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 4

TSK levels are increased in response to steatosis and liver damage in humans.

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TSK levels are increased in response to steatosis and liver damage in hu...
(A) Characteristics of the human patients included in our study. Liver samples were collected from 58 patients and triglycerides were extracted and measured. Patients were distributed into 2 groups based on the median triglyceride content of the samples. (B) Triglyceride content of the liver samples described in A (n = 29/group). (C) TSK mRNA expression levels measured in humans with low or high hepatic triglycerides (n = 29/group). (D) Western blot analysis and (E) quantification of TSK in serum of humans suffering from acetaminophen-induced ALF. Blood samples were collected from patients upon their admission to the intensive care unit. Other blood samples were collected after admission (between 3 and 9 days) (n = 26). The samples presented in D are the ones in which TSK was detected and quantified. (F) Proportion of ALF patients with detectable serum TSK at admission that either died or received a liver transplant versus the patients that survived. (G) Comparison of TSK levels at admission between patients that either died or received a liver transplant versus the patients that survived. In all panels, data are presented as the mean ± SEM. In A and B, *P < 0.05 vs. controls by 2-tailed, unpaired t test. In E, *P < 0.05 comparing TSK at admission vs. after admission by 2-tailed, paired t test. In F, *P < 0.05 vs. survivors by Fisher’s exact test. In G, *P < 0.05 vs. survivors by 2-tailed, unpaired t test.