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.

Adipose‐Specific Lipin‐1 Overexpression Renders Hepatic Ferroptosis and Exacerbates Alcoholic Steatohepatitis in Mice

“…It remains unresolved how overexpression of adipose‐specific lipin‐1 induces adiponectin production in the adipose of ethanol‐fed mice. Lipin‐1α and lipin‐1β are two major variants generated by lipin‐1 pre‐mRNA splicing . In concordance with drastic elevation of circulating adiponectin, adipose mRNA expression of lipin‐1α, but not lipin‐1β, was robustly increased by ethanol feeding to Lpin1 ‐Tg mice.…”

“…Lipin‐1α is one of the variants generated through splicing lipin‐1β with exon 7 skipping . Ethanol feeding to WT mice mildly but significantly increased adipose lipin‐1α mRNA abundance compared with WT control mice (Supporting Fig.…”

“…Lipin‐1‐mediated PAP activity catalyzes the conversion of phosphatide to diacylglycerol, the immediate precursor of triacylglycerol. Nuclear lipin‐1 protein is capable of interacting and regulating multiple pivotal transcription factors and cofactors …”

“…Lipin-1, a Mg 2+ -dependent phosphatidic acid phosphohydrolase (PAP), is a bifunctional molecule that regulates lipid metabolism in various tissues including liver and adipose. (3)(4)(5) Lipin-1-mediated PAP activity catalyzes the conversion of phosphatide to diacylglycerol, the immediate precursor of triacylglycerol. Nuclear lipin-1 protein is capable of interacting and regulating multiple pivotal transcription factors and cofactors.…”

Symposium review: Intravital imaging of the lactating mammary gland in live mice reveals novel aspects of milk-lipid secretion

“…An additional pathway, which is based on the stepwise esterification of sn-2-monoacylglycerol at the sn-1 and sn-3 positions, plays a major role in TG synthesis in intestinal cells and other tissues but is of minor importance in the mammary gland (Palmquist, 2006). There is a wealth of information on transcriptional regulation, enzyme isoforms employed, and species differences in the fatty acyl chains, which are esterified to the glycerol backbone (Palmquist, 2006;Bionaz and Loor, 2008;Wang et al, 2017). Much less is understood about how the nascent droplet of TG forms in the rER membrane.…”