Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis

Patrycja Puchalska; Shannon E. Martin; Xiaojing Huang; Justin E. Lengfeld; Bence Daniel; Mark J. Graham; Xianlin Han; Laszlo Nagy; Gary J. Patti; Peter A. Crawford

doi:10.1016/j.cmet.2018.10.015

Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis

Patrycja Puchalska, Shannon E. Martin, Xiaojing Huang, Justin E. Lengfeld, Bence Daniel, Mark J. Graham, Xianlin Han, Laszlo Nagy, Gary J. Patti, Peter A. Crawford

Molecular Medicine

Research output: Contribution to journal › Article › peer-review

66 Scopus citations

Abstract

Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we apply a stable isotope tracing, mass spectrometry-based untargeted metabolomics approach to reveal the metabolome penetrated by hepatocyte-derived glucose and ketone bodies. In both classically and alternatively polarized macrophages, [ ¹³ C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[ ¹³ C]β-hydroxybutyrate (D-βOHB) labeled almost none. [ ¹³ C]glucose labeled ∼500 features, and while unlabeled AcAc competed with only ∼15% of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT). AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-βOHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte-macrophage ketone shuttle that segregates AcAc from D-βOHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages.

Original language	English (US)
Pages (from-to)	383-398.e7
Journal	Cell Metabolism
Volume	29
Issue number	2
DOIs	https://doi.org/10.1016/j.cmet.2018.10.015
State	Published - Feb 5 2019

Bibliographical note

Funding Information:
The authors thank J. Matthew Gandy and Matthew Longo for mouse husbandry, Peter E. Phelan for guidance on primary macrophage isolation and culture, and Laura Kyro for graphics expertise. This work was supported in part by grants from the NIH ( DK091538 , DK115924 , CA235482 , ES028365 , and OD024624 ). B.D. is supported by the American Heart Association (AHA) postdoctoral fellowship ( 17POST33660450 ).

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

acetoacetate
beta-hydroxybutyrate
fibrosis
immunometabolism
ketone bodies
macrophages
nonalcoholic fatty liver disease
stable isotope tracing untargeted metabolomics

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10.1016/j.cmet.2018.10.015

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@article{719738ec624b465998b9615ae32c90de,

title = "Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis",

abstract = " Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we apply a stable isotope tracing, mass spectrometry-based untargeted metabolomics approach to reveal the metabolome penetrated by hepatocyte-derived glucose and ketone bodies. In both classically and alternatively polarized macrophages, [ 13 C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[ 13 C]β-hydroxybutyrate (D-βOHB) labeled almost none. [ 13 C]glucose labeled ∼500 features, and while unlabeled AcAc competed with only ∼15% of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT). AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-βOHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte-macrophage ketone shuttle that segregates AcAc from D-βOHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages.",

keywords = "acetoacetate, beta-hydroxybutyrate, fibrosis, immunometabolism, ketone bodies, macrophages, nonalcoholic fatty liver disease, stable isotope tracing untargeted metabolomics",

author = "Patrycja Puchalska and Martin, {Shannon E.} and Xiaojing Huang and Lengfeld, {Justin E.} and Bence Daniel and Graham, {Mark J.} and Xianlin Han and Laszlo Nagy and Patti, {Gary J.} and Crawford, {Peter A.}",

note = "Funding Information: The authors thank J. Matthew Gandy and Matthew Longo for mouse husbandry, Peter E. Phelan for guidance on primary macrophage isolation and culture, and Laura Kyro for graphics expertise. This work was supported in part by grants from the NIH ( DK091538 , DK115924 , CA235482 , ES028365 , and OD024624 ). B.D. is supported by the American Heart Association (AHA) postdoctoral fellowship ( 17POST33660450 ). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

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T1 - Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis

AU - Puchalska, Patrycja

AU - Martin, Shannon E.

AU - Huang, Xiaojing

AU - Lengfeld, Justin E.

AU - Daniel, Bence

AU - Graham, Mark J.

AU - Han, Xianlin

AU - Nagy, Laszlo

AU - Patti, Gary J.

AU - Crawford, Peter A.

N1 - Funding Information: The authors thank J. Matthew Gandy and Matthew Longo for mouse husbandry, Peter E. Phelan for guidance on primary macrophage isolation and culture, and Laura Kyro for graphics expertise. This work was supported in part by grants from the NIH ( DK091538 , DK115924 , CA235482 , ES028365 , and OD024624 ). B.D. is supported by the American Heart Association (AHA) postdoctoral fellowship ( 17POST33660450 ). Publisher Copyright: © 2018 Elsevier Inc.

PY - 2019/2/5

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N2 - Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we apply a stable isotope tracing, mass spectrometry-based untargeted metabolomics approach to reveal the metabolome penetrated by hepatocyte-derived glucose and ketone bodies. In both classically and alternatively polarized macrophages, [ 13 C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[ 13 C]β-hydroxybutyrate (D-βOHB) labeled almost none. [ 13 C]glucose labeled ∼500 features, and while unlabeled AcAc competed with only ∼15% of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT). AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-βOHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte-macrophage ketone shuttle that segregates AcAc from D-βOHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages.

AB - Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we apply a stable isotope tracing, mass spectrometry-based untargeted metabolomics approach to reveal the metabolome penetrated by hepatocyte-derived glucose and ketone bodies. In both classically and alternatively polarized macrophages, [ 13 C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[ 13 C]β-hydroxybutyrate (D-βOHB) labeled almost none. [ 13 C]glucose labeled ∼500 features, and while unlabeled AcAc competed with only ∼15% of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT). AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-βOHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte-macrophage ketone shuttle that segregates AcAc from D-βOHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages.

KW - acetoacetate

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KW - nonalcoholic fatty liver disease

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M3 - Article

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SN - 1550-4131

VL - 29

SP - 383-398.e7

JO - Cell Metabolism

JF - Cell Metabolism

IS - 2

ER -

Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis

Abstract

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