Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/2/252 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Evelyn A. Bates |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T09:06:22Z |
| format | Article |
| id | doaj.art-d673bff3a31949f9babcc166e038f8be |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-11T09:06:22Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-d673bff3a31949f9babcc166e038f8be2023-11-16T19:22:31ZengMDPI AGBiomolecules2218-273X2023-01-0113225210.3390/biom13020252Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver DiseaseEvelyn A. Bates0Zachary A. Kipp1Genesee J. Martinez2Olufunto O. Badmus3Mangala M. Soundarapandian4Donald Foster5Mei Xu6Justin F. Creeden7Jennifer R. Greer8Andrew J. Morris9David E. Stec10Terry D. Hinds11Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40508, USADepartment of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40508, USADepartment of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40508, USADepartment of Physiology & Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USAAlnylam Pharmaceuticals, Cambridge, MA 02142, USAAlnylam Pharmaceuticals, Cambridge, MA 02142, USADepartment of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40508, USADepartment of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USADepartment of Physiology & Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USADepartment of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADepartment of Physiology & Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USADepartment of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40508, USASeveral 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.https://www.mdpi.com/2218-273X/13/2/252obesityNAFLDinsulin resistanceinflammationUGT1A1HO-1 |
| spellingShingle | 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 Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease Biomolecules obesity NAFLD insulin resistance inflammation UGT1A1 HO-1 |
| title | Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease |
| title_full | Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease |
| title_fullStr | Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease |
| title_full_unstemmed | Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease |
| title_short | Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease |
| title_sort | suppressing hepatic ugt1a1 increases plasma bilirubin lowers plasma urobilin reorganizes kinase signaling pathways and lipid species and improves fatty liver disease |
| topic | obesity NAFLD insulin resistance inflammation UGT1A1 HO-1 |
| url | https://www.mdpi.com/2218-273X/13/2/252 |
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