Lipotoxicity is the induction of apoptosis due to the accumulation of high levels of lipids in non-adipose tissues and is associated with prevalent diseases in the United States such as type II diabetes, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Research shows that saturated fatty acids, such as palmitate, can cause lipotoxicity by incorporation into phospholipids followed by partitioning into the plasma membrane as well as the membranes of organelles.  This increases the saturation and rigidity of the membranes and leads to ER stress triggering apoptosis.  On the other hand, literature also suggests that co-treatment with unsaturated fatty acids, such as oleate, can “rescue” cells from palmitate-induced lipotoxicity.  Until recently, this mechanism was thought to be governed by the ability of oleate to increase triglyceride (TG) synthesis, thereby rerouting palmitate to TG stores instead of incorporation into phospholipids.  However, recent studies show that oleate can rescue cells from palmitate-induced apoptosis even when TG synthesis is blocked, indicating that the mechanism for protection from lipotoxicity is independent of TG synthesis.  The current idea in the field is that oleate rescues cells from palmitate-induced lipotoxicity by simply being a competitor for fatty acid uptake into phospholipids and membranes.  In our laboratory, we have used a 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) Assay and morphology analysis to confirm that palmitate-treated AML-12 cells (mouse hepatocytes) undergo apoptosis, whereas cells co-treated with oleate are protected.  Next, we plan to investigate the mechanisms by which palmitate is incorporated into phospholipids.  By using choline-deficient cell culture media, we can block the incorporation of palmitate into phosphatidylcholine through the <i>de novo</i> synthesis (Kennedy) pathway.  Further, using the PACOCF3 inhibitor of PLA2, we can block the pathway by which phospholipids are recycled (Land’s Cycle).  If we can determine how to prevent palmitate from incorporating into membranes and, in turn, initiating apoptosis, we believe our findings can be useful for therapies to treat lipotoxicity- related diseases.

Inhibitition of palmitate-induced lipotoxicity

253rd National Meeting (2017)

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