Developing Humanized PNPLA3 Mice

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dc.contributor.authorDempsey, Katherineen
dc.contributor.authorWang, Yangen
dc.contributor.authorLiang, Guoshengen
dc.contributor.authorCohen, Jonathan C.en
dc.contributor.authorHobbs, Helen H.en
dc.date.accessioned2023-09-08T16:59:04Z
dc.date.available2023-09-08T16:59:04Z
dc.date.issued2023-08-08
dc.descriptionThis poster was presented at the 2023 AMGEN & SURF Scholar Annual Research Symposium as part of the 10-week Summer Undergraduate Research Fellowship Program at UT Southwestern in Dallas, Texas. The research was conducted with the Hobbs-Cohen Lab in the Department of Molecular Genetics.en
dc.description.abstractFatty liver disease (FLD) is the leading cause of liver disease in the world. The disorder begins with an accumulation of triglycerides (TG) in cytoplasmic lipid droplets (LDs). The strongest genetic risk factor for FLD is a missense variant (I148M) in patatin-like phospholipase domain-containing protein 3 (PNPLA3). PNPLA3 is an insulin-regulated gene that is expressed at high levels in liver and adipose tissues. In fasted mice, levels of PNPLA3 mRNA are low and increase after feeding. It has been previously shown that PNPLA3 is a direct target gene of sterol regulatory element (SRE) binding protein 1c (SREBP-1c), and the binding site of the transcription factor was mapped to intron 1. The I148M substitution is located in a region that is well-conserved between mice and humans, so knock-in mice with this variant also develop FLD. Another variant (S453I) in PNPLA3 is associated with reduced hepatic TG levels in humans, but this variant resides in a non-conserved region of the protein. To determine how the S453I variant reduces hepatic TG levels, CRISPR-Cas9 was used to generate mice expressing human PNPLA3. Genotyping indicated that the insertion was successful, and human PNPLA3 protein expression was verified by immunoblotting analysis. Comparing relative mRNA expression levels in fasted versus refed mice demonstrated that human PNPLA3 retained its responsivity to insulin. Future studies can now be conducted using humanized PNPLA3 mice with the S453I variant to identify potential therapeutic targets.en
dc.identifier.citationDempsey, K., Wang, Y., Liang, G., Cohen, J., & Hobbs, H. (2023, August 8). Developing humanized PNPLA3 mice. Poster session presented at the 2023 AMGEN & SURF Scholar Annual Research Symposium, Dallas, Texas. Retrieved from https://hdl.handle.net/2152.5/10167en
dc.identifier.urihttps://hdl.handle.net/2152.5/10167
dc.language.isoenen
dc.titleDeveloping Humanized PNPLA3 Miceen
dc.typeOtheren

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