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Published online before print October 18, 2006, 10.1101/gad.1483906
GENES & DEVELOPMENT 20:2996-3009, 2006
©2006 by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/ $5.00
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Defects in energy homeostasis in Leigh syndrome French Canadian variant through PGC-1{alpha}/LRP130 complex

Marcus P. Cooper1, Lishu Qu1, Lindsay M. Rohas1, Jiandie Lin2, Wenli Yang1, Hediye Erdjument-Bromage3, Paul Tempst3, and Bruce M. Spiegelman1,4

1 Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA; 2 Department of Cell and Developmental Biology and Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA; 3 Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA

Leigh syndrome French Canadian variant (LSFC) is an autosomal recessive neurodegenerative disorder due to mutation in the LRP130 (leucine-rich protein 130 kDa) gene. Unlike classic Leigh syndrome, the French Canadian variant spares the heart, skeletal muscle, and kidneys, but severely affects the liver. The precise role of LRP130 in cytochrome c oxidase deficiency and hepatic lactic acidosis that accompanies this disorder is unknown. We show here that LRP130 is a component of the PGC-1{alpha} (peroxisome proliferator-activated receptor coactivator 1-{alpha}) transcriptional coactivator holocomplex and regulates expression of PEPCK (phosphoenolpyruvate carboxykinase), G6P (glucose-6-phosphatase), and certain mitochondrial genes through PGC-1{alpha}. Reduction of LRP130 in fasted mice via adenoviral RNA interference (RNAi) vector blocks the induction of PEPCK and G6P, and blunts hepatic glucose output. LRP130 is also necessary for PGC-1{alpha}-dependent transcription of several mitochondrial genes in vivo. These data link LRP130 and PGC-1{alpha} to defective hepatic energy homeostasis in LSFC, and reveal a novel regulatory mechanism of glucose homeostasis.

[Keywords: PGC-1{alpha}; LRP130; LPRPRC; Leigh syndrome; gluconeogenesis]

Received August 17, 2006; revised version accepted September 8, 2006.

4 Corresponding author.

E-MAIL bruce_spiegelman{at}dfci.harvard.edu; FAX (617) 632-4655.

Supplemental material is available at http://www.genesdev.org.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1483906.


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