The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis.
Acetaminophen
/ poisoning
Adult
Animals
Bile Acids and Salts
/ metabolism
Biomarkers
/ blood
Chemical and Drug Induced Liver Injury
/ blood
Cholesterol, HDL
/ blood
Disease Models, Animal
Female
HEK293 Cells
Humans
Intercellular Signaling Peptides and Proteins
/ blood
Liver
/ metabolism
Liver Failure, Acute
/ blood
Male
Mice
Mice, Knockout
Non-alcoholic Fatty Liver Disease
/ blood
Prognosis
Proteoglycans
/ blood
Survival Analysis
Hepatology
Metabolism
Obesity
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
08 08 2019
08 08 2019
Historique:
received:
29
04
2019
accepted:
27
06
2019
entrez:
9
8
2019
pubmed:
9
8
2019
medline:
1
9
2020
Statut:
epublish
Résumé
Nonalcoholic fatty liver disease (NAFLD) prevails in obesity and is linked to several health complications including dyslipidemia and atherosclerosis. How exactly NAFLD induces atherogenic dyslipidemia to promote cardiovascular diseases is still elusive. Here, we identify Tsukushi (TSK) as a hepatokine induced in response to NAFLD. We show that both endoplasmic reticulum stress and inflammation promote the expression and release of TSK in mice. In humans, hepatic TSK expression is also associated with steatosis, and its circulating levels are markedly increased in patients suffering from acetaminophen-induced acute liver failure (ALF), a condition linked to severe hepatic inflammation. In these patients, elevated blood TSK levels were associated with decreased transplant-free survival at hospital discharge, suggesting that TSK could have a prognostic significance. Gain- and loss-of-function studies in mice revealed that TSK impacts systemic cholesterol homeostasis. TSK reduces circulating HDL cholesterol, lowers cholesterol efflux capacity, and decreases cholesterol-to-bile acid conversion in the liver. Our data identify the hepatokine TSK as a blood biomarker of liver stress that could link NAFLD to the development of atherogenic dyslipidemia and atherosclerosis.
Identifiants
pubmed: 31391339
pii: 129492
doi: 10.1172/jci.insight.129492
pmc: PMC6693835
doi:
pii:
Substances chimiques
Bile Acids and Salts
0
Biomarkers
0
Cholesterol, HDL
0
Intercellular Signaling Peptides and Proteins
0
Proteoglycans
0
TSKU protein, human
0
tsukushi protein, mouse
0
Acetaminophen
362O9ITL9D
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : CIHR
ID : 271671
Pays : Canada
Organisme : CIHR
ID : 374552
Pays : Canada
Organisme : CIHR
ID : FDN143247
Pays : Canada
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