Master of Science
Kelly, Gregory M.
Regnault, Timothy RH.
Non-alcoholic fatty liver disease (NAFLD) is a major health burden in the Western world, as the Western diet (WD) appears to be the driving force of this disease. However, the individual contributions of the diet and the impacts of their individual metabolism are currently ill-defined. This study used HepG2 cells to understand the impact of the individual components of WD in early NAFLD development under basal insulin levels. Specifically, nutrient-induced changes in reactive oxygen species (ROS) and signaling pathways, such as sterol regulatory element binding proteins (SREBPs), were examined to identify the root cause of steatosis development. High-fat and WD-exposed cells were associated with triglyceride and lipid droplet accumulation, paired with changes in SREBPs and lipid processing genes. These cells displayed hallmarks of lipotoxicity, such as decreased cell number and increased ROS. Together, this work unravels the maladaptive phenotypes associated with WD consumption, as these events may be critical in the onset of NAFLD pathogenesis.
Summary for Lay Audience
The Western world is currently burdened with the rising rates of metabolic diseases, as many individuals continue to engage in unhealthy eating practices. One such pattern, characterized by excessive saturated fat and sugar consumption, is the Western diet (WD). This diet has been linked to the worsening of metabolic health, leading to the development of diseases such as type II diabetes mellitus and obesity. The liver is especially susceptible to the ongoing consumption of the WD, as it overwhelms the processes that breakdown fats and sugars. Excessive nutrient intake can disrupt these processes, leading to the accumulation and storage of fats (steatosis) – the hallmark of non-alcoholic fatty liver disease (NAFLD). NAFLD involves a spectrum of liver defects that are characterized by steatosis and inflammation. Over time, these events may lead to fibrosis, cirrhosis, cancer, and eventually death. While the mechanisms of this disease have been heavily studied in obese individuals who present with various metabolic abnormalities, people with lean NAFLD are currently underrepresented and the disease is misunderstood. Using a cell model, the goal of this study was to understand the consequences of WD-like consumption and individual nutrients on the mechanisms of steatosis development in early stages of NAFLD. This was not a model of obese NAFLD as cells were not exposed to certain complications associated with obesity, such as inflammation or high concentrations of insulin. Cells with high-fat and WD treatment displayed lipid accumulation and storage, followed by changes in the expression of genes that regulate lipid metabolism. Moreover, these treatments displayed decreases in cell number with accumulation of harmful products in the cells. Taken together, this work reveals that while the quantity of calories one consumes is alarming, the type of calories is equally concerning as certain nutrient components may disrupt normal liver functioning, resulting in hepatic steatosis and NAFLD. These findings are significant in that it investigates the direct effects of dietary components in dysregulated metabolic functioning in an otherwise healthy model, revealing key events in early steatosis development and furthering our understanding of NAFLD.
Valvano, Celina M., "Western diet-like culture conditions and oxidative stress on a cell model of non-alcoholic fatty liver disease" (2022). Electronic Thesis and Dissertation Repository. 8965.
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