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 2

Tsk expression correlates with liver steatosis in multiple mouse models.

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Tsk expression correlates with liver steatosis in multiple mouse models...
(A–C) Hepatic triglyceride content in (A) control and db/db mice (n = 5–6/group) (10 weeks old), (B) control and ob/ob mice (n = 4–5/group) (12 weeks old), or (C) LFD- and HFD-fed mice (n = 10/group) (11–13 weeks old fed LFD or HFD for 10 weeks). For each mouse model, the correlation between Tsk transcript levels and hepatic triglyceride content is presented. (D) Body weight of male mice fed a control or MCD diet for 21 days (n = 7/group). (E) Hepatic triglyceride content measured in mice fed a control or MCD diet (n = 7/group). (F) qPCR analysis of Tsk expression in the liver of control- and MCD diet–fed mice (n = 7/group). (G) Western blot analysis of plasma TSK levels in control- and MCD diet–fed mice. Representative samples are shown. (H) Correlation calculated between Tsk transcript levels and hepatic triglyceride content in control- and MCD diet–fed mice (n = 14). (I) Experimental scheme of the MCD reversal experiments. Mice were fed a control or MCD diet for 21 days before being switched back to a control diet for 3, 6, or 12 days. (J) Hepatic triglyceride content and (K) Tsk mRNA expression levels measured in mice included in the MCD reversal study described in I (n = 6–7/group). (L) Western blot analysis of plasma TSK levels in the MCD reversal study. Representative samples are shown. (M) qPCR analysis of Tsk expression in the liver of male mice housed at thermoneutrality (30°C) or exposed to cold (10°C) for 6 hours (n = 6/group) (left part) or in mice injected with saline (vehicle) or CL316243 (0.1 mg/kg) for 4 hours (n = 6/group) (right panel). In these experiments, male mice (10–12 weeks old) were used. (N) Hepatic triglyceride content in the experiment described in M. (O) Correlation calculated between Tsk transcript levels and hepatic triglyceride content in control mice and mice exposed to cold or injected with CL316243 as described in M (n = 24). In all panels, data represent the mean ± SEM. In A–F, M, and N significance was determined by 2-tailed, unpaired t test. *P < 0.05 versus controls. Pearson correlations (2-tailed) were calculated in A–C, H, and O. In D, 2-way ANOVA with Sidak’s multiple-comparisons test was performed. *P < 0.05 versus control. In J and K, 1-way ANOVA with Tukey’s multiple-comparisons test was performed. *P < 0.05 versus control. #P < 0.05 versus MCD.