Talk on Saturday 11:30-11:45am submitted by Zac Dewald
Myotonic Dystrophy Type 1 Adversely Alters affects Liver Function and Liver Lipid Synthesis
Zac Dewald (Biochemistry, University of Illinois), Auinash Kalsotra (Biochemistry, University of Illinois)
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. Furthermore, DM1 patients are abnormally sensitive to various analgesics and anesthetics, with complications ranging from prolonged anesthesia recovery to pulmonary dysfunction. These findings suggest a predisposition for liver dysfunction in DM1 patients.
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 suggest this is due to misregulation of fatty acid metabolism and homeostasis. Specifically, the 28th exon of acetyl-CoA carboxylase 1 (ACC1), the rate-limiting enzyme in fatty acid synthesis, shows increased inclusion in the livers of the DM1 mice. This exon is implicated in affecting ACC1 phosphorylation and activity, and we have shown that ACC1 levels decrease in the DM1 afflicted mice. We further demonstrate that DM1 mice livers are defective in drug metabolism and clearance, with marked impairment against zoxazolamine-induced paralysis and acetaminophen-induced hepatotoxicity. These results reveal that expression of CUG repeat-containing RNA disrupts normal hepatic functions and predisposes the liver to injury, fatty liver disease, and drug clearance pathologies which jeopardize the health of DM1 patients and complicate the treatment of DM1.
Keywords: Myotonic Dystrophy Type 1, NAFLD, Alternative Splicing