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

JCI Insight. 2019 Aug 8;4(15):e129492. doi: 10.1172/jci.insight.129492.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / poisoning
  • Adult
  • Animals
  • Bile Acids and Salts / metabolism
  • Biomarkers / blood
  • Biomarkers / metabolism
  • Chemical and Drug Induced Liver Injury / blood*
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / mortality
  • Cholesterol, HDL / blood
  • Cholesterol, HDL / metabolism*
  • Disease Models, Animal
  • Female
  • HEK293 Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins / blood*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Liver / metabolism
  • Liver / pathology
  • Liver Failure, Acute / blood*
  • Liver Failure, Acute / chemically induced
  • Liver Failure, Acute / mortality
  • Male
  • Mice
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / blood
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology*
  • Prognosis
  • Proteoglycans / blood*
  • Proteoglycans / genetics
  • Proteoglycans / metabolism*
  • Survival Analysis


  • Bile Acids and Salts
  • Biomarkers
  • Cholesterol, HDL
  • Intercellular Signaling Peptides and Proteins
  • Proteoglycans
  • TSKU protein, human
  • tsukushi protein, mouse
  • Acetaminophen