{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/124528"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/124528","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Myotonic dystrophy type one causes dysregulation of drug metabolism and fatty accumulation in the liver","abstract":"Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2026-05-01","abstract_html":"Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2026-05-01","abstract_has_math":false,"creators":["Dewald, Zachary L."],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Biochemistry","degree_department":null,"school":null,"contributors":["Kalsotra, Auinash","Fratti, Rutilio A.","Prasanth, Kannanganattu V.","Anakk, Sayeepriyadarshini"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-05","date_published":"2024-05","updated_at":"2026-07-22T22:25:02Z","subjects":["Myotonic Dystrophy","Rna Disease","Liver Disease","Tri-nucleotide Repeat Expansion Disease","Fatty Liver Disease","Liver Metabolism","Alternative Splicing","Mrna Processing","Liver Function"],"languages":["en","eng"],"rights":["Copyright 2024 Zachary Dewald"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/124528","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Kalsotra, Auinash","Fratti, Rutilio A.","Prasanth, Kannanganattu V.","Anakk, Sayeepriyadarshini"]},{"key":"dc:creator","label":"Author","values":["Dewald, Zachary L."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2024-05","2024-04-19"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biochemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Myotonic Dystrophy","Rna Disease","Liver Disease","Tri-nucleotide Repeat Expansion Disease","Fatty Liver Disease","Liver Metabolism","Alternative Splicing","Mrna Processing","Liver Function"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en","eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2024 Zachary Dewald"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/124528"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2026-05-01","The student, Zachary Dewald, accepted the attached license on 2024-04-15 at 09:39.","The student, Zachary Dewald, submitted this Dissertation for approval on 2024-04-15 at 09:49.","This Dissertation was approved for publication on 2024-04-19 at 17:01.","DSpace SAF Submission Ingestion Package generated from Vireo submission #20405 on 2024-09-16 at 00:43:41","Myotonic Dystrophy type 1 (DM1) is a multi-systemic muscular dystrophy affecting 1 in 3000 people, characterized by muscle wasting, myotonia, cognitive impairment, and cardiac and gastrointestinal abnormalities, among other symptoms. DM1 results from a (CTG)n repeat expansion in the 3’ UTR of the ubiquitously expressed gene DMPK. The (CUG)n-containing RNAs resulting from the transcription of this diseased DMPK gene aggregate in the nucleus, forming foci that sequester muscleblind-like (MBNL) family proteins, important splicing factors with roles in the developmental transition from juveniles to adults in many tissues. 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 exhibit heightened sensitivity to a wide range of analgesics and anesthetics, leading to complications ranging from prolonged anesthesia recovery to heightened pulmonary dysfunction. These findings suggest a predisposition for liver damage and dysfunction in DM1 patients, but this possibility has remained unexplored. To investigate the impact of DM1 in the liver, we generated a DM1 mouse model in which we can induce the expression of CUG-containing RNA, specifically in the liver. Through these mice, we demonstrate that the expression of the toxic CUG RNA sequesters MBNL proteins in the hepatocytes, causing a reduction in mature hepatocellular activity. However, unlike other tissues, loss of MBNL1 activity only reproduces a small portion of the transcriptome changes in DM1-afflicted hepatocytes. We characterized the transcriptomic changes driven by DM1 in the liver and showed that these lead to changes in hepatocellular morphology, inflammation, necrosis, and excessive lipid accumulation. Furthermore, we find that DM1 mice livers are defective in drug metabolism and clearance and, when challenged, exhibit an impaired response to zoxazolamine-induced paralysis and acetaminophen-induced hepatotoxicity. Finally, we observe that DM1 sensitizes the liver to diet-induced NAFLD, increasing the likelihood of NAFLD development in patients who consume high-fat, high-sugar diets. Our data suggests this results from broad misregulation of fatty acid metabolism and homeostasis within the affected hepatocytes. Specifically, the 28th exon of acetyl-CoA carboxylase 1 (ACC1), the rate-limiting enzyme in fatty acid synthesis, displays increased inclusion in the livers of the DM1 mice, which has been shown to limit ACC1 phosphorylation in mammals and affect ACC1 regulation and activity. We have also demonstrated that ACC1 levels decrease in the DM1-afflicted mice. These results reveal that expression of CUG repeat-containing RNA disrupts normal hepatic function, increasing the liver’s susceptibility to injury, fatty liver disease, and drug clearance pathologies. These afflictions pose risks to the health of DM1 patients and complicate the treatment of DM1. Moreover, given the well-defined disease pathologies and the importance the liver plays in drug metabolism, we propose that this model can be used as an ideal “first-pass” animal model in developing therapeutics to treat DM1."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Myotonic dystrophy type one causes dysregulation of drug metabolism and fatty accumulation in the liver"]}]}],"canonical_facts":{"dc:contributor":["Kalsotra, Auinash","Fratti, Rutilio A.","Prasanth, Kannanganattu V.","Anakk, Sayeepriyadarshini"],"dc:creator":["Dewald, Zachary L."],"dc:date":["2024-05","2024-04-19"],"dc:description":["Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2026-05-01","The student, Zachary Dewald, accepted the attached license on 2024-04-15 at 09:39.","The student, Zachary Dewald, submitted this Dissertation for approval on 2024-04-15 at 09:49.","This Dissertation was approved for publication on 2024-04-19 at 17:01.","DSpace SAF Submission Ingestion Package generated from Vireo submission #20405 on 2024-09-16 at 00:43:41","Myotonic Dystrophy type 1 (DM1) is a multi-systemic muscular dystrophy affecting 1 in 3000 people, characterized by muscle wasting, myotonia, cognitive impairment, and cardiac and gastrointestinal abnormalities, among other symptoms. DM1 results from a (CTG)n repeat expansion in the 3’ UTR of the ubiquitously expressed gene DMPK. The (CUG)n-containing RNAs resulting from the transcription of this diseased DMPK gene aggregate in the nucleus, forming foci that sequester muscleblind-like (MBNL) family proteins, important splicing factors with roles in the developmental transition from juveniles to adults in many tissues. 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 exhibit heightened sensitivity to a wide range of analgesics and anesthetics, leading to complications ranging from prolonged anesthesia recovery to heightened pulmonary dysfunction. These findings suggest a predisposition for liver damage and dysfunction in DM1 patients, but this possibility has remained unexplored. To investigate the impact of DM1 in the liver, we generated a DM1 mouse model in which we can induce the expression of CUG-containing RNA, specifically in the liver. Through these mice, we demonstrate that the expression of the toxic CUG RNA sequesters MBNL proteins in the hepatocytes, causing a reduction in mature hepatocellular activity. However, unlike other tissues, loss of MBNL1 activity only reproduces a small portion of the transcriptome changes in DM1-afflicted hepatocytes. We characterized the transcriptomic changes driven by DM1 in the liver and showed that these lead to changes in hepatocellular morphology, inflammation, necrosis, and excessive lipid accumulation. Furthermore, we find that DM1 mice livers are defective in drug metabolism and clearance and, when challenged, exhibit an impaired response to zoxazolamine-induced paralysis and acetaminophen-induced hepatotoxicity. Finally, we observe that DM1 sensitizes the liver to diet-induced NAFLD, increasing the likelihood of NAFLD development in patients who consume high-fat, high-sugar diets. Our data suggests this results from broad misregulation of fatty acid metabolism and homeostasis within the affected hepatocytes. Specifically, the 28th exon of acetyl-CoA carboxylase 1 (ACC1), the rate-limiting enzyme in fatty acid synthesis, displays increased inclusion in the livers of the DM1 mice, which has been shown to limit ACC1 phosphorylation in mammals and affect ACC1 regulation and activity. We have also demonstrated that ACC1 levels decrease in the DM1-afflicted mice. These results reveal that expression of CUG repeat-containing RNA disrupts normal hepatic function, increasing the liver’s susceptibility to injury, fatty liver disease, and drug clearance pathologies. These afflictions pose risks to the health of DM1 patients and complicate the treatment of DM1. Moreover, given the well-defined disease pathologies and the importance the liver plays in drug metabolism, we propose that this model can be used as an ideal “first-pass” animal model in developing therapeutics to treat DM1."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/124528"],"dc:language":["en","eng"],"dc:rights":["Copyright 2024 Zachary Dewald"],"dc:subject":["Myotonic Dystrophy","Rna Disease","Liver Disease","Tri-nucleotide Repeat Expansion Disease","Fatty Liver Disease","Liver Metabolism","Alternative Splicing","Mrna Processing","Liver Function"],"dc:title":["Myotonic dystrophy type one causes dysregulation of drug metabolism and fatty accumulation in the liver"],"dc:type":["text"],"thesis:degree_discipline":["Biochemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:25:02Z"}