Journal article
Humanized Monoacylglycerol Acyltransferase 2 Mice Develop Metabolic Dysfunction-Associated Steatohepatitis
Journal of lipid research, v 65(12), 100695
04 Nov 2024
PMID: 39505262
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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-ubiquintinated 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.
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Details
- Title
- Humanized Monoacylglycerol Acyltransferase 2 Mice Develop Metabolic Dysfunction-Associated Steatohepatitis
- Creators
- Jose Corbalan - The Institute of Metabolic Disorders, Genesis Research and Development Institute, Hamilton, NJ 08691, USAPranavi Jagadeesan - Research & Development InstituteKarla K. Frietze - Research & Development InstituteRulaiha Taylor - Rutgers, The State University of New JerseyGrace L. Gao - Rutgers, The State University of New JerseyGrant Gallagher - Oncoveda, Genesis Research and Development Institute, Hamilton, NJ 08691, USAJoseph T. Nickels - Rutgers, The State University of New Jersey
- Publication Details
- Journal of lipid research, v 65(12), 100695
- Publisher
- Elsevier; AMSTERDAM
- Number of pages
- 22
- Grant note
- Genesis Global Group, Inc.
Genesis Global Group, Inc.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:001371291800001
- Scopus ID
- 2-s2.0-85214319300
- Other Identifier
- 991021958015504721
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- Web of Science research areas
- Biochemistry & Molecular Biology