Poster abstracts
Poster number 169 submitted by Zac Dewald
Myotonic Dystrophy type 1 alters ACC1 function and induces liver lipid accumulation
Zac Dewald (Department of Biochemistry, University of Illinois at Urbana-Champaign), Jeongmin Lee (Department of Biochemistry, University of Illinois at Urbana-Champaign), Oluwafolajimi Adesanya (Department of Biochemistry, University of Illinois at Urbana-Champaign), Auinash Kalsotra (Department of Biochemistry and Carl R. Woese Institute of Genomic Biology, University of Illinois at Urbana-Champaign)
Abstract:
Myotonic Dystrophy type 1 (DM1) is multi-systemic muscular dystrophy, affecting 1 in 3000 people. DM1 is caused by a (CTG)n repeat expansion in the ubiquitously expressed gene DMPK. The (CUG)n containing RNAs resulting from the transcription of diseased DMPK sequester several RBPs, many of which regulate juvenile-to-adult development of many tissues. Studies have shown that in addition to muscle pathologies, DM1 patients exhibit increased susceptibility toward glucose intolerance, non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome. These findings suggested an interaction between DM1 and liver glucose and lipid regulation.
To understand the effects of DM1 in the liver, we generated a DM1 mouse model which expresses CUG repeat-containing RNA specifically within the liver. Through these mice, we show that the expression of toxic CUG RNA in hepatocytes sequesters MBNL proteins, causing a reduction in mature hepatocellular activity. We have shown these transcriptomic changes driven by DM1 lead to changes in liver morphology, injury, and increased lipid accumulation. We show that DM1 sensitizes the liver to diet induced NAFLD, increasing the likelihood of NAFLD development when patients consume high fat, high sugar diets. Our data shows this is due to misregulation of fatty acid metabolism, synthesis, and transport. Of specific interest is the 28th exon of acetyl-CoA carboxylase 1 (ACC1), the rate-limiting enzyme in fatty acid synthesis. This exon shows increased inclusion in the livers of the DM1 mice. This exon is implicated in affecting ACC1 phosphorylation and activity. We have shown that in addition to the exon switching, ACC1 levels in in the DM1 afflicted mice increase. We further demonstrate that DM1 mice livers show marked changes in enzymes associated with lipid transport and oxidation. Finally, we show that both inhibition of ACC1 and reversal of the splicing change on exon 28 reverse the lipid accumulation brought on by DM1. These results reveal that expression of CUG repeat-containing RNA disrupts normal hepatic functions and predisposes the liver to injury and fatty liver disease, which jeopardizes the health of DM1 patients and complicates the treatment of DM1.
Keywords: Myotonic Dystrophy Type 1, Alternative Splicing, Liver, Mouse Model, Trinucleotide Repeat Expansion Disease, MBNL, NAFLD, Drug Metabolism, ACC1
Keywords: Myotonic Dystrophy type 1, Alternative splicing, Trinucleotide repeat expansion disease