The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis
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
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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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 5

TSK does not affect NAFLD development.

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TSK does not affect NAFLD development. (A) Male mice (10 weeks old) were...
(A) Male mice (10 weeks old) were injected with AAV8-GFP or AAV8-TSK. Plasma samples were analyzed by Western blot 4 weeks following AAV8 injection. Representative samples are shown. (B) Western blot showing that mice injected with AAV8-TSK exhibit a stable rise in circulating TSK protein levels. (C) Hematoxylin and eosin–stained (H&E–stained) sections of liver samples collected from AAV8-GFP and AAV8-TSK mice. Representative images are shown. Original magnification, ×10. (D) Water, triglyceride, protein, and glycogen content of liver samples collected from AAV8-GFP and AAV8-TSK mice (n = 12/group). (E) qPCR analysis of various genes in the liver of AAV8-GFP and AAV8-TSK mice (n = 11–12/group). (F) Schematic overview of the strategy used to produce TSK-KO mice. (G) Genotyping validation showing the wild-type and KO alleles in Tsk+/+, Tsk+/–, and Tsk–/– mice. (H) Western blot analysis of plasma samples collected from wild-type (Tsk+/+) and KO (Tsk–/–) mice injected with CCl4. Blood was collected 24 hours after the injection of CCl4. (I) H&E–stained sections of liver samples collected from male wild-type (Tsk+/+) and KO (Tsk–/–) mice fed either LFD or HFD for 19 weeks. Representative images are shown. (J) Water, triglyceride, protein, and glycogen content of liver samples collected from wild-type (Tsk+/+) and KO (Tsk–/–) mice fed either LFD or HFD (n = 6–8/group). (K) qPCR analysis of various genes in the liver of wild-type (Tsk+/+) and KO (Tsk–/–) mice fed either LFD or HFD diet for 19 weeks (n = 6–8/group). In all panels, data are presented as the mean ± SEM. In D and E, significance was determined by 2-tailed, unpaired t test. In J and K, 2-way ANOVA with multiple comparisons was performed between wild-type (Tsk+/+) and KO (Tsk–/–) mice for each diet. *P < 0.05 versus wild-type (Tsk+/+) mice. Absence of asterisk denotes no significant changes between the groups.