Saturday, May 4, 2024
5/4/2024
Project Summary/Abstract Our Overall Objective is to unravel the pathogenesis of alcohol-associated liver disease (ALD) and identify new therapeutic targets. ALD is one of the leading causes of morbidity and mortality worldwide among chronic liver diseases, but there are no FDA-approved treatments for ALD. Our recent studies have identified lipogenesis as an important factor promoting ALD. However, the molecular mechanisms for lipogenesis are still poorly understood. Alternative splicing is a critical mechanism that increases transcriptome complexity and expands proteome diversity and function. To date, little is known about the role of serine-arginine rich protein kinase 2 (SRPK2), a critical splicing regulator, in chronic liver disease. Intriguingly, our preliminary results have shown that SRPK2 abundance is upregulated in rodents and humans with ALD, which is associated with the induction of the lipogenic transcription factor SREBP-1. These data have prompted us to determine the potential role of SRPK2 in the pathogenesis of ALD. Overexpression of SRPK2 is sufficient to increase lipogenic gene expression in hepatocytes. Conversely, adenoviral knockdown of SRPK2 alters pre-mRNA splicing of lipin 1, a lipogenic regulator, and attenuates alcoholic steatosis in mice. While fibroblast growth factor 21 (FGF21) is emerging as a potential therapeutic candidate for diabetes in clinical trials, knowledge regarding the role of the hepatokine FGF21 in alternative splicing dysregulation during ALD is lacking. A pilot study shows that FGF21 overexpression in transgenic mice ameliorates alcoholic steatosis and lipotoxicity; this beneficial effect is associated with SRPK2 inhibition. Thus, our Central Hypothesis is that SRPK2-mediated regulation of alternative splicing triggers lipid accumulation and promotes alcoholic liver injury, and inhibition of SRPK2 has therapeutic implications for ALD. To expand on these exciting observations, we propose three Specific Aims: 1) To elucidate the molecular mechanism by which SRPK2-mediated regulation of alternative pre-mRNA is coupled to the control of lipid metabolism and promotes the progression of ALD; 2) To determine whether the hepatokine FGF21 functions as a novel regulator of SRPK2 in the control of triglyceride and cholesterol metabolism in ALD; and 3) To assess whether targeting SRPK2 has therapeutic implications for ALD. We will comprehensively test our hypothesis with cutting-edge cellular, molecular, and biochemical methods for pre- mRNA splicing, hepatocyte-specific FGF21 knockout mice, and in vivo pharmacological and molecular manipulation approaches. Complementary state-of-the-art techniques, including alternative splicing profiling and lipidomics analyses, will allow us to characterize aberrant changes in pre-mRNA splicing machinery and lipid metabolites in the livers of alcohol-fed mice. Overall, accomplishing this project will identify pre-mRNA splicing mechanisms that contribute to ALD pathologies and will provide a rationale for targeting elements of the SRPK2- regulated splicing process as a novel therapeutic strategy for ALD, such as FGF21.
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