The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis

被引：48

作者：

Mouchiroud, Mathilde ^{[1
]}

Camire, Etienne ^{[1
]}

Aldow, Manal ^{[1
]}

Caron, Alexandre ^{[2
]}

Jubinville, Eric ^{[1
]}

Turcotte, Laurie ^{[1
]}

Kaci, Ines ^{[1
]}

Beaulieu, Marie-Josee ^{[1
]}

Roy, Christian ^{[1
]}

Labbe, Sebastien M. ^{[1
,3
]}

Varin, Thibault V. ^{[1
,4
]}

Gelinas, Yves ^{[1
]}

Lamothe, Jennifer ^{[1
]}

Trottier, Jocelyn ^{[5
,6
]}

Mitchell, Patricia L. ^{[1
]}

Guenard, Frederic ^{[4
]}

Festuccia, William T. ^{[7
]}

Joubert, Philippe ^{[1
]}

Rose, Christopher F. ^{[8
]}

Karvellas, Constantine J. ^{[9
]}

Barbier, Olivier ^{[5
,6
]}

Morissette, Mathieu C. ^{[1
,10
]}

Marette, Andre ^{[1
,4
,10
]}

Laplante, Mathieu ^{[1
,10
,11
]}

机构：

[1] Univ Laval, CRIUCPQ, Quebec City, PQ, Canada

[2] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Div Hypothalam Res, Dallas, TX USA

[3] IPS Therapeut, Sherbrooke, PQ, Canada

[4] Univ Laval, INAF, Quebec City, PQ, Canada

[5] Ctr Rech Ctr Hosp Univ Quebec, Lab Mol Pharmacol Endocrinol Nephrol Axis, Quebec City, PQ, Canada

[6] Univ Laval, Fac Pharm, Quebec City, PQ, Canada

[7] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Sao Paulo, Brazil

[8] Ctr Hosp Univ Montreal CRCHUM, Hepatoneuro Lab, Montreal, PQ, Canada

[9] Univ Alberta, Sch Publ Hlth Sci, Dept Crit Care Med, Liver Unit,Div Gastroenterol, Edmonton, AB, Canada

[10] Univ Laval, Dept Med, Quebec City, PQ, Canada

[11] Univ Laval, Ctr Rech Canc, Quebec City, PQ, Canada

来源：

JCI INSIGHT | 2019年 / 4卷 / 15期

基金：

加拿大健康研究院;

关键词：

NONALCOHOLIC FATTY LIVER; INSULIN-RESISTANCE; CARDIOVASCULAR-DISEASE; PHARMACOLOGICAL ACTIVATION; HEPATIC STEATOSIS; X-RECEPTOR; OBESITY; MOUSE; PREVALENCE; PROTEIN;

D O I：

10.1172/jci.insight.129492

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 HOL 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.

引用

页数：17

共 79 条

[1] Involvement of Tsukushi in diverse developmental processes [J].