Abstract
ABSTRACTGenome-wide association studies (GWAS) have detected association between variants in or near the Lysophospholipase-like 1 (LYPLAL1) locus and metabolic traits, including central obesity, fatty liver and waist-to-hip ratio. LYPLAL1 is also known to be upregulated in the adipose tissue of obese patients. However, the physiological role of LYPLAL1 is not understood. To investigate the function of Lyplal1 in vivo we investigated the phenotype of the Lyplal1tm1a(KOMP)Wtsi homozygous mouse. Body composition was unaltered in Lyplal1 knockout mice as assessed by dual-energy X-ray absorptiometry (DEXA) scanning, both on normal chow and on a high-fat diet. Adipose tissue distribution between visceral and subcutaneous fat depots was unaltered, with no change in adipocyte cell size. The response to both insulin and glucose dosing was normal in Lyplal1tm1a(KOMP)Wtsi homozygous mice, with normal fasting blood glucose concentrations. RNAseq analysis of liver, muscle and adipose tissue confirmed that Lyplal1 expression was ablated with minimal additional changes in gene expression. These results suggest that Lyplal1 is dispensable for normal mouse metabolic physiology and that despite having been maintained through evolution Lyplal1 is not an essential gene, suggesting possible functional redundancy. Further studies will be required to clarify its physiological role.
Highlights
Lysophospholipase-like 1 (LYPLAL1) is a protein with a poorly understood biological role, despite its evolutionary conservation (Fig. S1)
Lyplal1 mRNA levels were negligible in all organs tested, with the tm1a allele resulting in >95% knockout of Lyplal1 at the RNA level in the kidney and gastrocnemius muscle, and >99% knockout in all other tissues tested
LYPLAL1 has been linked to many metabolic phenotypes in humans and rodents, through Genome-wide association studies (GWAS) and expression studies (Bandstein et al, 2016; Benjamin et al, 2011; Bille et al, 2011; Chu et al, 2017; Fox et al, 2012; Goodarzi et al, 2013; Heid et al, 2010; Lei et al, 2015; Lindgren et al, 2009; Manning et al, 2012; Randall et al, 2013; Schmid et al, 2012; Scott et al, 2012; Speliotes et al, 2011; Steinberg et al, 2007)
Summary
Lysophospholipase-like 1 (LYPLAL1) is a protein with a poorly understood biological role, despite its evolutionary conservation (Fig. S1). The crystal structure of LYPLAL1 is similar to that of APT1 (acyl protein thioesterase 1, known as LYPLA1), but the shape of its active site indicates that unlike APT1, which depalmitoylates Gα and Ras proteins, it cannot bind long-chain substrates. Biochemical data confirm this, demonstrating that LYPLAL1 accepts shortchain 4-nitrophenyl esters (Bürger et al, 2012). Despite identification of a small-molecule inhibitor, the natural substrate of LYPLAL1 and its physiological role remain unknown.
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