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

NAFLD is the most common liver disease globally. However, most NAFLD patients 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) Is there any non-invasive biomarker reliable for the prognosis of NAFLD? (3) Is there any specific pharmacological target for treating complicated NAFLD? Because the liver is a key metabolic organ that governs energy metabolism, the multi-organ orchestration might account for the aforementioned discrepancy. Adipose tissue, skeletal muscle and the intestine are the crucial players in the biogenesis of NAFLD through adipokines, myokines and enteroendocrine hormones. Moreover, genetic factors have been identified as disease modifier of NAFLD. Extracellular vesicles (EVs) are key communicators for inter-organ cross-talk, and are able to discriminate the presence of NAFLD. However, the multi-organ involvement and genetic predisposition for NAFLD have not been well understood in Taiwanese patients. With the aid of high-throughput technologies on multi-omics 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. Taken together, based on our recent studies regarding NAFLD (Pentoxifylline ameliorates non-alcoholic fatty liver disease in hyperglycaemic and dyslipidaemic mice by upregulating fatty acid β-oxidation. Sci Rep 2016 Sep 9;6:33102), adipokine (Resistin reinforces interferon λ-3 to eliminate hepatitis C virus with fine-tuning from RETN single-nucleotide polymorphisms. Sci Rep. 2016 Aug 1;6:30799.), and our previous studies based on HCV core transgenic mice, 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 achievements of the first year of the current proposal are listed as follows: 1. Adipokine: Association between Leptin and Complement in Hepatitis C Patients with Viral Clearance: Homeostasis of Metabolism and Immunity (Plos One 2016 Nov 21;11(11):e0166712.). 2. Metabolomics: Recovery of pan-genotypic and genotype-specific amino acid alterations in chronic hepatitis C after viral clearance: transition at the crossroad of metabolism and immunity (Amino Acids. 2016 Nov 10.). Besides, we had set up the methodology to extract the EV proteins, all the experimental mice showed phenotype of NAFLD. All above confirmed the feasibility of the current proposal. However, the NAFLD-associated enigmas mentioned above remain unclear, as our studies in EV and genes are not completed yet, and other NAFLD-associated mechanisms need longer than 1 year to confirm in animal models. Thus, the grants for the second and third year of the current proposal are crucial to complete the study. The 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:PC10701-0809
External Project ID:MOST106-2314-B182-041-MY2