Elevated levels of triglycerides have long been associated with increased risk of cardiovascular disease and diabetes. However, in spite of their importance to biomedical health, how triglyceride-synthesizing enzymes work at the molecular and structural level is unclear. We are particularly interested in lipins, which are phosphatidic acid phosphatases that catalyze the penultimate step of triglcyeride synthesis. Human lipins also serve as transcriptional co-activators for PPARα and PGC-1α (two master regulators of lipogenesis) to upregulate fatty acid oxidation genes. Our aim is to provide a molecular description for the multiple functions of lipins.
Phospholipase D (PLD) hydrolyzes phosphatidylcholine to generate the lipid second messenger phosphatidic acid, which in turn plays key roles in cell proliferation, vesicular trafficking, endocytosis, and cell migration. PLD activity is tightly regulated and not only requires the anionic lipid PI(4,5)P2 for basal activity but is strongly stimulated by Arf, Rho, and PKC. Our goal is to provide unambigious insight into the mechanisms gating PLD activation.
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