The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis
Open accessAbstract
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.
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Hepatic and plasma levels of tsukushi are strongly stimulated by stimuli that augment thermogenesis and energy expenditure, including adrenergic agonists and cold exposure.
“Hepatic and plasma levels of this hepatokine are strongly stimulated by stimuli that augment thermogenesis and energy expenditure (including adrenergic agonists and cold exposure) [78,88,89].”
From Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions (2021) · cites this paper as [78]
Plasma levels of TSK have been linked to NAFLD and NASH pathologies.
“Plasma levels of TSK have been linked to NAFLD and NASH pathologies [269,270].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [269]
TSK is an inducible hepatokine that regulates energy expenditure and is strongly associated with NAFLD, NASH, and obesity.
“Tsukushi (TSK) is an inducible hepatokine that regulates energy expenditure and is strongly associated with NAFLD, NASH, and obesity [269,270].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [269]
TSK was recently identified as an atypical member of the small leucine-rich proteoglycan family that regulates developmental processes in various organisms.
“TSK was recently identified as an atypical member of the small leucine-rich proteoglycan family that regulates developmental processes in various organisms [[269], [270], [271]].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [269]
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- Authors
- Mouchiroud, M., Camiré, É., Aldow, M., Caron, A., Jubinville, É., Turcotte, L., Kaci, I., Beaulieu, M.-J., Roy, C., Labbé, S. M., Varin, T. V., Gélinas, Y., Lamothe, J., Trottier, J., Mitchell, P. L., Guénard, F., Festuccia, W. T., Joubert, P., Rose, C. F., Karvellas, C. J., Barbier, O., Morissette, M. C., Marette, A., & Laplante, M.
- Affiliations
- Institut universitaire de cardiologie et de pneumologie de Québec (CA)
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec – Université Laval (CRIUCPQ), Québec City, Québec, Canada.
- The University of Texas Southwestern Medical Center (US)
- Centre hospitalier universitaire de Québec (CA)
- Université Laval (CA)
- Universidade de São Paulo (BR)
- Centre Hospitalier de l’Université de Montréal (CA)
- University of Alberta (CA)
- Corresponding author
- Laplante, Mathieu
- ORCID
- Venue
- JCI Insight
- Published
- 2019-08-08
- Volume
- 4
- Issue
- 15
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC6693835
- OpenAlex
- W2965080804
- Cited by
- 57
- References
- 83
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 6 · 2023: 9 · 2022: 11 · 2021: 11 · 2020: 7 · 2019: 1
- FWCI
- 5.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- JCI Insight (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (Operation grant)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- Tsukushi, hepatokines, non-alcoholic fatty liver disease, cholesterol homeostasis, dyslipidemia, atherosclerosis, endoplasmic reticulum stress, liver inflammation, steatosis, acute liver failure, paracetamol, HDL cholesterol, cholesterol efflux capacity, bile acid synthesis, transplant-free survival
- MeSH terms
- Acetaminophen, Adult, Animals, Bile Acids and Salts, Disease Models, Animal, Female, Humans, Cholesterol, HDL, Liver, Male, Prognosis, Proteoglycans, Biomarkers, Survival Analysis, Liver Failure, Acute, Mice, Knockout, Intercellular Signaling Peptides and Proteins, Mice, Chemical and Drug Induced Liver Injury, HEK293 Cells, Non-alcoholic Fatty Liver Disease
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