Intestinal Deletion of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Promotes Expansion of the Resident Stem Cell Compartment

Authors

Alexandria M Doerfler
Jun Han
Kelsey E Jarrett
Li Tang
Antrix Jain
Alexander Saltzman
Marco De Giorgi
Marcel Chuecos
Ayrea E Hurley
Ang Li
Pauline Morand
Claudia Ayala
David R Goodlett
Anna Malovannaya
James F Martin
Thomas Q de Aguiar Vallim
Noah Shroyer
William R Lagor

Publication Date

4-1-2022

Journal

Arteriosclerosis, Thrombosis, and Vascular Biology

DOI

10.1161/ATVBAHA.122.317320

PMID

35172604

PMCID

PMC8957608

PubMedCentral® Posted Date

4-1-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Acyl Coenzyme A, Animals, Cholesterol, Female, Intestines, Male, Mice, Stem Cells, Sterols, Hmgcr, Cholesterol, Absorption of cardiovascular diseases, Lipids and Cholesterol, Physiology, Animal Models of Human Disease, Basic Science Research

Abstract

BACKGROUND: The intestine occupies the critical interface between cholesterol absorption and excretion. Surprisingly little is known about the role of de novo cholesterol synthesis in this organ, and its relationship to whole body cholesterol homeostasis. Here, we investigate the physiological importance of this pathway through genetic deletion of the rate-limiting enzyme.

METHODS: Mice lacking 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) in intestinal villus and crypt epithelial cells were generated using a Villin-Cre transgene. Plasma lipids, intestinal morphology, mevalonate pathway metabolites, and gene expression were analyzed.

RESULTS: Mice with intestine-specific loss of Hmgcr were markedly smaller at birth, but gain weight at a rate similar to wild type littermates, and are viable and fertile into adulthood. Intestine lengths and weights were greater relative to body weight in both male and female Hmgcr intestinal knockout (i-KO) mice. Male i-KO had decreased plasma cholesterol levels, while fasting triglycerides were lower in both sexes. Lipidomics revealed substantial reductions in numerous non-sterol isoprenoids and sterol intermediates within the epithelial layer, but cholesterol levels were preserved. Hmgcr i-KO mice also showed robust activation of SREBP-2 target genes in the epithelium, including the low-density lipoprotein receptor (LDLR). At the cellular level, loss of Hmgcr is compensated for quickly after birth through a dramatic expansion of the stem cell compartment, which persists into adulthood.

CONCLUSIONS: Loss of Hmgcr in the intestine is compatible with life through compensatory increases in intestinal absorptive surface area, LDLR expression, and expansion of the resident stem cell compartment.

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