Hexokinase 2-mediated gene expression via histone lactylation is required for hepatic stellate cell activation and liver fibrosis.
Lactate was implicated in the activation of hepatic stellate cells (HSCs). However, the mechanism by which lactate exerts its effect remains elusive. Using RNA-seq and CUT&Tag chromatin profiling, we found that induction of hexokinase 2 (HK2) expression in activated HSCs is required for induced gene expression by histone lactylation but not histone acetylation. Inhibiting histone lactylation by Hk2 deletion or pharmacological inhibition of lactate production diminishes HSC activation, whereas exogenous lactate but not acetate supplementation rescues the activation phenotype. Thus, lactate produced by activated HSCs determines the HSC fate via histone lactylation. We found that histone acetylation competes with histone lactylation, which could explain why class I HDAC (histone deacetylase) inhibitors impede HSC activation. Finally, HSC-specific or systemic deletion of HK2 inhibits HSC activation and liver fibrosis in vivo. Therefore, we provide evidence that HK2 may be an effective therapeutic target for liver fibrosis.
Pubmed ID: 37463576 RIS Download
Research resources used in this publication
None foundAdditional research tools detected in this publication
None foundAntibodies used in this publication
- IRDye 680RD Goat anti-Mouse IgG (RRID:AB_10956588)
- IRDye 800CW Goat anti-Rabbit IgG (RRID:AB_621843)
- CUTANA™ Rabbit IgG CUT&RUN Negative Control Antibody (RRID:AB_2923178)
- Rabbit (DA1E) mAb IgG XP Isotype Control (RRID:AB_1550038)
- anti-bromodeoxyuridine, anti-BrdU (RRID:AB_10013660)
- Goat anti-Mouse IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 594 (RRID:AB_2534073)
- Goat Anti-Rabbit IgG (H+L) Antibody, Alexa Fluor 488 Conjugated (RRID:AB_143165)
- GAPDH (D16H11) XP Rabbit mAb (RRID:AB_10622025)
- Pyruvate Dehydrogenase E1-alpha subunit antibody [8D10E6 ] (RRID:AB_10866116)
- Phospho-Pyruvate Dehydrogenase α1 (Ser293) Antibody (RRID:AB_2799014)
- Mouse Anti-Histone H3 Monoclonal Antibody, Unconjugated, Clone 96C10 (RRID:AB_1642229)
- Anti-Histone H3 Antibody, Unconjugated (RRID:AB_331563)
- Histone H3 (acetyl K18) antibody - ChIP Grade (RRID:AB_298692)
- Acetylated-Lysine Antibody (RRID:AB_331805)
- Lactyl-Histone H3 (Lys18) Rabbit mAb (RRID:AB_2909438)
- Anti-L-lactyllysine rabbit pAb (RRID:AB_2868521)
- GCK (H-88) (RRID:AB_2107620)
- β-Actin (13E5) Rabbit mAb (RRID:AB_2223172)
- Anti-β-Actin Antibody (RRID:AB_476744)
- COL1A1 (E3E1X) Mouse mAb (RRID:AB_2920541)
- Mouse Anti-Actin, alpha-Smooth Muscle Monoclonal Antibody, Unconjugated, Clone 1A4 (RRID:AB_262054)
- HK1 Monoclonal Antibody (7A7) (RRID:AB_10983588)
- Hexokinase 2 antibody (RRID:AB_11182717)
- Rabbit Anti-Hexokinase II Monoclonal Antibody, Unconjugated, Clone C64G5 (RRID:AB_2232946)
Associated grants
- Agency: NIA NIH HHS, United States
Id: R01 AG016927 - Agency: NCI NIH HHS, United States
Id: R01 CA090764 - Agency: NCI NIH HHS, United States
Id: R01 CA258299 - Agency: NCI NIH HHS, United States
Id: F30 CA225058 - Agency: BLRD VA, United States
Id: I01 BX000733 - Agency: NCI NIH HHS, United States
Id: R01 CA206167 - Agency: BLRD VA, United States
Id: I01 BX005092
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This is a list of tools and resources that we have found mentioned in this publication.
IRDye 680RD Goat anti-Mouse IgG (antibody)
RRID:AB_10956588
This polyclonal targets IgG
View all literature mentionsIRDye 800CW Goat anti-Rabbit IgG (antibody)
RRID:AB_621843
This polyclonal secondary targets IgG
View all literature mentionsCUTANA™ Rabbit IgG CUT&RUN Negative Control Antibody (antibody)
RRID:AB_2923178
This isotype control targets not applicable
View all literature mentionsRabbit (DA1E) mAb IgG XP Isotype Control (antibody)
RRID:AB_1550038
This isotype control targets not applicable
View all literature mentionsanti-bromodeoxyuridine, anti-BrdU (antibody)
RRID:AB_10013660
This monoclonal targets cells that have bromodeoxyuridine incorporated in their DNA
View all literature mentionsGoat anti-Mouse IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 594 (antibody)
RRID:AB_2534073
This polyclonal secondary targets IgG (H+L)
View all literature mentionsGoat Anti-Rabbit IgG (H+L) Antibody, Alexa Fluor 488 Conjugated (antibody)
RRID:AB_143165
This polyclonal targets IgG (H+L)
View all literature mentionsGAPDH (D16H11) XP Rabbit mAb (antibody)
RRID:AB_10622025
This monoclonal targets GAPDH
View all literature mentionsPyruvate Dehydrogenase E1-alpha subunit antibody [8D10E6 ] (antibody)
RRID:AB_10866116
This monoclonal targets Pyruvate Dehydrogenase E1-alpha subunit antibody [8D10E6 ]
View all literature mentionsPhospho-Pyruvate Dehydrogenase α1 (Ser293) Antibody (antibody)
RRID:AB_2799014
This unknown targets PDHA1;PDHA2
View all literature mentionsMouse Anti-Histone H3 Monoclonal Antibody, Unconjugated, Clone 96C10 (antibody)
RRID:AB_1642229
This monoclonal targets Histone H3
View all literature mentionsAnti-Histone H3 Antibody, Unconjugated (antibody)
RRID:AB_331563
This polyclonal targets Histone H3
View all literature mentionsHistone H3 (acetyl K18) antibody - ChIP Grade (antibody)
RRID:AB_298692
This polyclonal targets Histone H3 (acetyl K18) antibody - ChIP Grade
View all literature mentionsAcetylated-Lysine Antibody (antibody)
RRID:AB_331805
This polyclonal targets Acetylated-Lysine
View all literature mentionsLactyl-Histone H3 (Lys18) Rabbit mAb (antibody)
RRID:AB_2909438
This recombinant monoclonal targets Lactyl-Histone H3 (Lys18)
View all literature mentionsAnti-L-lactyllysine rabbit pAb (antibody)
RRID:AB_2868521
This polyclonal targets lactyllysine
View all literature mentionsβ-Actin (13E5) Rabbit mAb (antibody)
RRID:AB_2223172
This monoclonal targets beta-Actin
View all literature mentionsAnti-β-Actin Antibody (antibody)
RRID:AB_476744
This monoclonal targets slightly modified β-cytoplasmic actin N-terminal peptide, Ac-Asp-Asp-Asp-Ile-Ala-Ala-Leu-Val-Ile-Asp-Asn-Gly-Ser-Gly-Lys, conjugated to KLH
View all literature mentionsCOL1A1 (E3E1X) Mouse mAb (antibody)
RRID:AB_2920541
This monoclonal targets COL1A1
View all literature mentionsMouse Anti-Actin, alpha-Smooth Muscle Monoclonal Antibody, Unconjugated, Clone 1A4 (antibody)
RRID:AB_262054
This monoclonal targets Actin, alpha, Smooth Muscle
View all literature mentionsHK1 Monoclonal Antibody (7A7) (antibody)
RRID:AB_10983588
This monoclonal targets HK1
View all literature mentionsHexokinase 2 antibody (antibody)
RRID:AB_11182717
This polyclonal targets Hexokinase 2
View all literature mentionsRabbit Anti-Hexokinase II Monoclonal Antibody, Unconjugated, Clone C64G5 (antibody)
RRID:AB_2232946
This monoclonal targets Hexokinase II
View all literature mentions
