Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease
Evelyn A. Bates,
Zachary A. Kipp,
Genesee J. Martinez,
Olufunto O. Badmus,
Mangala M. Soundarapandian,
Donald Foster,
Mei Xu,
Justin F. Creeden,
Jennifer R. Greer,
Andrew J. Morris,
David E. Stec,
Terry D. Hinds
Affiliations
Evelyn A. Bates
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40508, USA
Zachary A. Kipp
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40508, USA
Genesee J. Martinez
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40508, USA
Olufunto O. Badmus
Department of Physiology & Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA
Mangala M. Soundarapandian
Alnylam Pharmaceuticals, Cambridge, MA 02142, USA
Donald Foster
Alnylam Pharmaceuticals, Cambridge, MA 02142, USA
Mei Xu
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40508, USA
Justin F. Creeden
Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
Jennifer R. Greer
Department of Physiology & Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA
Andrew J. Morris
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
David E. Stec
Department of Physiology & Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA
Terry D. Hinds
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40508, USA
Several population studies have observed lower serum bilirubin levels in patients with non-alcoholic fatty liver disease (NAFLD). Yet, treatments to target this metabolic phenotype have not been explored. Therefore, we designed an N-Acetylgalactosamine (GalNAc) labeled RNAi to target the enzyme that clears bilirubin from the blood, the UGT1A1 glucuronyl enzyme (GNUR). In this study, male C57BL/6J mice were fed a high-fat diet (HFD, 60%) for 30 weeks to induce NAFLD and were treated subcutaneously with GNUR or sham (CTRL) once weekly for six weeks while continuing the HFD. The results show that GNUR treatments significantly raised plasma bilirubin levels and reduced plasma levels of the bilirubin catabolized product, urobilin. We show that GNUR decreased liver fat content and ceramide production via lipidomics and lowered fasting blood glucose and insulin levels. We performed extensive kinase activity analyses using our PamGene PamStation kinome technology and found a reorganization of the kinase pathways and a significant decrease in inflammatory mediators with GNUR versus CTRL treatments. These results demonstrate that GNUR increases plasma bilirubin and reduces plasma urobilin, reducing NAFLD and inflammation and improving overall liver health. These data indicate that UGT1A1 antagonism might serve as a treatment for NAFLD and may improve obesity-associated comorbidities.
