ESPEYB16 12. Type 2 Diabetes, Metabolic Syndrome and Lipid Metabolism Lipid Metabolism (4 abstracts)
12.14. An integrative systems genetic analysis of mammalian lipid metabolism
Parker BL , Calkin AC , Seldin MM , Keating MF , Tarling EJ , Yang P , Moody SC , Liu Y , Zerenturk EJ , Needham EJ , Miller ML , Clifford BL , Morand P , Watt MJ , Meex RCR , Peng KY , Lee R , Jayawardana K , Pan C , Mellett NA , Weir JM , Lazarus R , Lusis AJ , Meikle PJ , James DE , de Aguiar Vallim TQ & Drew BG
Nature 2019;567:187–193.
URL https://doi.org/10.1038/s41586-019-0984-y
Summary: Novel diagnostic and prognostic biomarkers in the blood that can predict early fatty liver disease were identified, using a proteomic and lipidomic-wide systems genetic approach in 107 genetically distinct mouse strains. In addition, the novel lipid-regulatory protein, PSMD9, was identified as a regulator of lipid metabolism, with potential therapeutic implications.
Comment: Although nonalcoholic fatty liver disease (NAFLD) is not one of the defining criteria for the MetS, it is a common manifestation and a risk factor for T2DM and cardiovascular disease, liver cancer and liver failure. However, fatty liver disease usually has no early symptoms and diagnosis is often late.1 To predict individuals at a higher genetic risk of developing hepatic lipotoxicity, Genetic Reference Panels (GRP) techniques were used; these enable differentiating the impact of genetics and the environment on complex traits. Allowing accurate control of the environment, as well as access to critical metabolic tissues, GRPs of 107 inbred mouse strains were engaged, and lipidomics and proteomics were performed. Several lipids that were significantly correlated between the liver and plasma were identified. This discovery might lead to a blood test to avoid invasive biopsy or surgery, to determine persons at increased risk of advanced fatty liver disease.
In addition, correlations between the lipidomic and proteomic datasets identified proteins associated with the proteasome and proteolysis that were strongly correlated with hepatic lipid abundance. A proteosomal chaperone protein, non-ATPase regulatory subunit 9 (PSMD9), strongly correlated with multiple hepatic and plasma lipid species.
Silencing of PSMD9, by using antisense oligonucleotides, reduced plasma lipids and prevented hepatic steatosis. Overexpression of hepatic PSMD9 using adenovirus promoted lipid accrual. The identification of PSMD9 as a regulator of lipid metabolism has potential therapeutic implications for new drug targets.
Reference: 1. Moore JB, Thorne JL. Predicting and reducing hepatic lipotoxicity in non-alcoholic fatty liver disease. Lab Animal. 2019; 48(5): 143-4.
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ESPE Yearbook of Paediatric Endocrinology
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