| Description |
MicroRNAs are integral during a proper immune response. These small, noncoding RNAs provide fine-tuned control for gene expression programs intracellularly. Particularly, a specific miRNA called miR-146a exerts an anti-inflammatory effect on cells. By regulating expression of certain inflammatory genes, miR-146a contributes to acute inflammatory resolution and long term inflammatory control. This dissertation delineates the role of miR-146a in preventing diet induced obesity in Chapter 3, and in preventing carcinogen-induced hepatocellular carcinoma (HCC) in Chapter 4. Chapter 3 demonstrates that mice lacking miR-146a have exaggerated weight gain compared to wildtype mice when fed a high fat diet. These mice experience increased adiposity, hepatosteatosis, and dysregulated blood glucose which is indicative of a diabetic phenotype. This research found that miR-146a regulates not only inflammation, but also gene pathways involved in glycolysis and cellular respiration during obesity. It also shows that miR-146a regulates the mTOR pathway, an important pathway functioning in cell growth, proliferation, survival, and autophagy, as well as in metabolism and insulin sensitivity. Administration of rapamycin, an mTOR inhibitor, reduces obesity in miR-146a-/- mice. This work identifies a new role for miR-146a in regulating cellular metabolic processes, demonstrating that both diet and genetics influence obesity and diabetic phenotypes. Chapter 4 builds on the work in Chapter 3, with a focus on cancer. Liver steatosis and fibrosis are predisposing factors in hepatocarcinogenesis. Female miR-146a-/- mice are sensitive to chemically induced HCC, while WT females are resistant. miR-146a-/- females exhibit heightened immune infiltration, nonalcoholic fatty liver disease (NASH), and elevated circulating markers of liver damage. CD8+ T cells are elevated in miR-146a-/- livers, and aged CD8+ T cells from miR-146a-/- mice express heightened markers of aging and exhaustion, including PD1, Tox, Granzyme K, and importantly CCL5. The elevated CCL5 produced by CD8+ T cells may recruit myeloid-derived suppressor cells (MDSCs) to the tumor site, contributing to a tumor tolerogenic environment. Indeed, when both CCL5 and miR-146a are knocked out in mice, CD8+ T cells remain heightened, but CCL5 deficiency leads to decreased MDSCs and lower overall tumor burden. |
