TY - JOUR
T1 - The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis
AU - Mouchiroud, Mathilde
AU - Camiré, Étienne
AU - Aldow, Manal
AU - Caron, Alexandre
AU - Jubinville, Éric
AU - Turcotte, Laurie
AU - Kaci, Inès
AU - Beaulieu, Marie Josée
AU - Roy, Christian
AU - Labbé, Sébastien M.
AU - Varin, Thibault V.
AU - Gélinas, Yves
AU - Lamothe, Jennifer
AU - Trottier, Jocelyn
AU - Mitchell, Patricia L.
AU - Guénard, Frédéric
AU - Festuccia, William T.
AU - Joubert, Philippe
AU - Rose, Christopher F.
AU - Karvellas, Constantine J.
AU - Barbier, Olivier
AU - Morissette, Mathieu C.
AU - Marette, André
AU - Laplante, Mathieu
N1 - Funding Information:
The authors are grateful to Yves Deshaies, Émile Levy, Roger McLeod, and Benoît Arsenault for advice and assistance. The authors also acknowledge the invaluable collaboration of the surgery team, bariatric surgeons, and biobank staff of the IUCPQ. This work was supported by grants from the Canadian Institutes of Health Research (CIHR) (271671, 374552, and FDN143247), Les Fonds de recherche du Québec – Santé (FRQS) (24726), Le Réseau de recherche en santé cardiométabolique, diabète et obésité (CMDO), Le Réseau de bio-imagerie du Québec (RBIQ), Diabète Québec, La Fondation de l’Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval (IUCPQ-UL), and Merck Sharpe and Dohme Corp./Faculté de Médecine de l’Université Laval to ML. AC is a CIHR Banting postdoctoral fellow.
Funding Information:
The authors are grateful to Yves Deshaies, ?mile Levy, Roger McLeod, and Beno?t Arsenault for advice and assistance. The authors also acknowledge the invaluable collaboration of the surgery team, bariatric surgeons, and biobank staff of the IUCPQ. This work was supported by grants from the Canadian Institutes of Health Research (CIHR) (271671, 374552, and FDN143247), Les Fonds de recherche du Qu?bec - Sant? (FRQS) (24726), Le R?seau de recherche en sant? cardiom?tabolique, diab?te et ob?sit? (CMDO), Le R?seau de bio-imagerie du Qu?bec (RBIQ), Diab?te Qu?bec, La Fondation de l'Institut universitaire de cardiologie et de pneumologie de Qu?bec - Universit? Laval (IUCPQ-UL), and Merck Sharpe and Dohme Corp./Facult? de M?decine de l'Universit? Laval to ML. AC is a CIHR Banting postdoctoral fellow.
Publisher Copyright:
© 2019, American Society for Clinical Investigation.
PY - 2019/8/8
Y1 - 2019/8/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85071074136&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071074136&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.129492
DO - 10.1172/jci.insight.129492
M3 - Article
C2 - 31391339
AN - SCOPUS:85071074136
SN - 2379-3708
VL - 4
JO - JCI Insight
JF - JCI Insight
IS - 15
M1 - 129492
ER -