Role of lipid metabolic pathways in the progression of hepatic lipotoxicity

Abstract

The steady rise in Western obesity rates has been closely linked to significant increases in a multitude of accompanying health problems including obesity, type II diabetes and non-alcoholic fatty liver disease (NAFLD). NAFLD severity ranges from simple steatosis to acute steatohepatitis, but the molecular mechanisms controlling progression of this disease are poorly understood. The liver plays a central role in whole body homeostasis and, therefore, impairments in hepatic function are detrimental to a variety of biological processes. These hepatic dysfunctions are thought to be triggered by elevated free fatty acid flux from either dietary intake or adipose tissue efflux that results in etopic deposition of fat in the liver. It is known to be accompanied by increased signaling thorough cellular stress pathways, oxidant stress and eventual apoptosis. This phenotype is collectively termed hepatic lipotoxicity.

Recent literature suggests that elevated free fatty acids (FFAs), especially saturated fatty acids (SFAs), play a central role in lipotoxic mechanisms, both in experimental models and in NAFLD patients. Relevant cellular processes that have been causally linked to lipotoxicity include endoplasmic reticulum (ER) stress, oxidative stress, mitochondrial dysfunction, and apoptosis. In contrast, increased triglyceride synthesis has been shown to have a protective effect against lipotoxicity, despite being one of the hallmark traits of NAFLD. The overarching theme of this dissertation is designing studies to better understand how the degree of intrahepatic lipid saturation controls cell fate in response to an elevated FFA load and the mechanisms through which these fatty acids act. Our results indicate that disordered phospholipid metabolism, specifically over saturation of membrane bilayers initiates a signaling cascade which culminates in cell death. Interventions designed to prevent saturation of the phospholipids improves hepatic cell fate when in environments of saturated fatty acid overload. Developing a more nuanced understanding of the molecular mechanisms underlying NAFLD progression will lead to more targeted and effective therapeutics for this increasingly prevalent disease, which to date has no proven pharmacologic treatment to prevent or reverse its course.