Department of Pediatrics; Program in Bioinformatics and Integrative Biology
Amino Acids, Peptides, and Proteins | Biochemistry | Cellular and Molecular Physiology | Endocrinology, Diabetes, and Metabolism | Enzymes and Coenzymes | Lipids | Nucleic Acids, Nucleotides, and Nucleosides | Nutritional and Metabolic Diseases
Protein arginine methyltransferase 5 (PRMT5) regulates gene expression either transcriptionallyly by symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3, or at the post-translational level by methylation of non-histone target proteins. While emerging evidence suggests that PRMT5 functions as an oncogene, its role in metabolic diseases is not well defined. We investigated the role of PRMT5 in promoting high fat-induced hepatic steatosis. High fat diet up-regulated PRMT5 levels in the liver, but not in other metabolically relevant tissues such as skeletal muscle or white and brown adipose tissue. This was associated with repression of master transcription regulators involved in mitochondrial biogenesis. In contrast, lentiviral shRNA-mediated reduction of PRMT5 significantly decreased PI3K/AKT signaling in mouse AML12 liver cells. PRMT5 knockdown or knockout decreased basal AKT phosphorylation, but boosted the expression of PPARalpha and PGC-1alpha with a concomitant increase of mitochondrial biogenesis. Moreover, by overexpressing an exogenous wild-type or enzyme-dead mutant PRMT5, or by inhibiting PRMT5 enzymatic activity with a small molecule inhibitor, we demonstrated that the enzymatic activity of PRMT5 is required for regulation of PPARalpha and PGC-1alpha expression and mitochondrial biogenesis. Our results suggest that targeting PRMT5 may have therapeutic potential for treatment of fatty liver. Biology, Inc.
Akt PKB, PGC-1α, PPARα, PRMT5, epigenetics, fatty acid oxidation, mitochondria, mitochondrial biogenesis, non-alcoholic fatty liver, signaling
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© 2018 by The American Society for Biochemistry and Molecular Biology, Inc. Publisher PDF posted after 12 months as allowed by the publisher's author rights policy at http://www.jbc.org/site/misc/edpolicy.xhtml#copyright.
DOI of Published Version
J Biol Chem. 2018 Jul 13;293(28):10884-10894. doi: 10.1074/jbc.RA118.002377. Epub 2018 May 17. Link to article on publisher's site
The Journal of biological chemistry
Huang L, Liu J, Zhang X, Sibley K, Najjar SM, Lee MM, Wu JQ. (2018). Inhibition of protein arginine methyltransferase 5 enhances hepatic mitochondrial biogenesis. Open Access Articles. https://doi.org/10.1074/jbc.RA118.002377. Retrieved from https://escholarship.umassmed.edu/oapubs/3463
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