LPIN1 (lipin-1) review notes

UniProt: Q14693 (LPIN1_HUMAN), 890 aa, HGNC:13345. Source file: LPIN1-uniprot.txt.

Core biology (from UniProt + primary literature)

LPIN1/lipin-1 is a Mg2+-dependent phosphatidate phosphatase (PAP1) (EC 3.1.3.4) that
catalyzes the penultimate step of glycerolipid synthesis: dephosphorylation of
phosphatidic acid (PA) -> diacylglycerol (DAG) + Pi.

• UniProt FUNCTION: "Acts as a magnesium-dependent phosphatidate phosphatase enzyme which
  catalyzes the conversion of phosphatidic acid to diacylglycerol during triglyceride,
  phosphatidylcholine and phosphatidylethanolamine biosynthesis and therefore controls the
  metabolism of fatty acids at different levels"
  [file:human/LPIN1/LPIN1-uniprot.txt].
• Catalytic activity RHEA:27429, EC=3.1.3.4; cofactor Mg(2+) (and to lesser extent Mn(2+))
  [file:human/LPIN1/LPIN1-uniprot.txt].
• Bifunctional: "Acts also as nuclear transcriptional coactivator for PPARGC1A/PPARA
  regulatory pathway to modulate lipid metabolism gene expression (By similarity)"
  [file:human/LPIN1/LPIN1-uniprot.txt]. Interacts (via LXXIL motif) with PPARA; interacts
  with PPARGC1A and MEF2C (all By similarity from mouse Q91ZP3).
• HAD-like fold with the DXDXT catalytic motif; lipins are NOT integral membrane proteins
  and translocate from cytosol to membranes PMID:23426360.

Enzymatic characterization (experimental, human protein)

• PMID:20231281 (Han & Carman 2010, EXP): purified human lipin 1 alpha/beta/gamma isoforms
  have PA phosphatase activity dependent on Mg2+/Mn2+; Km 0.35/0.24/0.11 mM for the three
  isoforms; inhibited by sphingoid bases, propranolol, Ca2+, Zn2+ PMID:20231281.
• PMID:23426360 (Eaton et al. 2013, IDA): lipin-1 PAP activity assayed with PA/PE mixtures;
  mTOR-dependent phosphorylation regulates membrane binding PMID:23426360.
• PMID:29765047 (Li et al. 2018, IDA; full text available): KAT5/Tip60-mediated acetylation
  at Lys-425/Lys-595 drives cytosol->ER translocation and DAG generation for TAG synthesis
  PMID:29765047. Basis for the experimental ER / cytosol localization annotations.
• PMID:39577771 (Stukey et al. 2025, EXP; full text): sertraline is a novel PAP inhibitor of
  human lipin 1 (alpha/beta/gamma) PMID:39577771.
• PMID:31695197 (MacVicar et al. 2019, IDA): mTORC1-LIPIN1-YME1L axis; LIPIN1 decreases
  mitochondrial PE and promotes proteolysis PMID:31695197. Basis for phosphatidylethanolamine metabolic process
  annotation.
• PMID:18694939 (Grimsey et al. 2008, EXP; full text): lipin 1 is the major PAP1 enzyme in
  HeLa cells; siRNA depletion cuts cellular PAP1 ~86% PMID:18694939. Also cytosolic localization: lipin 1-HA shows
  predominantly cytosolic staining PMID:18694939. PAP1 activity of lipin 1 is inhibited by mitotic phosphorylation
  PMID:18694939.

Adipose / developmental role

• PMID:11138012 (Peterfy et al. 2001, ISS basis): Lpin1 is the fld gene; encodes "a novel
  nuclear protein which we have named lipin"; required for normal adipose tissue development
  PMID:11138012. This is the
  mouse-gene discovery paper; human nucleus annotation is ISS from mouse Q91ZP3.
• PMID:23028044 (Nadra et al. 2012, ISS basis for cold-induced thermogenesis): cell-autonomous
  lipin 1 required for WAT and BAT; Lpin1 loss alters PPARalpha/PGC-1alpha/UCP1 and cold
  sensitivity PMID:23028044. Mouse study; human annotation ISS
  from mouse.

Localization (UniProt SUBCELLULAR LOCATION)

Cytoplasm/cytosol; Endoplasmic reticulum membrane; Nucleus membrane (By similarity). Note:
"Translocates from the cytosol to the endoplasmic reticulum following acetylation by KAT5"
[file:human/LPIN1/LPIN1-uniprot.txt]. Lipin-1 has NO transmembrane domain (peripheral
membrane / soluble). The Reactome nuclear-envelope/nucleoplasm annotations reflect its
regulated dephosphorylation there (CTDNEP1:CNEP1R1, CDK1) and the nuclear-lamina context.

Disease

Biallelic LPIN1 mutations cause autosomal-recessive recurrent acute myoglobinuria (ARARM,
MIM:268200) = recurrent childhood rhabdomyolysis [file:human/LPIN1/LPIN1-uniprot.txt DISEASE;
PMID:18817903 (not cited in GOA)].

Interactome annotation

The single IPI "protein binding" (GO:0005515) comes from PMID:32814053, a large Y2H
neurodegenerative-disease interactome map (LPIN1 was one of ~500 ND-related baits; interactors
include HTT, ATXN10, WFS1 etc). Uninformative bare protein binding; MARK_AS_OVER_ANNOTATED.

Curation decisions summary

• Core MF: phosphatidate phosphatase activity (GO:0008195) — multiple human-protein IDA/EXP.
• Core BP: triglyceride biosynthetic process (GO:0019432); diacylglycerol biosynthetic process
  (GO:0006651, proposed); phosphatidic acid metabolic process (GO:0046473) captured via the
  reaction. Phosphatidylethanolamine metabolic process (GO:0046337) is a real downstream
  metabolic role (DAG feeds PE synthesis) — ACCEPT/non-core.
• Nuclear transcriptional-coactivator role (GO:0003713 / GO:0045944): real but By-similarity/IBA
  in human; keep as non-core.
• IEA rat-ortholog terms (animal organ regeneration GO:0031100; negative regulation of
  myelination GO:0031642) are peripheral single-ortholog Ensembl transfers → over-annotated.
• Mitochondrial outer membrane (GO:0005741, IBA) and mitochondrial fission role: by similarity /
  supported by PMID:31695197 mitochondrial PE role; keep as non-core.