PPP1R3B

PPP1R3B (GL) is a glycogen-targeting regulatory subunit of protein phosphatase 1 that governs the partitioning of hepatic energy storage between glycogen and lipid (PMID:28473467, PMID:40378221). It physically scaffolds the PP1 catalytic subunit together with glycogen synthase and glycogen phosphorylase and binds glycogen directly, thereby coupling phosphatase activity to glycogen particles (PMID:30853975). In liver, PPP1R3B promotes glycogen synthase activation by dephosphorylation and is required to maintain glycogen synthase protein abundance; its loss leaves the residual enzyme phosphorylated and inactive, impairs glucose incorporation into glycogen, and disrupts fasting energy homeostasis (PMID:28473467). Reciprocal mouse genetics establish PPP1R3B as a metabolic switch: deletion shifts hepatic storage toward lipid while overexpression drives glycogen accumulation, effects corroborated by human genetic association with liver fat and plasma lipids (PMID:29266543, PMID:40378221). Postprandial glycogenesis depends on feeding-induced, mTORC1- and FOXO1-driven transcriptional induction of Ppp1r3b, and re-expression of Ppp1r3b restores glycogen synthase activity in livers lacking mTORC1 signaling (PMID:38290087). PPP1R3B expression is further constrained by the lncRNA LOC157273 and modulated by the noncoding variant rs4841132, which independently regulate PPP1R3B level and hepatocyte glycogen content (PMID:33231259, PMID:32754192). Beyond hepatocytes, PPP1R3B promotes M2 macrophage polarization and regulates macrophage glycogen metabolism through a p-STAT3/PPAR-γ axis, and its absence accelerates atherosclerotic plaque progression (PMID:40984828).

1. 2017 High

   Establishing whether PPP1R3B is functionally required for hepatic glycogen storage, this work showed it controls glycogen synthase abundance and activation state in vivo.

   Evidence Liver-specific knockout/overexpression mice with glycogen content, glycogen synthase activity/phosphorylation assays and isotope tracing

   PMID:28473467

   Open questions at the time

   • Does not resolve the direct biochemical interactions among PP1, glycogen synthase, and glycogen
   • Mechanism by which PPP1R3B stabilizes glycogen synthase protein not defined
2. 2018 High

   Addressing whether PPP1R3B's role is glycogen-specific or general to energy storage, this study showed it selectively promotes glycogen rather than triglyceride accumulation.

   Evidence Reciprocal mouse knockout/overexpression with hepatic glycogen, triglyceride and plasma ALT measurements

   PMID:29266543

   Open questions at the time

   • Did not yet demonstrate the lipid-storage rerouting seen in later models
   • Cause of elevated ALT on overexpression not mechanistically explained
3. 2019 Medium

   To define the molecular partnerships underlying targeting function, the oyster ortholog was shown to bind the PP1 catalytic subunit, glycogen synthase, glycogen phosphorylase, and glycogen itself.

   Evidence Co-IP, yeast two-hybrid, co-sedimentation and RNAi knockdown in oyster (CgPPP1R3B)

   PMID:30853975

   Open questions at the time

   • Interactions demonstrated in a non-mammalian ortholog, not human PPP1R3B
   • No structural definition of glycogen- or substrate-binding interfaces
4. 2020 Medium

   Identifying upstream regulation, knockdown of lncRNA LOC157273 was shown to derepress PPP1R3B and increase hepatocyte glycogen, framing LOC157273 as a negative regulator.

   Evidence siRNA knockdown with RT-PCR, RNA-seq and insulin-stimulated glycogen assay in primary human hepatocytes

   PMID:32754192

   Open questions at the time

   • Single-lab, single-readout direction
   • Mechanism by which LOC157273 suppresses PPP1R3B transcription unknown
5. 2021 High

   Connecting a GWAS noncoding variant to function, CRISPR editing of rs4841132 was shown to raise PPP1R3B and glycogen while independently lowering LOC157273.

   Evidence CRISPR/Cas9 deletion with overexpression/knockdown and glycogen measurement in human hepatocarcinoma cells

   PMID:33231259

   Open questions at the time

   • How the variant locus simultaneously and independently controls two transcripts not resolved
   • Cell-line context may not reflect primary hepatocyte regulation
6. 2024 High

   Placing PPP1R3B in a signaling pathway, this work showed postprandial glycogenesis requires mTORC1/FOXO1-driven transcriptional induction of Ppp1r3b, with re-expression rescuing glycogen synthase activity.

   Evidence Liver-specific mTORC1-loss mice, metabolomics, isotope tracing and viral Ppp1r3b re-expression rescue

   PMID:38290087

   Open questions at the time

   • Direct transcription-factor occupancy at the Ppp1r3b locus not fully defined
   • Relationship between this signaling axis and LOC157273 regulation unknown
7. 2025 High

   Consolidating the storage-partitioning concept, reciprocal mouse models plus human genetics defined PPP1R3B as a switch routing hepatic energy between glycogen and lipid.

   Evidence Mouse overexpression/deletion with glycogen and lipid measurement and human genetic association with liver fat and plasma lipids

   PMID:40378221

   Open questions at the time

   • Mechanism linking reduced glycogen flux to increased lipid synthesis not delineated
   • Tissue-autonomous versus systemic contributions to lipid phenotype unresolved
8. 2025 Medium

   Extending function beyond hepatocytes, PPP1R3B was shown to drive M2 macrophage polarization and macrophage glycogen metabolism through a p-STAT3/PPAR-γ axis, with loss accelerating atherosclerosis.

   Evidence PPP1R3B modulation in macrophages with RNA-seq, multi-omics pathway analysis and polarization assays

   PMID:40984828

   Open questions at the time

   • Dual nuclear/mitochondrial STAT3 role inferred from omics, not biochemically resolved
   • Direct connection between PPP1R3B phosphatase targeting and STAT3 phosphorylation not established

• How PPP1R3B coordinates its PP1-targeting biochemistry with the macrophage p-STAT3/PPAR-γ signaling role, and the structural basis of its glycogen and substrate engagement in humans, remain unresolved.
• No human structural model of glycogen/substrate binding
• Mechanistic link between glycogen-targeting and STAT3 signaling unestablished