Physiological Dissection of the Mevalonate Pathway

Baylor College Of Medicine, Houston TX

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Abstract

PROJECT SUMMARY The mevalonate pathway is responsible for the de novo synthesis of cholesterol and other biologically important isoprenoids from acetyl-CoA. Rates of cholesterol synthesis vary greatly amongst different cell types in the body. The long term goal of this project is to better understand the physiological function and regulation of the mevalonate pathway in different tissues. The intestine occupies the critical interface for cholesterol absorption and excretion from the body. Interestingly, the human intestine synthesizes more cholesterol per gram of tissue than the liver, suggesting important tissue and cell-type specific needs for this metabolite. Cholesterol is a critical component of cellular membranes, which is in high demand by intestinal stem cells (ISC) that continuously divide to replenish the epithelial surface of the villi every 3-5 days. In addition, since mammals do not have a catabolic pathway for cholesterol, its only route of disposal is through excretion in the feces. We will address key gaps in knowledge in terms of how de novo cholesterol synthesis impacts ISC activity, as well as interfaces with the opposing processes of cholesterol absorption and excretion by enterocytes. In this competing renewal R01 application, we will use genetically engineered mouse models and primary human organoids to elucidate the physiological function of the mevalonate pathway in the intestine. Cholesterol synthesis is controlled by the rate- limiting enzyme 3-hydroxy-3-methylglutaryl Coenzyme A reductase (Hmgcr), the target of the statin drugs. We recently generated mice with intestine-specific deletion of Hmgcr (Vil1-Cre) to genetically ablate the pathway. Loss of Hmgcr revealed an unexpected effect on stem cell homeostasis, with a doubling of the resident stem cell compartment. We also found that enterocytes are able to preserve cholesterol levels in the absence of synthesis, most likely through greater uptake of lipoprotein cholesterol, accompanied by increased cholesterol in the feces. Based on these findings, we hypothesize that the loss of Hmgcr drives a program of stem cell self-renewal and expansion, mediated by increased sterol regulatory element binding protein 2 (SREBP-2) activity. We also hypothesize that inhibition of cholesterol synthesis in the absorptive epithelial surface drives lipoprotein uptake from the basolateral surface, promoting trans-intestinal cholesterol excretion (TICE) and removal from the body. In this project we will 1) Determine the mechanism for stem cell expansion following loss of Hmgcr in the intestine, and 2) Determine if mevalonate pathway inhibition in enterocytes promotes cholesterol elimination. Results from this project will provide valuable insights into the regulation of the intestinal stem cell niche by cholesterol, and improve our understanding of how enterocyte cholesterol synthesis controls cholesterol balance.