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.
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Research Article Hepatology Metabolism

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

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

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Figure 1

TSK is a hepatokine induced by obesity.

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TSK is a hepatokine induced by obesity. (A) Summary of the experimental ...
(A) Summary of the experimental approach designed to identify liver-specific secreted proteins regulated in conditions of obesity. (B) Gene expression profile comparing the expression of Tsk in various mouse tissues and cell types. The microarray data used in this panel are available through NCBI’s Gene Expression Omnibus (accession number GSE10246). (C–E) qPCR analysis of Tsk transcript expression in the liver of (C) littermate control and db/db mice (n = 5–6/group) (10 weeks old), (D) littermate control and ob/ob mice (n = 4–5/group) (12 weeks old), and (E) LFD- and HFD-fed C57BL/6J mice (n = 10/group) (11–13 weeks old fed LFD or HFD for 10 weeks). Data represent the mean ± SEM. Significance was determined by 2-tailed, unpaired t test. *P < 0.05 versus controls. (F) Schematic representation of human and mouse TSK protein. (G) Western blot analysis of cell lysates and culture media of HEK 293T cells overexpressing human TSK. Cells were plated the day before and culture medium was changed at time 0. Cells were lysed and culture medium was collected at the indicated times. AKT was used as a loading control. (H) Western blot analysis of cell lysates and culture media of HEK 293T cells overexpressing human TSK or a mutated form lacking the signal peptide (Δ-TSK). Samples were processed as described in G. (I and J) Western blot analysis of (I) tissues samples or (J) plasma collected from C57BL/6J mice injected with AAV8-GFP or AAV8-TSK. Mice were sacrificed 4 weeks following AAV8 injection. (K and L) Western blot analysis of plasma TSK levels in (K) control and db/db mice and (L) control and ob/ob mice. Representative samples are shown.