An integrative systems genetic analysis of mammalian lipid metabolism
Benjamin L. Parker,Anna C. Calkin,Anna C. Calkin,Marcus M. Seldin,Michael F. Keating,Michael F. Keating,Elizabeth J. Tarling,Pengyi Yang,Sarah C. Moody,Yingying Liu,Eser J. Zerenturk,Elise J. Needham,Matthew L. Miller,Bethan L. Clifford,Pauline Morand,Matthew J. Watt,Ruth C. R. Meex,Kang-Yu Peng,Richard T. Lee,Kaushala S. Jayawardana,Calvin Pan,Natalie A. Mellett,Jacquelyn M. Weir,Ross Lazarus,Aldons J. Lusis,Peter J. Meikle,David E. James,Thomas Q. de Aguiar Vallim,Brian G. Drew,Brian G. Drew +29 more
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TLDR
This study interrogated lipid regulatory networks in 107 genetically distinct mouse strains to reveal key insights into the control and network structure of mammalian lipid metabolism, leading to the identification and validation of PSMD9 as a previously unknown lipid regulatory protein.Abstract:
Dysregulation of lipid homeostasis is a precipitating event in the pathogenesis and progression of hepatosteatosis and metabolic syndrome. These conditions are highly prevalent in developed societies and currently have limited options for diagnostic and therapeutic intervention. Here, using a proteomic and lipidomic-wide systems genetic approach, we interrogated lipid regulatory networks in 107 genetically distinct mouse strains to reveal key insights into the control and network structure of mammalian lipid metabolism. These include the identification of plasma lipid signatures that predict pathological lipid abundance in the liver of mice and humans, defining subcellular localization and functionality of lipid-related proteins, and revealing functional protein and genetic variants that are predicted to modulate lipid abundance. Trans-omic analyses using these datasets facilitated the identification and validation of PSMD9 as a previously unknown lipid regulatory protein. Collectively, our study serves as a rich resource for probing mammalian lipid metabolism and provides opportunities for the discovery of therapeutic agents and biomarkers in the setting of hepatic lipotoxicity. The integration of liver and plasma quantitative lipidomic and proteomic data from 107 distinct mouse strains provides important insights into regulators of mammalian lipid metabolism.read more
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The integrative biology of type 2 diabetes.
Michael Roden,Gerald I. Shulman +1 more
TL;DR: Recent studies providing insights into insulin resistance and increased hepatic gluconeogenesis associated with obesity and type 2 diabetes are summarized, focusing on data from humans and relevant animal models.
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Blood metabolome predicts gut microbiome α-diversity in humans.
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Trapped ion mobility spectrometry and PASEF enable in-depth lipidomics from minimal sample amounts.
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FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption.
Bethan L. Clifford,Leslie R. Sedgeman,Kevin J. Williams,Pauline Morand,Angela Cheng,Kelsey E. Jarrett,Alvin P. Chan,Madelaine C. Brearley-Sholto,Annika Wahlström,Julianne W. Ashby,William D. Barshop,James A. Wohlschlegel,Anna C. Calkin,Anna C. Calkin,Yingying Liu,Anders Thorell,Peter J. Meikle,Brian G. Drew,Brian G. Drew,Julia J. Mack,Hanns-Ulrich Marschall,Elizabeth J. Tarling,Peter A. Edwards,Thomas Q. de Aguiar Vallim +23 more
TL;DR: The authors showed that FXR activation in mice or humans specifically reduces hepatic levels of mono-and polyunsaturated fatty acids (MUFA and PUFA) and selective decreases in fatty acid synthesis.
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