Characterization and Roles of Membrane Lipids in Fatty Liver Disease

Abstract

Obesity has reached global epidemic proportions and it affects the development of insulin resistance, type 2 diabetes, fatty liver disease and other metabolic diseases. Membrane lipids are important structural and signaling components of the cell membrane. Recent studies highlight their importance in lipid homeostasis and are implicated in the pathogenesis of fatty liver disease. Here, we discuss the numerous membrane lipid species and their metabolites including, phospholipids, sphingolipids and cholesterol, and how dysregulation of their composition and physiology contribute to the development of fatty liver disease. The development of new genetic and pharmacological mouse models has shed light on the role of lipid species on various mechanisms/pathways; these lipids impact many aspects of the pathophysiology of fatty liver disease and could potentially be targeted for the treatment of fatty liver disease.

Keywords: fatty liver disease; insulin resistance; membrane lipids; metabolic syndrome; obesity.

Figure 1

Model for ceramide-induced fatty liver and other metabolic disorders. In obesity, ceramide levels are upregulated, and this leads to accumulation of lipids, fatty liver and insulin resistance. On the other hand, inflammation can cause an increase in ceramide levels that promotes pro-inflammatory cytokine production. Increase in ceramide also cause apoptosis. Yellow: end results; Blue: linked specifically to obesity; green: linked specifically to inflammation.

Figure 2

Model for phosphatidylcholine (PC)/phosphatidylethanolamine (PE)-induced fatty liver disease. Light blue, red, and dark blue are three different PE/PC membrane disruption pathways. Light blue shows the effects of a low choline diet, which significantly lowers intracellular PC levels due to lack of its primary reactant. The liver will try to compensate for this lowering by increasing extracellular PE. Red shows the effects of disrupting the PEMT pathway, which significantly decreases TAG secretion and increases TAG intracellular accumulation. Dark blue shows the effects of silencing the expression of mitochondrial protein Mfn2. In the ER, PS is converted to PE, which is then sent into the mitochondria for modification to PC. Knocking out this membrane protein causes a NAFLD/NASH phenotype due to the halting of PE and PC creation. All three disruptions upset the intracellular PE/PC ratio, which in turn causes membrane destabilization.