Metabolic Determinants of Hepatic Lipotoxicity

Abstract

Lipotoxicity from free fatty acid overload has been implicated in a variety of diseases including type II diabetes and non-alcoholic fatty liver disease (NAFLD). Incubation of hepatic cells in vitro with saturated fatty acids induces apoptosis characterized by the accumulation of reactive oxygen species, depleted endoplasmic reticulum calcium, and metabolic dysfunction. Without a consensus mechanism linking these lipotoxic responses, it is difficult to develop novel nutritional or pharmacologic interventions to combat the effects of NAFLD. Using an arsenal of fluorescent dyes and pharmacologic inhibitors, we identified a unified mechanism by which elevated saturated fatty acid redistributes intracellular calcium stores from the endoplasmic reticulum to the mitochondria leading to oxidative stress and apoptosis. 13C metabolic flux analysis of hepatic cells in lipotoxic conditions revealed this redistribution of calcium alters mitochondrial metabolism, resulting in increased glutamate anaplerosis. These findings shed light on mechanisms of hepatic lipotoxicity and suggest strategies for the treatment of NAFLD.