EVALUATING THE RELATIONSHIP BETWEEN BROWN ADIPOSE TISSUE, LIVER STEATOSIS AND HEPATOCELLULAR CARCINOMA AND THE POTENTIAL ROLE OF PESTICIDES AND SALICYLATE

Abstract

Obesity is tightly linked to the development of liver steatosis which is an important risk factor for the development of metabolic dysfunction associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). Specifically, obesity increases the risk of developing HCC by over 80% indicating the urgent need to understand and treat the obesity-MASLD-HCC spectrum of diseases. Environmental toxicants including some commonly used pesticides have been linked to the development of obesity, MASLD and HCC however, the mechanisms contributing to these effects are incompletely understood. Mechanistically, defects in fatty acid metabolism including increases in de-novo lipogenesis, mitochondrial dysfunction, and reductions in brown adipose tissue (BAT) metabolic activity are important contributing factors to MASLD and HCC. A key regulator of both liver and BAT metabolism is the AMP-activated protein kinase (AMPK). These data suggest that environmental factors may contribute to obesity, MASLD and HCC by inhibiting AMPK while therapeutic activation of AMPK may exert beneficial effects. In this thesis we find that two commonly used pesticides, chlorpyrifos and deltamethrin, suppressed the metabolic activity of cultured brown adipocytes. Subsequent studies in mice found that chlorpyrifos promoted obesity and liver steatosis and that this was linked to reductions in BAT metabolic activity and AMPK action. In contrast, when deltamethrin was delivered to mice it had no effect on obesity. Lastly, we evaluated the effects of the rheumatoid arthritis drug and AMPK activator Salsalate in mice and found that it reduced MASLD and HCC and enhanced the effectiveness of Lenvatinib, a tyrosine kinase inhibitor used in HCC treatment. This work furthers our understanding of the mechanisms by which commonly used pesticides may promote obesity and MASLD and provides evidence for the potential repurposing of Salsalate as a combinatorial treatment strategy for MASLD driven HCC.