Fructose stimulated de novo lipogenesis is promoted by inflammation.
Acetyl Coenzyme A
/ pharmacology
Animals
Endotoxemia
/ blood
Female
Fructose
/ pharmacology
Fructosephosphates
/ pharmacology
Gastrointestinal Microbiome
Hepatocytes
/ drug effects
Humans
Inflammation
/ metabolism
Intestines
/ drug effects
Lipidomics
Lipogenesis
/ drug effects
Macrophages
/ metabolism
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease
/ metabolism
Regeneration
/ drug effects
Toll-Like Receptors
/ agonists
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
02
12
2019
accepted:
13
07
2020
pubmed:
26
8
2020
medline:
31
12
2020
entrez:
26
8
2020
Statut:
ppublish
Résumé
Benign hepatosteatosis, affected by lipid uptake, de novo lipogenesis and fatty acid (FA) oxidation, progresses to non-alcoholic steatohepatitis (NASH) on stress and inflammation. A key macronutrient proposed to increase hepatosteatosis and NASH risk is fructose. Excessive intake of fructose causes intestinal-barrier deterioration and endotoxaemia. However, how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis remain unknown. Here we show, using mice, that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signalling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) peptide counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxaemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to FA in both mouse and human hepatocytes.
Identifiants
pubmed: 32839596
doi: 10.1038/s42255-020-0261-2
pii: 10.1038/s42255-020-0261-2
pmc: PMC8018782
mid: NIHMS1655772
doi:
Substances chimiques
Fructosephosphates
0
Toll-Like Receptors
0
fructose-1-phosphate
15978-08-2
Fructose
30237-26-4
Acetyl Coenzyme A
72-89-9
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1034-1045Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK108743
Pays : United States
Organisme : NCI NIH HHS
ID : R03 CA223717
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK120714
Pays : United States
Organisme : NIEHS NIH HHS
ID : P42 ES010337
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA211794
Pays : United States
Organisme : NIH HHS
ID : S10 OD020025
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007469
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK063491
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA188652
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA027681
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI043477
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA198103
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA192642
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA218254
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES027595
Pays : United States
Organisme : NIAID NIH HHS
ID : K22 AI139444
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA207177
Pays : United States
Organisme : NIDDK NIH HHS
ID : K01 DK116917
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA234128
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
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