Fat-regulating phosphatidic acid phosphatase: a review of its roles and regulation in lipid homeostasis

George M Carman,Gil-Soo Han

doi:10.1194/jlr.s087452

George M Carman, Gil-Soo Han

Open Access

https://doi.org/10.1194/jlr.s087452

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Abstract

Phosphatidic acid (PA) phosphatase is an evolutionarily conserved enzyme that plays a major role in lipid homeostasis by controlling the cellular levels of its substrate, PA, and its product, diacylglycerol. These lipids are essential intermediates for the synthesis of triacylglycerol and membrane phospholipids; they also function in lipid signaling, vesicular trafficking, lipid droplet formation, and phospholipid synthesis gene expression. The importance of PA phosphatase to lipid homeostasis and cell physiology is exemplified in yeast, mice, and humans by a host of cellular defects and lipid-based diseases associated with loss or overexpression of the enzyme activity. In this review, we focus on the mode of action and regulation of PA phosphatase in the yeast Saccharomyces cerevisiae The enzyme Pah1 translocates from the cytosol to the nuclear/endoplasmic reticulum membrane through phosphorylation and dephosphorylation. Pah1 phosphorylation is mediated in the cytosol by multiple protein kinases, whereas dephosphorylation is catalyzed on the membrane surface by an integral membrane protein phosphatase. Posttranslational modifications of Pah1 also affect its catalytic activity and susceptibility to degradation by the proteasome. Additional mechanistic understanding of Pah1 regulation should be instrumental for the identification of small-molecule inhibitors or activators that can fine-tune PA phosphatase function and thereby restore lipid homeostasis.

Highlights

Phosphatidic acid (PA) phosphatase is an evolutionarily conserved enzyme that plays a major role in lipid homeostasis by controlling the cellular levels of its substrate, PA, and its product, diacylglycerol
The substrate PA is a precursor for membrane phospholipids that are synthesized via the liponucleotide intermediate CDP-DAG [7] (Fig. 1)
The importance of PA phosphatase to lipid homeostasis and cell physiology is highlighted in yeast cells lacking the enzyme and in mice and humans containing the mutations of the enzyme genes (e.g., Lpin and LPIN, respectively)

Summary

Introduction

Phosphatidic acid (PA) phosphatase is an evolutionarily conserved enzyme that plays a major role in lipid homeostasis by controlling the cellular levels of its substrate, PA, and its product, diacylglycerol. Phosphatidic acid (PA) phosphatase,2 the enzyme that catalyzes the Mg2+-dependent dephosphorylation of PA to produce diacylglycerol (DAG) (Fig. 1), has emerged as a vital regulator of lipid homeostasis in eukaryotic organisms [1]. By the nature of its reaction, PA phosphatase controls the synthesis of TAG and membrane phospholipids, and the abundance of lipid signaling molecules.

Results

Conclusion