To Explore the Pathophysiology and Prognosis of Non-Alcoholic Fatty Liver in Taiwan by Systemic Decoding the Inter-Organ Dialogues Orchestrating the Formation of Fatty Liver: a Joint Study Based on Human and Animal Model

Non-alcoholic fatty liver disease (NAFLD) is defined by a non-alcoholic nature in the presence of fatty liver. According to World Health Organization estimates, approximately 2300 million individuals likely have NAFLD worldwide. In Taiwan, the estimated local prevalence for NAFLD is as high as 66.5%. Therefore, NAFLD is the most common liver disease globally. Most patients with NAFLD outlive their liver disease and are more likely to develop fatal complications from cardiovascular disease or malignancy. There are some intriguing issues regarding NAFLD: (1) The extent of hepatic fat does not necessarily correlate with the severity of hepatic injury and extra-hepatic complications. What accounts for this discrepancy? (2) Besides liver biopsy, is there any non-invasive biomarker reliable for the prognosis of NAFLD? (3) In addition to exercise and diet control, is there any specific pharmacological target for treating complicated NAFLD? Because the liver is a key metabolic organ that governs energy metabolism, NAFLD is thus associated with abnormal basal metabolism with multi-organ insulin resistance. The multi-organ orchestration might account for the aforementioned discrepancy and why the associated complications are not confined to the liver. Adipose tissue, skeletal muscle and the intestine are the crucial players in the biogenesis of NAFLD through adipokines, mokines and enteroendocrine hormones. Moreover, some genetic factors, including Patatin-like phospholipase domain-containing protein 3 and Transmembrane 6 superfamily 2, have been identified as disease modifier and regulator of NAFLD, respectively. However, the multi-organ involvement and genetic predisposition for NAFLD have not been well understood in Taiwanese patients. More specifically, extracellular vesicles (EVs) are key communicators for inter-organ cross-talk. They carry signatures from parental cells to target cells and are involved in almost all physiological processes. In fact, specific EV signatures are able to discriminate the presence of NAFLD. With the aid of high-throughput technologies on multiomics studies of EVs in the body fluids, there is a high probability of decoding the inter-organ dialogues associated with the pathophysiology and prognosis for NAFLD. By using a consecutive series of Taiwanese patients with NAFLD documented by magnetic resonance spectroscopy (MRS), we have shown that the adipokine, plasminogen activator inhibitor-1 is independently associated with NAFLD. Furthermore, using conditional transgenic mice that over-express the hepatitis C virus (HCV) core in the liver, we developed three non-obese transgenic mouse lines with phenotypes varying from simple hepatic steatosis to steatohepatitis. This may reflect the hepatic histology of humans with non-obese NAFLD. Commercialized db/db mutant mice may serve as an animal model of obese NAFLD. Taken together, based on our previous studies, the present proposal is designed to decode the multi-organ dialogues accounting for the pathophysiology and associated complications of NAFLD by analyzing adipokine, myokine and enteroendocrine profiles and gene-environmental interactions, powered by EV approaches with mutiomic science integration in a prospective NAFLD cohort in Taiwan. In parallel, the therapeutic target of NAFLD will be probed using HCV core transgenic mice and db/db mice with equivalent phenotypes. The current 3-year proposal holds promise to unveil the clinical controversies, disclose the biomarkers and provide therapeutic interventions targeting crucial factors to control NAFLD disease progression in Taiwan.

Project ID:PC10507-1269
External Project ID:MOST105-2314-B182-023