Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis
Mathilde Mouchiroud, … , André Marette, Mathieu Laplante
Mathilde Mouchiroud, … , André Marette, Mathieu Laplante
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e129492. https://doi.org/10.1172/jci.insight.129492.
View: Text | PDF
Research Article Hepatology Metabolism

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

  • Text
  • PDF
Abstract

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.

Authors

Mathilde Mouchiroud, Étienne Camiré, Manal Aldow, Alexandre Caron, Éric Jubinville, Laurie Turcotte, Inès Kaci, Marie-Josée Beaulieu, Christian Roy, Sébastien M. Labbé, Thibault V. Varin, Yves Gélinas, Jennifer Lamothe, Jocelyn Trottier, Patricia L. Mitchell, Frédéric Guénard, William T. Festuccia, Philippe Joubert, Christopher F. Rose, Constantine J. Karvellas, Olivier Barbier, Mathieu C. Morissette, André Marette, Mathieu Laplante

×

Figure 6

TSK impacts systemic cholesterol homeostasis.

Options: View larger image (or click on image) Download as PowerPoint
TSK impacts systemic cholesterol homeostasis.
(A and B) Plasma cholester...
(A and B) Plasma cholesterol levels measured in samples collected from male (A) C57BL/6J mice (n = 12/group) or (B) LDLR-KO mice (n = 9/group) injected with AAV8-GFP or AAV8-TSK. O/E, overexpression. Blood samples from mice were analyzed 4 weeks following AAV8 injection. (C and D) Cholesterol efflux capacity measured using plasma collected from (C) C57BL/6J mice (n = 16–19/group) and LDLR-KO mice (n = 10/group) injected with AAV8-GFP or AAV8-TSK or (D) wild-type (Tsk+/+) and KO (Tsk–/–) mice (n = 10–13/group). (E and F) qPCR analyses of the liver of male mice sacrificed after either 5 days (left) or 28 days (right) (n = 12/group) following injection with AAV8-GFP or AAV8-TSK. (G and H) Bile acid (BA) profiling in (G) the liver and (H) the plasma of mice sacrificed 28 days (n = 6–8/group) following injection with AAV8-GFP or AAV8-TSK. Values are log transformed. In all panels, data are presented as the mean ± SEM. Significance was determined by 2-tailed, unpaired t test. *P < 0.05 versus control.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts