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Date of Award
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition that affects approximately 25 percent of people worldwide. One variant that has been strongly linked to NAFLD is the PNPLA3-I148M variant. Another variant, the PNPLA3-S453I variant, has been linked to reduced hepatic fat content and a lower incidence of NAFLD in African Americans. The aim of this research was to explore the molecular mechanism underlying how the combinations of these mutations may affect the PNPLA3 mRNA and protein expression. We hypothesized that the PNPLA3-I148M and PNPLA3-S453I variants may alter the mRNA stability of PNPLA3 in hepatocytes. Four stable cell lines were created containing various combinations of these mutations. Lipid droplet formation, mRNA and protein expression, as well as mRNA stability were analyzed. Our data showed that the PNPLA3 isoforms possessed variable protein expression, with the PNPLA3-I148M variant associated with the highest protein accumulation in the cells. This was, at least in part, due to prolonged mRNA degradation. Relative to PNPLA3-I148M, the PNPLA3-S453I variant in general lead to a reduced protein level and a shorter mRNA half-life. This variability in PNPLA3 mRNA and protein expression is correlated with the neutral lipid accumulation and lipid droplet formation as well. However, the reason why the wildtype isoform of PNPLA3 possessed a higher mRNA and protein level, but a similar mRNA stability to the PNPLA3-S453I isoforms remains unclear. We concluded that the PNPLA3 variants are associated with NAFLD, at least in part, by regulating mRNA stability. More research is needed to fully address their impacts on the function of PNPLA3.
Choudhury, Tasnim, "Role Of Genetic Variants In Regulating Pnpla3 Expression" (2021). Wayne State University Theses. 829.