Project 460397

Obesity is defined as the excessive accumulation of white adipose tissue and is the most important risk factor for the development of insulin resistance, type 2 diabetes, dyslipidemia, liver diseases and cardiovascular diseases. The rising rates of obesity worldwide is paralleled by a rise in the global prevalence of non-alcoholic fatty liver disease (NAFLD), a broad spectrum of liver diseases characterized by lipid accumulation in hepatocytes. NAFLD is generally viewed as the hepatic manifestation of metabolic syndrome. In individuals with NAFLD, cardiovascular disease is the leading cause of mortality, followed by cancer and then liver disease. Although associations between NAFLD, metabolic dysfunctions and cardiovascular diseases have been reported, the molecular mechanisms by which NAFLD impairs metabolism and cause pathologies in distant tissues is still unclear. Recent advances suggest that the liver may significantly impact systemic metabolism and disease progression through the secretion of specific proteins. These proteins, often termed as hepatokines, are secreted by the liver and mediate inter-organ communication through autocrine, paracrine and endocrine signaling. Using a comprehensive analytical platform developed by my group, we recently report the identification of Tsukushi (TSK) as a novel hepatokine. We found that TSK is highly expressed and secreted in response to lipids excess, stress and inflammation, which are common features of NAFLD. Studies in transgenic mice revealed that TSK reduces HDL cholesterol and cholesterol efflux capacity. Our data identify the hepatokine TSK as a new blood biomarker of liver stress that could link NAFLD to the development of dyslipidemia and atherosclerosis. The research project that we propose here aims to explore the biology of the hepatokine TSK and to better understand its roles in both health and disease in humans.