No abstract

Accumulation of sphingolipids, especially sphingosines, in the lysosomes is attributed to the pathogenesis of several lysosomal storage diseases. In search for a lysosomal protein that mediates the release of sphingosines, we identified SPNS1 which shares the highest homology to SPNS2, a sphingosine-1-phosphate (S1P) transporter. We generated knockout cells and mice for Spns1 and employed lipidomics and metabolomics to identify SPNS1 ligands. We found that knockouts of Spns1 resulted in the accumulation of sphingolipids, including sphingosines in embryonic brains and cell lines. These results suggest that deficiency of SPNS1 affects the clearance of sphingolipids in lysosomes. Biochemical assays demonstrated that sphingosines released from lysosomes required SPNS1. Furthermore, by performing a comprehensive analysis of metabolites from livers of postnatal Spns1 knockout mice (gSpns1-cKO), we detected a striking accumulation of lysoglycerophospholipids including LPC, LPE, LPG, and lysoplasmalogens. Interestingly, the release of these lysoglycerophospholipids also required SPNS1. Global knockout of Spns1 (gSpns1-KO) resulted in embryonic lethality between E12.5-E13.5 with developmental defects. Postnatal deletion of Spns1 in mice caused lipid accumulation in the lysosomes and pathological conditions reminiscent of lysosomal storage diseases. These results reveal a critical molecular role of SPNS1 as a transporter for lysosphingolipids and lysoglyerophospholipids from the lysosomes and link its physiological functions with lysosomal storage diseases.

No abstract

BACKGROUND: Rapid economic development in Asian countries in the middle range of gross national income has been coupled with the emergence of stunted child -overweight mother households (SCOM). The discrepancies in socioeconomic status among households even worsen this opposed situation of insufficiency and excess. OBJECTIVES:This thesis will provide an up-to-date trend and prevalence of SCOM in 11 Asian middle-income countries from 2005 to 2018. The analysis aims to determine whether the probability of SCOM is associated with economic growth and household-level characteristics including relative wealth, maternal education and place of residence. It also identifies the differences in the key determinants of SCOM and other types of malnutrition. METHODS: World Bank economic indicators and cross-sectional data from Demographic andHealth Surveys are combined to perform the analysis. SCOM households are defined by having at least one stunted child living with an overweight mother in the same dwelling. The anthropometric cut-off for stunted child is height-for-age Z scores < -2 SD and for overweight mother is BMI ≥ 25kg/m 2 . A multivariate logit regression and multinomial logit model are applied to determine the association of SCOM and growth rate, wealth index, maternal education and place of residence, as well as to compare with other types of malnutrition households. RESULTS AND IMPLICATIONS:SCOM is positively associated with growth rate and is more prevalent in countries in the middle of the income range. The rate of childhood stunting is decreasing but still very high, coupled with the increase in maternal overweight, which drives the increasing trend of SCOM overtime. Significant risk factors for SCOM are higher wealth index and living in urban areas. Maternal education does not show a significant impact but appears to decrease the positive effect of household income on SCOM. Policy-makers tackling malnutrition in Asia should be aware of the emergence of SCOM in low-and middle-income countries, particularly if they experience high growth rates. In this respect, prevention programs should consider nutrition concerns of the household as a whole and avoid recommendations that would alter household diets and jeopardize vulnerable persons within the same household. 5