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Rescue of neuropsychiatric phenotypes in a mouse model of 16p11.2 duplication syndrome by genetic correction of an epilepsy network hub

ABSTRACT: Authors: Marc P. Forrest1,2, Marc Dos Santos1,2, Nicolas H. Piguel1,2, Yi-Zhi Wang3, Nicole A. Hawkins4, Vikram A. Bagchi1,2, Leonardo E. Dionisio1,2, Sehyoun Yoon1,2, Dina Simkin3,4, Maria Dolores Martin-de-Saavedra1,2, Ruoqi Gao1,2, Katherine E. Horan1,2, Alfred L. George Jr.2,4, Mark S. LeDoux5,6, Jennifer A. Kearney 2,4, Jeffrey N. Savas2,3, Peter Penzes1,2* Affiliations: 1Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. 2Center for Autism and Neurodevelopment, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA 3Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. 4Department of Pharmacology Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. 5Department of Psychology, University of Memphis, Memphis, TN 38152, USA. 6Veracity Neuroscience LLC, Memphis, TN 38157, USA. *Correspondence to: p.penzes@northwestern.edu

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Jeffrey N. Savas, PhD

PROVIDER: MSV000090884 | MassIVE | Mon Dec 12 11:10:00 GMT 2022

SECONDARY ACCESSION(S): PXD038753

REPOSITORIES: MassIVE

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Project description:Mutations in the gene encoding lipin 1 cause hepatic steatosis in fld mice, a genetic model of lipodystrophy. Lipin 1 appears to be highly involved in the control of fatty acid metabolism. Lipin 1 is most often located in the nucleus, but other studies suggest that lipin also has effects in the cytoplasm. However, the molecular function of lipin 1 is unclear. To evaluate the effects of activation of the lipin 1 system in liver, lipin 1beta was overexpressed in mouse liver using an adenoviral vector. We found that lipin 1 overexpression increased the expression of many genes involved in mitochondrial fatty acid oxidation while repressing expression of genes involved in lipogenesis. We believe that lipin is a transcriptional coactivator of the peroxisome proliferator-activated receptor (PPAR) complex. However, the many molecular aspects of its function remain unclear. Abstract of published manuscript follows: Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway.Finck BN, Gropler MC, Chen Z, Leone TC, Croce MA, Harris TE, Lawrence JC Jr, Kelly DP. Center for Cardiovascular Research and Washington University School of Medicine, St. Louis, Missouri 63110; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110. Perturbations in hepatic lipid homeostasis are linked to the development of obesity-related steatohepatitis. Mutations in the gene encoding lipin 1 cause hepatic steatosis in fld mice, a genetic model of lipodystrophy. However, the molecular function of lipin 1 is unclear. Herein, we demonstrate that the expression of lipin 1 is induced by peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha), a transcriptional coactivator controlling several key hepatic metabolic pathways. Gain-of-function and loss-of-function strategies demonstrated that lipin selectively activates a subset of PGC-1alpha target pathways, including fatty acid oxidation and mitochondrial oxidative phosphorylation, while suppressing the lipogenic program and lowering circulating lipid levels. Lipin activates mitochondrial fatty acid oxidative metabolism by inducing expression of the nuclear receptor PPARalpha, a known PGC-1alpha target, and via direct physical interactions with PPARalpha and PGC-1alpha. These results identify lipin 1 as a selective physiological amplifier of the PGC-1alpha/PPARalpha-mediated control of hepatic lipid metabolism. Keywords: response to lipin 1 activation

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Rescue of neuropsychiatric phenotypes in a mouse model of 16p11.2 duplication syndrome by genetic correction of an epilepsy network hub

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