Date of Award

2019

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Molecular Biology

Abstract

Hepatic steatosis (fatty liver) is increasingly prevalent in the US, and is characterized by triglyceride accumulation within hepatocytes. This is a direct result of an imbalance between lipid import, export, de novo lipogenesis, and beta oxidation. Hepatic steatosis can also progress to nonalcoholic steatohepatitis (NASH) which is characterized by increased hepatocyte damage, inflammation, and fibrosis. Further progression can lead to liver failure or hepatocellular carcinoma, requiring liver transplant or causing death. Our lab recently created Mllt3 conditional whole body knockout mice. These mice developed hepatic steatosis and NASH following Mllt3 deletion. MLLT3 is a master gene regulator that is part of different chromatin remodeling complexes involved in activating or repressing gene expression. MLLT3 also contains a YEATS domain histone acylation reader with a preference for crotonylated histone tails. Crotonylation post-translational modifications are found within promoters and enhancers of active genes. Thus, MLLT3 functions in epigenetic gene regulation.We hypothesized that MLLT3 plays critical roles in maintaining liver lipid homeostasis by regulating expression of specific genes related to the generation of lipid species through its YEATS domain as well as through its function within specific chromatin modulating complexes. In order to determine the liver-intrinsic role of MLLT3 in hepatic steatosis, I used both in vitro and in vivo models. I knocked down MLLT3 in the HepG2 and Huh7 human hepatocellular carcinoma cell lines. This resulted in rapid accumulation of lipids which suggests a cell-intrinsic function of MLLT3 in hepatic lipid homeostasis. I analyzed primary liver tissue from hepatocyte-specific Mllt3 deletion mice that our lab generated. Results from both model systems indicate that several genes which regulate different metabolic pathways, including de novo lipogenesis, are affected upon MLLT3/Mllt3 knockdown/knockout. Further study may define MLLT3 as a novel therapeutic target in attenuation of fatty liver disease.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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