Intestinal deletion of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase promotes expansion of the resident stem cell compartment.

Objective: The intestine occupies the critical interface between cholesterol absorption and excretion. Despite this, surprisingly little is known about the role of de novo cholesterol synthesis in this organ, and its relationship to whole body cholesterol homeostasis. In addition to cholesterol, the mevalonate pathway is responsible for the synthesis of numerous non-sterol isoprenoids. Here we investigate the physiological importance of the mevalonate pathway within the intestine, through genetic deletion of the rate-limiting enzyme.Approach and Results: Mice lacking 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) in intestinal villus and crypt epithelial cells were generated using a Villin-Cre transgene. In contrast to intestine-specific Srebp-2 and Scap knockouts, mice with intestinal-specific loss of Hmgcr are viable through adulthood and fertile. Hmgcr was efficiently deleted based on mRNA levels, as well as quantitative analysis of Hmgcr alleles by droplet digital PCR. Lipidomics revealed substantial reductions in the abundance of numerous non-sterol isoprenoids and sterol intermediates within the epithelial layer, while cholesterol levels were preserved. Although the intestinal knockout mice are born smaller, there is no net defect in feed efficiency or triglyceride absorption due to compensatory changes in bile acid composition and intestinal growth. At the cellular level, loss of Hmgcr is compensated for quickly after weaning through a dramatic expansion of the stem cell compartment within the crypts.Conclusions: Genetic loss of Hmgcr in the intestine is compatible with life, through mechanisms involving compensatory changes in bile acid composition, increased absorptive surface area, and expansion of the resident stem cell compartment.