Faculty, Staff and Student Publications

Publication Date

9-2-2025

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2508912122

PMID

40875810

PMCID

PMC12415208

PubMedCentral® Posted Date

8-28-2025

PubMedCentral® Full Text Version

Post-print

Abstract

The glycerol-3-phosphate (G-3-P) pathway is central to the synthesis of triacylglycerols (TAGs) and glycerophospholipids, essential for membrane biogenesis and lipid storage. The first and rate-limiting step in this pathway is catalyzed by glycerol-3-phosphate acyltransferases (GPATs), with microsomal GPAT3 and GPAT4 being evolutionarily conserved and predominant in most tissues. While previous studies have implicated Calcineurin B homologous protein 1 (CHP1) as a cofactor for GPAT4, the broader role of CHP1 in regulating microsomal GPATs and TAG biosynthesis remains unclear. Here, we demonstrate that CHP1 is a critical regulator of both GPAT3 and GPAT4, essential for their stability, enzymatic activity, and lipid droplet (LD) localization. Structural modeling and mutational analyses identified key hydrophobic interfaces mediating the CHP1-GPAT interaction, which are required for optimal GPAT activity and LD growth. Loss of CHP1 impairs LD expansion and disrupts the localization of GPAT3/4 and downstream enzymes in the TAG synthesis pathway, including 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) and diacylglycerol O-acyltransferase 2 (DGAT2). Mechanistically, CHP1 helps circumvent seipin-mediated restriction of late LD-targeting enzymes, facilitating their access to mature LDs. Together, our findings reveal CHP1 as a dual-function regulator that stabilizes and activates microsomal GPATs while enabling the coordinated recruitment of TAG biosynthetic enzymes to LDs. This work uncovers a previously unrecognized mechanism for regulating LD growth and glycerolipid metabolism, with broad implications for lipid homeostasis and metabolic diseases.

Keywords

Triglycerides, Lipid Droplets, Glycerol-3-Phosphate O-Acyltransferase, Animals, Humans, Mice, Microsomes

Published Open-Access

yes

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