Humanized monoacylglycerol acyltransferase 2 mice develop metabolic dysfunction-associated steatohepatitis
Mice lacking monoacylglycerol acyltransferase 2 (mMGAT21) are resistant to diet-induced fatty liver, suggesting hMOGAT2 inhibition is a viable option for treating metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH). We generated hu...
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Elsevier
2024-12-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227524002001 |
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| author | J. Jose Corbalan Pranavi Jagadeesan Karla K. Frietze Rulaiha Taylor Grace L. Gao Grant Gallagher Joseph T. Nickels, Jr. |
| author_facet | J. Jose Corbalan Pranavi Jagadeesan Karla K. Frietze Rulaiha Taylor Grace L. Gao Grant Gallagher Joseph T. Nickels, Jr. |
| author_sort | J. Jose Corbalan |
| collection | DOAJ |
| description | Mice lacking monoacylglycerol acyltransferase 2 (mMGAT21) are resistant to diet-induced fatty liver, suggesting hMOGAT2 inhibition is a viable option for treating metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH). We generated humanized hMOGAT2 mice (HuMgat2) for use in pre-clinical studies testing the efficacy of hMOGAT2 inhibitors for treating MASLD/MASH. HuMgat2 mice developed MASH when fed a steatotic diet. Computer-aided histology revealed the presence of hepatocyte cell ballooning, immune cell infiltration, and fibrosis. Hepatocytes accumulated Mallory-Denk bodies containing phosphorylated p62/sequestosome-1-ubiquitinated protein aggregates likely caused by defects in autophagy. Metainflammation and apoptotic cell death were seen in the livers of HuMgat2 mice. Treating HuMgat2 mice with elafibranor reduced several MASH phenotypes. RNASeq analysis predicted changes in bile acid transporter expression that correlated with altered bile acid metabolism indicative of cholestasis. Our results suggest that HuMgat2 mice will serve as a pre-clinical model for testing hMOGAT2 inhibitor efficacy and toxicity and allow for the study of hMOGAT2 in the context of MASH. |
| format | Article |
| id | doaj-art-bd10068f6a054b3bb24bf0d905c5b374 |
| institution | OA Journals |
| issn | 0022-2275 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-bd10068f6a054b3bb24bf0d905c5b3742025-08-20T02:07:16ZengElsevierJournal of Lipid Research0022-22752024-12-01651210069510.1016/j.jlr.2024.100695Humanized monoacylglycerol acyltransferase 2 mice develop metabolic dysfunction-associated steatohepatitisJ. Jose Corbalan0Pranavi Jagadeesan1Karla K. Frietze2Rulaiha Taylor3Grace L. Gao4Grant Gallagher5Joseph T. Nickels, Jr.6The Institute of Metabolic Disorders, Genesis Research and Development Institute, Genesis Biotechnology Group, Hamilton, NJ, USAThe Institute of Metabolic Disorders, Genesis Research and Development Institute, Genesis Biotechnology Group, Hamilton, NJ, USAThe Institute of Metabolic Disorders, Genesis Research and Development Institute, Genesis Biotechnology Group, Hamilton, NJ, USADepartment of Pharmacology and Toxicology, Earnest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USADepartment of Pharmacology and Toxicology, Earnest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA; Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, USAOncoveda, Genesis Research and Development Institute, Genesis Biotechnology Group, Hamilton, NJ, USAThe Institute of Metabolic Disorders, Genesis Research and Development Institute, Genesis Biotechnology Group, Hamilton, NJ, USA; Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, USA; For correspondence: Joseph T. NickelsMice lacking monoacylglycerol acyltransferase 2 (mMGAT21) are resistant to diet-induced fatty liver, suggesting hMOGAT2 inhibition is a viable option for treating metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH). We generated humanized hMOGAT2 mice (HuMgat2) for use in pre-clinical studies testing the efficacy of hMOGAT2 inhibitors for treating MASLD/MASH. HuMgat2 mice developed MASH when fed a steatotic diet. Computer-aided histology revealed the presence of hepatocyte cell ballooning, immune cell infiltration, and fibrosis. Hepatocytes accumulated Mallory-Denk bodies containing phosphorylated p62/sequestosome-1-ubiquitinated protein aggregates likely caused by defects in autophagy. Metainflammation and apoptotic cell death were seen in the livers of HuMgat2 mice. Treating HuMgat2 mice with elafibranor reduced several MASH phenotypes. RNASeq analysis predicted changes in bile acid transporter expression that correlated with altered bile acid metabolism indicative of cholestasis. Our results suggest that HuMgat2 mice will serve as a pre-clinical model for testing hMOGAT2 inhibitor efficacy and toxicity and allow for the study of hMOGAT2 in the context of MASH.http://www.sciencedirect.com/science/article/pii/S0022227524002001lipidsMASHMASLDmonoacylglycerol acyltransferasebile acidsRNASeq |
| spellingShingle | J. Jose Corbalan Pranavi Jagadeesan Karla K. Frietze Rulaiha Taylor Grace L. Gao Grant Gallagher Joseph T. Nickels, Jr. Humanized monoacylglycerol acyltransferase 2 mice develop metabolic dysfunction-associated steatohepatitis Journal of Lipid Research lipids MASH MASLD monoacylglycerol acyltransferase bile acids RNASeq |
| title | Humanized monoacylglycerol acyltransferase 2 mice develop metabolic dysfunction-associated steatohepatitis |
| title_full | Humanized monoacylglycerol acyltransferase 2 mice develop metabolic dysfunction-associated steatohepatitis |
| title_fullStr | Humanized monoacylglycerol acyltransferase 2 mice develop metabolic dysfunction-associated steatohepatitis |
| title_full_unstemmed | Humanized monoacylglycerol acyltransferase 2 mice develop metabolic dysfunction-associated steatohepatitis |
| title_short | Humanized monoacylglycerol acyltransferase 2 mice develop metabolic dysfunction-associated steatohepatitis |
| title_sort | humanized monoacylglycerol acyltransferase 2 mice develop metabolic dysfunction associated steatohepatitis |
| topic | lipids MASH MASLD monoacylglycerol acyltransferase bile acids RNASeq |
| url | http://www.sciencedirect.com/science/article/pii/S0022227524002001 |
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