UBC Theses and Dissertations
Regulation of lipin phosphorylation and lipid homeostasis by glycogen synthase kinase 3 Chan, Leslie Jing
It is imperative for cell survival and function to maintain proper steady-state lipid levels, or lipid homeostasis. This has significant physiological consequences, as lipid homeostasis is disrupted in metabolic diseases including obesity and diabetes, which necessitates a greater understanding of this cellular phenomenon. The lipin family of phosphatidic acid phosphatases are conserved enzymes that control the cellular balance of phospholipid and triglyceride synthesis, and mammalian lipins can also regulate lipid synthesis through interacting with transcription factors in the nucleus. Unsurprisingly, lipins are tightly regulated enzymes and a conserved mechanism of lipin regulation is phosphorylation by kinases, which can control the subcellular localization of lipins from the cytoplasm to other cellular compartments. To date, various kinases have been identified that phosphorylate lipins including the mechanistic target of rapamycin complex 1 (mTORC1), which controls lipin 1 localization from the cytoplasm to the nucleus and the ability of lipin 1 to repress sterol regulatory element binding protein (SREBP) target-gene transcription and thus cholesterol and fatty acid biosynthesis and uptake. A high-throughput screen seeking novel kinase regulators of lipins has never been performed. In this work, we designed an overexpression screen in yeast and identified Mck1, a glycogen synthase kinase 3 (GSK3) kinase, as a novel regulator of lipins and lipid homeostasis. We further discovered that this relationship was conserved from yeast to mammals by characterizing that mammalian GSK3 phosphorylates lipin 1 directly. GSK3 activity, downstream of the PI3K/Akt pathway, towards lipin 1 was found to control its localization, and in the absence of GSK3 activity, lipin 1 translocated to the nucleus and repressed SREBP target-gene expression. We observed that regulation of SREBP-target gene expression in this pathway was dependent on lipin 1 and additionally that both GSK3 paralogs, GSK3α and GSK3β, appeared to be involved. Finally, we characterized the role of GSK3 in lipid metabolism using mouse models and found that mice lacking GSK3α or GSK3β in the liver demonstrated resistance to some effects of diet-induced obesity including weight gain and the expression of certain SREBP target genes, suggesting that GSK3 in the liver plays a role in the development of these phenotypes.
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