"Delineating Novel Checkpoints in Metabolic Syndromes" by Jonathan Sun

Date of Award

Spring 2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Experimental Pathology

First Advisor

Fernandez-Hernando, Carlos

Abstract

The global rise in obesity and overnutrition has rapidly increased diagnosedmetabolic syndromes, including fatty liver disease and hypercholesterolemia. This growing burden of metabolic diseases elicits an immense health and economic burden on society, as metabolic syndromes are significant risk factors for co-morbidities such as cancer and heart failures, leading to an attributable cost of $147 billion in US healthcare spending. Given this, it is of high importance to uncover the dynamic metabolic programs that drive the progression of these metabolic syndromes toward end-stage diseases. Metabolic rewiring during overnutrition can regulate the expression of feedback loops, referred hereupon as metabolic checkpoints, that potentiate downstream signaling pathways important for disease progression. In this study, we leverage diet-induced animal models to decipher novel metabolic checkpoints during Non-Alcoholic Fatty Liver Disease (NAFLD) progression and hypercholesterolemia, enabling the proposal of novel therapeutic strategies for disease mitigation. Using single-cell RNA-sequencing, we identified Fatty Acid Binding Protein 5 (FABP5) to be specifically upregulated in cancer cells and Tumor-associated Macrophages (TAMs) during the development of obesity-induced Hepatocellular Carcinoma (HCC). We found the cancer-promoting function of FABP5 to be highly cell-type dependent. Here, we describe a dual functioning role of FABP5 in diet-induced HCC, on one hand participating in the transformation of hepatocytes by protecting against lipid peroxidation and, on another, promoting immunosuppressive phenotype in TAMs to curtail anti-tumor immune response. Additionally, we illustrate that a small molecule approach to inhibit FABP5 can induce dual-functional effects in hepatocyte- transformed cancer cells and TAMs, leading to the suppression of HCC development. Additionally, we also evaluated the function of microRNA-33 (miR33), located in the intronic region of Sterol Regulatory Element Binding Protein 2 (SREBP2), during conditions of Nonalcoholic Steatohepatitis (NASH) progression or hypercholesterolemia. We found that the expression of miR33 is tightly regulated by the transcriptional activation of SREBP2, a master regulator of cholesterol biosynthesis. During NASH development, hepatocytes downregulate the expression of miR33. As such, the absence of miR33 can further reduce lipid accumulation by promoting mitochondrial Fatty Acid Oxidation (FAO). On the other hand, miR33 serves as a potent regulator of activation, clonal expansion, and cell death in CD8 + T-cells. Of relevance, elevated circulating cholesterol leads to the suppression of miR33, which shortens CD8 + T-cell lifespan and leads to exacerbated immune response to cancer and infection. Thus, the miR33 signaling axis controls distinct gene networks in diverse cell types, highlighting the importance of cell-type-specific delivery for therapeutic modulation.

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