Schmidt, Alexandra, Victoria
(2023)
Investigating the Role of Sirt2 in Hepatic Metabolism
with Application to Hepatocellular Carcinoma.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Sirtuin-2 (Sirt2) is a lysine deacylase enzyme in the sirtuin family. Despite its implication in several age-related diseases, there remain gaps in our understanding of Sirt2’s biological influence. Sirt2 deacetylates metabolic enzymes and has been shown to play a role in tumorigenesis, but these findings have not been well-defined in vivo. Therefore, I used mouse models to better understand Sirt2’s role in metabolism and its contribution to cancer. First, I characterized a sex-specific metabolic phenotype in Sirt2-/- mice. In males, Sirt2 ablation resulted in decreased body fat, moderate hypoglycemia upon fasting, and perturbed glucose handling during exercise. Primary hepatocytes exhibited reduced glycolysis and mitochondrial respiration. Unbiased proteomic profiling of the liver lysine acetylome showed many hyper-acetylated proteins in the absence of Sirt2 only in males. Many mitochondrial enzymes were hyper-acetylated with loss of Sirt2, but Sirt2 was undetectable in isolated liver mitochondria. Loss of Sirt2 did not lead to transcriptional dysregulation, so a nuclear mechanism to explain the metabolic phenotype was ruled out. Lactate dehydrogenase (LDH), which plays a role in gluconeogenesis, was among the hyper-acetylated proteins in Sirt2-/- male livers. LDH enzymatic activity was reduced in Sirt2-/- male liver. Recently, Sirt2 inhibition was proposed as a treatment for the most common form of liver cancer, hepatocellular carcinoma (HCC), despite contradictory findings of its potential as both a tumor promotor and suppressor. Sirt2’s role in HCC was evaluated in vivo using an inducible c-MYC transgene in Sirt2+/+ and Sirt2-/- mice. Sirt2-/- HCC mice had smaller, less proliferative, and more differentiated liver tumors, suggesting Sirt2 is a tumor promotor in this context. Although Myc was hyper-acetylated in male Sirt2-/- normal tissue, there was no evidence for direct Sirt2 and Myc interaction; further investigation into a mechanism to explain Sirt2-mediated delay of HCC tumorigenesis is necessary. Developing a better understanding of acquired metabolic disease has become a top priority in public health. Additionally, patients with HCC need improved, less invasive treatment options. I have shown that Sirt2 plays a role in maintaining glucose homeostasis in vivo and that inhibition of this enzyme could result in better health outcomes for those with HCC.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
3 January 2023 |
| Date Type: |
Publication |
| Defense Date: |
12 October 2022 |
| Approval Date: |
3 January 2023 |
| Submission Date: |
16 November 2022 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
180 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Human Genetics |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Sirt2, sirtuin, acetylation, mitochondria, metabolism, glycolysis, gluconeogenesis, hepatocellular carcinoma, post-translational modification, pyruvate |
| Date Deposited: |
03 Jan 2023 15:20 |
| Last Modified: |
03 Jan 2023 15:20 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/43856 |
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