally, using pharmacological tools, we validate the lyso-PS lipase activity of ABHD6in vivo, and functionally designate this enzyme as a major lyso-PS lipase in primary hepatocytes, and the mammalian liver and kidneys.HIGHLIGHTSLyso-PS lipase enzymatic activity is present in the membrane proteomic fraction of most mammalian tissuesAnin vitroinhibitor screen identifies ABHD6 as a putative lyso-PS lipase in the liver and kidneyABHD6 functions as a lyso-PS lipase in primary hepatocytesABHD6 also performs lyso-PS lipase activityin vivoand regulates lyso-PS levels in the liver and kidney