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Kuang-Tzu Huang
Associate Professor
Chronic liver diseases
Hepatocellular carcinoma
Lipid metabolism / adipocyte function
Signal transduction / gene regulation
Research Overview
Pigment epithelium-derived factor (PEDF) in non-alcoholic steatohepatitis
Non-alcoholic fatty liver disease (NAFLD), often considered a main hepatic manifestation of metabolic syndrome, is the leading cause of chronic liver diseases worldwide, affecting nearly one-third of the general population. The obesity epidemic is closely connected to the rising prevalence and severity of NAFLD. The spectrum of its histopathology ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), with the risk for progressive fibrosis that may lead to cirrhosis and hepatocellular carcinoma. While simple steatosis is a relatively benign condition with hepatic triglyceride accumulation, the buildup of toxic lipid catabolites can induce oxidative stress and chronic inflammation that are associated with insulin resistance and excessive adipose tissue lipolysis, ultimately triggering disease progression. As the pathophysiology that underlies the progression from hepatic steatosis to NASH remains largely unknown and there is currently no effective pharmacological treatment, characterization of the molecular mechanisms will help understand the crucial factors responsible for development of the disease.
Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein with a wide range of biological activities, most notably in neural differentiation and inhibition of angiogenesis. The role of PEDF in lipid metabolism was established when adipose triglyceride lipase (ATGL), the key enzyme for triglyceride breakdown, was characterized as its binding partner. We have recently discovered that PEDF inhibits adipogenic differentiation by modulating the levels of fatty acid translocase (CD36), through activation of ATGL. Since CD36 is a major enzyme that facilitates fatty acid uptake, we hypothesize that the PEDF-ATGL-CD36 pathway may also affect hepatic lipid accumulation and its associated pathological events. Our goal is to define the regulatory role of PEDF, ATGL and CD36 during NASH progression and further delineate the contributions of PEDF-ATGL signaling in the pathogenic activities that lead to advanced disease, including hepatic fatty acid uptake, adipocyte hypertrophy and inflammatory responses. We also aim to demonstrate the comprehensive roles of CD36 in various aspects of NASH progression by blocking its enzymatic activity in vivo.
Functional characterization of calreticulin in the liver fibrogenic process
Liver fibrosis, characterized by excessive deposition of extracellular matrix (ECM) leading to hepatic dysfunction, remains a major health burden in Taiwan and worldwide. Patients with advanced fibrosis/cirrhosis are also at high risk of developing hepatocellular carcinoma. Liver fibrosis is a consequence of chronic liver injury, which leads to production of profibrotic factors from damaged hepatocytes and infiltrating inflammatory cells, resulting in activation of hepatic stellate cells (HSCs). Upon activation, HSCs transdifferentiate into proliferative and contractile ECM-producing myofibroblasts. Meanwhile, chronic liver damage also causes hepatocyte death and release of intracellular proteins such as chaperones.
Calreticulin (CRT) normally resides in the lumen of endoplasmic reticulum (ER) and functions as a molecular chaperone, important in protein folding and calcium homeostasis. Nevertheless, CRT has recently gained much attention for its role in the extracellular space, where it directs immunomodulatory activities by appearing as a danger signal for the innate immune system. In a mouse model of liver fibrosis, we observed an overall increase in CRT expression. Interestingly, immunohistochemical staining revealed that the increase in CRT is highly localized in the perisinusoidal regions and surrounding hepatocytes. Further examination also suggested the existence of cell surface CRT. Interestingly, when recombinant CRT was applied to HSC cell culture, decreased expression of HSC activation markers was observed. Exogenous CRT also resulted in decreased HSC cell number. We therefore hypothesize that both intracellular and extracellular CRT are involved but may have distinct roles in HSC activation. Our current aims are to define the biological functions of CRT in the ER and in the extracellular space in the liver fibrogenic pricess, and evaluate the in vivo actions of CRT in mouse models.
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