MAPL mediated SUMOylation regulates bile acid synthesis and metabolic homeostasis
Vanessa Goyon1, Etienne Coyaud2, Rodolfo Zunino1, Nancy Braverman3, Mary-Ellen Harper4, Brian Raught2, Heidi McBride1* 1Montreal Neurological Institute, Montreal, Canada; 2Princess Margaret Cancer Centre, Toronto, Canada; 3Human Genetics and Pediatrics, Montreal Children's Hospital, Montreal, Canada; 4Biochemistry, Microbiology & Immunology, Ottawa, Canada *Corresponding Author
Mitochondrial anchored protein ligase, MAPL (also MULAN, MUL1, GIDE, HADES), resides in the mitochondrial outer membrane and peroxisomes, where it acts as a SUMO E3 ligase on several substrates, including the fission GTPase Drp1. In addition to the established interactions with the mitochondrial and peroxisomal fission machinery, a BioID analysis of MAPL interacting proteins identified the peroxisomal bile acid transporter ABCD3/PMP70 as a primary partner. The germline deletion of MAPL in mice led to a very lean phenotype, with animals showing increased insulin sensitivity and resistance to weight gain on a high fat diet. Metabolomics and transcriptomics revealed an increase in bile acid synthesis. Analysis of liver extracts confirmed that ABCD3 is SUMOylated in a MAPL-dependant manner, consistent with the requirement for MAPL as a regulator of ABCD3. The stimulation of bile synthesis results in mild ER stress and the secretion of Fgf21 from liver, providing an explanation for the lean phenotype. This demonstrates a role for MAPL and SUMOylation in the regulation of bile acid synthesis, with global metabolic effects in mice.
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