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JCI Insight. 2019 Aug 8;4(15). pii: 129492. doi: 10.1172/jci.insight.129492. eCollection 2019 Aug 8.

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

Author information

1
Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval (CRIUCPQ), Québec City, Québec, Canada.
2
Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3
IPS Thérapeutique, Sherbrooke, Québec, Canada.
4
Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Université Laval, Québec City, Québec, Canada.
5
Laboratory of Molecular Pharmacology, Endocrinology-Nephrology Axis, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec City, Québec, Canada.
6
Faculty of Pharmacy, Université Laval, Québec City, Québec, Canada.
7
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
8
Hepato-Neuro Laboratory, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
9
Liver Unit, Division of Gastroenterology, Department of Critical Care Medicine, School of Public Health Science, University of Alberta, Edmonton, Alberta, Canada.
10
Département de Médecine and.
11
Centre de Recherche sur le Cancer de l'Université Laval, Université Laval, Québec City, Québec, Canada.

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.

KEYWORDS:

Hepatology; Metabolism; Obesity

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