Alexandria M Doerfler1,2, Jun Han3,4, Kelsey E Jarrett2,5,6, Li Tang2,7, Antrix Jain8, Alexander Saltzman8, Marco De Giorgi2, Marcel Chuecos2,9, Ayrea E Hurley2, Ang Li2,10, Pauline Morand11, Claudia Ayala2, David R Goodlett3,12, Anna Malovannaya8,13,14,15, James F Martin1,2,5,9,16,17,18, Thomas Q de Aguiar Vallim6,11,19,20, Noah Shroyer9,21, William R Lagor1,2,5,9,17,10. 1. Molecular Physiology and Biophysics Graduate Program (A.M.D., J.F.M., W.R.L.), University of California Los Angeles. 2. Department of Molecular Physiology and Biophysics (A.M.D., K.E.J., L.T., M.D.G., M.C., A.E.H., A.L., C.A., J.F.M., W.R.L.), University of California Los Angeles. 3. Baylor College of Medicine, Houston, TX. Genome British Columbia Proteomics Centre (J.H., D.R.G.), University of California Los Angeles. 4. Division of Medical Sciences (J.H.), University of California Los Angeles. 5. Integrative Molecular and Biomedical Sciences Graduate Program (K.E.J., J.F.M., N.S., W.R.L.), University of California Los Angeles. 6. University of Victoria, BC, Canada. Division of Cardiology, Department of Medicine (K.E.J., T.Q.d.A.V.), University of California Los Angeles. 7. Hunan Provincial Key Lab on Bioinformatics, School of Computer Science and Engineering, Central South University, Changsha, China (L.T.). 8. Mass Spectrometry Proteomics Core (A.J., A.S., A.M.), University of California Los Angeles. 9. Translational Biology and Molecular Medicine Graduate Program (M.C., J.F.M., N.S., W.R.L.), University of California Los Angeles. 10. Department of Bioengineering, Rice University, Houston, TX (A.L., W.R.L.). 11. Department of Biological Chemistry (P.M., T.Q.d.A.V.), University of California Los Angeles. 12. Department of Biochemistry and Microbiology (D.R.G.), University of California Los Angeles. 13. Verna and Marrs McLean Department of Biochemistry and Molecular Biology (A.M.), University of California Los Angeles. 14. Department of Molecular and Cellular Biology (A.M.), University of California Los Angeles. 15. Dan L Duncan Comprehensive Cancer Center (A.M.), University of California Los Angeles. 16. Program in Developmental Biology (J.F.M.), University of California Los Angeles. 17. Cardiovascular Research Institute (J.F.M., W.R.L.), University of California Los Angeles. 18. Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Houston (J.F.M.). 19. Molecular Biology Institute (T.Q.d.A.V.), University of California Los Angeles. 20. Johnsson Comprehensive Cancer Center (T.Q.d.A.V.), University of California Los Angeles. 21. Department of Medicine, Section of Gastroenterology and Hepatology (N.S.), University of California Los Angeles.
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 mice. Male intestinal knockout had decreased plasma cholesterol levels, whereas fasting triglycerides were lower in both sexes. Lipidomics revealed substantial reductions in numerous nonsterol isoprenoids and sterol intermediates within the epithelial layer, but cholesterol levels were preserved. Hmgcr intestinal knockout mice also showed robust activation of SREBP-2 (sterol-regulatory element binding protein-2) target genes in the epithelium, including the LDLR (low-density lipoprotein receptor). 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.
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 mice. Male intestinal knockout had decreased plasma cholesterol levels, whereas fasting triglycerides were lower in both sexes. Lipidomics revealed substantial reductions in numerous nonsterol isoprenoids and sterol intermediates within the epithelial layer, but cholesterol levels were preserved. Hmgcr intestinal knockout mice also showed robust activation of SREBP-2 (sterol-regulatory element binding protein-2) target genes in the epithelium, including the LDLR (low-density lipoprotein receptor). 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.
Authors: Salim S Virani; Alvaro Alonso; Emelia J Benjamin; Marcio S Bittencourt; Clifton W Callaway; April P Carson; Alanna M Chamberlain; Alexander R Chang; Susan Cheng; Francesca N Delling; Luc Djousse; Mitchell S V Elkind; Jane F Ferguson; Myriam Fornage; Sadiya S Khan; Brett M Kissela; Kristen L Knutson; Tak W Kwan; Daniel T Lackland; Tené T Lewis; Judith H Lichtman; Chris T Longenecker; Matthew Shane Loop; Pamela L Lutsey; Seth S Martin; Kunihiro Matsushita; Andrew E Moran; Michael E Mussolino; Amanda Marma Perak; Wayne D Rosamond; Gregory A Roth; Uchechukwu K A Sampson; Gary M Satou; Emily B Schroeder; Svati H Shah; Christina M Shay; Nicole L Spartano; Andrew Stokes; David L Tirschwell; Lisa B VanWagner; Connie W Tsao Journal: Circulation Date: 2020-01-29 Impact factor: 29.690
Authors: Linda Madisen; Theresa A Zwingman; Susan M Sunkin; Seung Wook Oh; Hatim A Zariwala; Hong Gu; Lydia L Ng; Richard D Palmiter; Michael J Hawrylycz; Allan R Jones; Ed S Lein; Hongkui Zeng Journal: Nat Neurosci Date: 2009-12-20 Impact factor: 24.884
Authors: Marco De Giorgi; Kelsey E Jarrett; Jason C Burton; Alexandria M Doerfler; Ayrea Hurley; Ang Li; Rachel H Hsu; Mia Furgurson; Kalyani R Patel; Jun Han; Christoph H Borchers; William R Lagor Journal: J Lipid Res Date: 2020-10-27 Impact factor: 5.922