Dual function lipin proteins and glycerolipid metabolism

Abstract

Lipin family proteins are emerging as crucial regulators of lipid metabolism. In triglyceride synthesis, lipins act as lipid phosphatase enzymes at the endoplasmic reticular membrane, catalyzing the dephosphorylation of phosphatidic acid to form diacylglycerol, which is the penultimate step in this process. However, lipin proteins are not integral membrane proteins, and can rapidly translocate within the cell. In fact, emerging evidence suggests that lipins also play crucial roles in the nucleus as transcriptional regulatory proteins. Thus, lipins are poised to regulate cellular lipid metabolism at multiple regulatory nodal points. This review summarizes the history of lipin proteins, and discusses the current state of our understanding of lipin biology.

Fig. 1

Phylogenetic tree of lipin family orthologs and paralogs (adapted from the Tree families database, http://www.treefam.org/). Red circles represent duplication events. A.t. Arabidopsis thaliana D. d. - Dictyostelium discoideum S. p. - Schizosaccharomyces pombe S. c. - Saccharomyces cerevisiae H. s. - Homo sapiens M. m. - Mus musculus D. r. - Danio rerio G. g. - Gallus gallus X. t. - Xenopus tropicalis C. i. - Ciona intestinalis D. m. - Drosophila melanogaster C. e. - Caenorhabditis elegans C. br. - Caenorhabditis briggsae C. re. - Caenorhabditis remanei

Fig. 2

Cartoon of mouse lipin 1 and S. cerevisiae Pah1p illustrating phosphorylation sites and domain features. NLIP and CLIP are conserved NH2- and COOH-LIPin homology domains [4], LHR and NHR are Low and No homology domains within yeast lipin that have no homology with mammalian lipins [30], β and γ gamma represent alternatively spliced exons, DxDxT is haloacid dehalogenase domain [3], NLS is Nuclear Localization Sequence [4, 17, 40, 59]/polybasic domain (PBD) is the PA-binding motif in mammalian lipins [40], serine-rich domain (SRD) mediates the interaction with 14-3-3 proteins [59], AαH is the amphipathic α-Helix responsible for membrane association [19], residues in red are the amino acid residues mutated to alanine in PAH1-7A [19], CDK are the sites phosphorylated directly by CDK [20], Rap is the lipin 1 residue sensitive to rapamycin [30], bracketed phosphosites within lipin 1 indicate either site may be phosphorylated. Figure adapted from Harris et al, 2007.

Fig. 3

This schematic depicts the intracellular trafficking of lipin 1 multimers. At top, lipin 1 protein with domains described in Fig. 2 is shown. At center, hyperphosphorylation of the SRD of lipin 1 leads to associations with 14-3-3 proteins and cytosolic retention. mTOR has been identified as a kinase that phosphorylates lipin 1 and regulates its localization. Dephosphorylation by unknown protein phosphatase(s) (PPase) direct lipin to the nucleus or ER compartments. The NLS/PBD targets lipin 1 to PA-rich membranes while the DxDxT catalytic motif is required for the dephosphorylation of PA to form DAG. DGAT then terminally acylates DAG to make TAG and form the core of nascent lipid droplets (LD). The NLS/PBD also mediates the nuclear localization of lipin 1. In the nucleus, lipin 1 interacts with DNA-bound transcription factors (TF) to regulate their activity.