학술논문
Loss of hepatic SMLR1 causes hepatosteatosis and protects against atherosclerosis due to decreased hepatic VLDL secretion.
Document Type
Academic Journal
Author
van Zwol W; Department of Pediatrics , University Medical Center Groningen, University of Groningen , Groningen , the Netherlands.; Rimbert A; Université de Nantes, CNRS, INSERM, l'institut du thorax , Nantes , France.; Wolters JC; Department of Pediatrics , University Medical Center Groningen, University of Groningen , Groningen , the Netherlands.; Smit M; Department of Pediatrics , University Medical Center Groningen, University of Groningen , Groningen , the Netherlands.; Bloks VW; Department of Pediatrics , University Medical Center Groningen, University of Groningen , Groningen , the Netherlands.; Kloosterhuis NJ; Department of Pediatrics , University Medical Center Groningen, University of Groningen , Groningen , the Netherlands.; Huijkman NCA; Department of Pediatrics , University Medical Center Groningen, University of Groningen , Groningen , the Netherlands.; Koster MH; Department of Pediatrics , University Medical Center Groningen, University of Groningen , Groningen , the Netherlands.; Tharehalli U; Department of Pediatrics , University Medical Center Groningen, University of Groningen , Groningen , the Netherlands.; de Neck SM; Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine , Utrecht University , Utrecht , the Netherlands.; Bournez C; Division of Drug Discovery and Safety , Leiden Academic Center for Drug Research, Leiden University , Leiden , The Netherlands.; Fuh MM; Department of Biochemistry and Molecular Cell Biology , University Medical Center Hamburg-Eppendorf , Hamburg , Germany.; Kuipers J; Department of Biomedical Sciences of Cells and Systems , University of Groningen, University Medical Center Groningen , Groningen , the Netherlands.; Rajan S; Department of Foundations of Medicine , NYU Long Island School of Medicine , Mineola , New York , USA.; de Bruin A; Department of Pediatrics , University Medical Center Groningen, University of Groningen , Groningen , the Netherlands.; Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine , Utrecht University , Utrecht , the Netherlands.; Ginsberg HN; Department of Medicine , Columbia University, Vagelos College of Physicians and Surgeons , New York , New York , USA.; van Westen GJP; Division of Drug Discovery and Safety , Leiden Academic Center for Drug Research, Leiden University , Leiden , The Netherlands.; Hussain MM; Department of Foundations of Medicine , NYU Long Island School of Medicine , Mineola , New York , USA.; Scheja L; Department of Biochemistry and Molecular Cell Biology , University Medical Center Hamburg-Eppendorf , Hamburg , Germany.; Heeren J; Department of Biochemistry and Molecular Cell Biology , University Medical Center Hamburg-Eppendorf , Hamburg , Germany.; Zimmerman P; NEBION AG , Zurich , Switzerland.; van de Sluis B; Department of Pediatrics , University Medical Center Groningen, University of Groningen , Groningen , the Netherlands.; Kuivenhoven JA; Department of Pediatrics , University Medical Center Groningen, University of Groningen , Groningen , the Netherlands.
Source
Publisher: Wolters Kluwer Health, Inc Country of Publication: United States NLM ID: 8302946 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1527-3350 (Electronic) Linking ISSN: 02709139 NLM ISO Abbreviation: Hepatology Subsets: MEDLINE
Subject
Language
English
Abstract
Background and Aims: The assembly and secretion of VLDL from the liver, a pathway that affects hepatic and plasma lipids, remains incompletely understood. We set out to identify players in the VLDL biogenesis pathway by identifying genes that are co-expressed with the MTTP gene that encodes for microsomal triglyceride transfer protein, key to the lipidation of apolipoprotein B, the core protein of VLDL. Using human and murine transcriptomic data sets, we identified small leucine-rich protein 1 ( SMLR1 ), encoding for small leucine-rich protein 1, a protein of unknown function that is exclusively expressed in liver and small intestine.
Approach and Results: To assess the role of SMLR1 in the liver, we used somatic CRISPR/CRISPR-associated protein 9 gene editing to silence murine Smlr1 in hepatocytes ( Smlr1 -LKO). When fed a chow diet, male and female mice show hepatic steatosis, reduced plasma apolipoprotein B and triglycerides, and reduced VLDL secretion without affecting microsomal triglyceride transfer protein activity. Immunofluorescence studies show that SMLR1 is in the endoplasmic reticulum and Cis-Golgi complex. The loss of hepatic SMLR1 in female mice protects against diet-induced hyperlipidemia and atherosclerosis but causes NASH. On a high-fat, high-cholesterol diet, insulin and glucose tolerance tests did not reveal differences in male Smlr1 -LKO mice versus controls.
Conclusions: We propose a role for SMLR1 in the trafficking of VLDL from the endoplasmic reticulum to the Cis-Golgi complex. While this study uncovers SMLR1 as a player in the VLDL assembly, trafficking, and secretion pathway, it also shows that NASH can occur with undisturbed glucose homeostasis and atheroprotection.
(Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
Approach and Results: To assess the role of SMLR1 in the liver, we used somatic CRISPR/CRISPR-associated protein 9 gene editing to silence murine Smlr1 in hepatocytes ( Smlr1 -LKO). When fed a chow diet, male and female mice show hepatic steatosis, reduced plasma apolipoprotein B and triglycerides, and reduced VLDL secretion without affecting microsomal triglyceride transfer protein activity. Immunofluorescence studies show that SMLR1 is in the endoplasmic reticulum and Cis-Golgi complex. The loss of hepatic SMLR1 in female mice protects against diet-induced hyperlipidemia and atherosclerosis but causes NASH. On a high-fat, high-cholesterol diet, insulin and glucose tolerance tests did not reveal differences in male Smlr1 -LKO mice versus controls.
Conclusions: We propose a role for SMLR1 in the trafficking of VLDL from the endoplasmic reticulum to the Cis-Golgi complex. While this study uncovers SMLR1 as a player in the VLDL assembly, trafficking, and secretion pathway, it also shows that NASH can occur with undisturbed glucose homeostasis and atheroprotection.
(Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)