How lipid droplets "TAG" along: Glycerolipid synthetic enzymes and lipid storage

Abstract

Triacylglycerols (TAG) serve as the predominant form of energy storage in mammalian cells, and TAG synthesis influences conditions such as obesity, fatty liver, and insulin resistance. In most tissues, the glycerol 3-phosphate pathway enzymes are responsible for TAG synthesis, and the regulation and function of these enzymes is therefore important for metabolic homeostasis. Here we review the sites and regulation of glycerol-3-phosphate acyltransferase (GPAT), acylglycerol-3-phosphate acyltransferase (AGPAT), lipin phosphatidic acid phosphatase (PAP), and diacylglycerol acyltransferase (DGAT) enzyme action. We highlight the critical roles that these enzymes play in human health by reviewing Mendelian disorders that result from mutation in the corresponding genes. We also summarize the valuable insights that genetically engineered mouse models have provided into the cellular and physiological roles of GPATs, AGPATs, lipins and DGATs. Finally, we comment on the status and feasibility of therapeutic approaches to metabolic disease that target enzymes of the glycerol 3-phosphate pathway. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink.

Keywords: Acyltransferase; Human disease mutation; Mouse model; Triacylglycerol synthesis.

Fig. 1

Glycerolipid biosynthetic pathway enzyme localization to subcellular compartments. Four major enzyme families control lipid synthesis including glycerol phosphate acyltransferase (GPAT), acylglycerolphosphate acyltransferase (AGPAT), lipin (phosphatidate phosphatase), and diacylglycerol aceyltransferase (DGAT) enzymes. LD: lipid droplets; iLD: initial lipid droplets; eLD: expanding lipid droplets; nLD: Nuclear lipid droplets; G-3-P: Glycerol-3-phosphate; LPA: Lysophosphatidic acid; PA: Phosphatidic acid; DAG: Diacylglycerol; TAG: Triacylglycerol; FA-CoA: Fatty acyl-CoA.

Fig. 2

Regulation of key enzymes in glycerolipid biosynthesis, including GPAT, AGPAT, Lipin, DGAT and MGAT enzymes. Transcriptional regulation, epigenetic and miroRNA regulation, and post-translational regulation are summarized. Activation processes are marked in green and inhibition processes are marked in red. ChREBP: Carbohydrate-responsive element binding protein; SRE: Sterol regulatory element; SREBP-1: Sterol regulatory element-binding protein 1; NF-Y: Nuclear factor-Y; TSS: Transcription start site; Ac: Histone acetylaiton; Me: DNA methylation; P: Phosphorylation; Ser: Serine; Thr: Threonine; GRE: Glucocorticoid response element: GR: Glucocorticoid receptor; GCs: Glucocorticoids; HREs: Hormone-response elements; ERRE1: ERR response element 1; ERRγ: Estrogen related receptor gamma; ARE: Antioxidant response element; NRRE: Nuclear receptor response element; OA: Oleic acid; AA: Amino acid; EPI: Epinephrine; Ub: Ubiquitination; SUMO: Sumoylation; ER: Endoplasmic reticulum; Cyto: Cytoplasm.

Fig. 3

Proposed structure and catalytic mechanism of GPAT enzymes from studies of lower organisms. (A) Cartoon structure of squash GPAT (pdb code: 1IUQ) with sulfate ion occupying the putative binding site for the phosphate moieties of G3P and LPA. The non-hydrolyzable acyl-CoA analog (magenta sticks) and palmitic acid (green sticks) from structures of M. smegmatis PatA (pdb codes: 5F34 and 5F2Z) are overlaid with the squash GPAT structure to highlight the putative hydrophobic active site cleft for acyl-CoA. The HX₄D catalytic motif is shown in blue sticks. (B) Proposed catalytic mechanism for GPAT enzymes involving charge relay between the Asp and His residues of the HX₄D motif. G3P, glycerol 3-phosphate; LPA, lyso-phosphatidic acid.