AAV9-mediated (Pro)renin Receptor Antagonism Reduces High Fat Diet Induced Hyperglycemia and Hepatic Steatosis in Mouse Model of Non-alcoholic Fatty Liver Disease
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Authors
Afrin, Sanzida
Issue Date
2020
Type
Thesis
Language
Keywords
(Pro)renin receptor , AAV-PHP.eB , AAV9 , Adeno-associated virus , High fat diet , Non-alcoholic fatty liver disease
Alternative Title
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of liver diseases worldwide. It has been associated with impaired metabolism and increased accumulation of triglyceride (TG) in the liver, most of which is derived from exogenous sources including diet. Recent studies showed involvement of (pro)renin receptor (PRR) in various pathways of lipoprotein and energy metabolism, including PRR inhibition resulting in reprograming of hepatic lipid metabolism and consequently affecting diet-induced obesity and hepatosteatosis. In this study, we investigated the role of PRR activation in the mechanism of high fat diet (HFD)-induced fatty liver disease using a PRR antagonist, PRO20, in a mouse model of fatty liver disease induced by chronic high fat diet. PRO20 was delivered by adeno-associated virus, serotype 9 (AAV9) vector via systemic route, based on the findings of a prior experiment in this study. Here we validated AAV-PHP.eB and AAV9 in Neuro-2A cells, and confirmed AAV-PHP.eB and AAV9 expression in the brain and in non-CNS tissues. In addition, we report that, AAV9-mediated PRO20 reduces HFD-induced hyperglycemia and hepatic steatosis. A dose dependent study with a higher dose of PRO20 is under way, to better understand the mechanism and outcome of hepatic PRR knockdown in HFD model of NAFLD.